Research Topics

Molecular Oncology & Cancer Genetics
Tumor Immunology & Inflammation
Hematopoiesis and Bone Marrow/Stem Cell Transplantation
Molecular Coagulation
Clinical Pharmacology & Experimental Therapies
Cancer Epidemiology and Prevention

Molecular Oncology and Cancer Genetics

Kathleen A. Cooney , M.D.

Research in the Cooney laboratory focuses on the molecular genetics of sporadic and inherited prostate cancer. In 1995, Dr. Cooney established the University of Michigan Prostate Cancer Genetics Project (PCGP) which is a family-based study of inherited prostate cancer susceptibility. To date, the PCGP has enrolled over 1000 families with early-onset and/or hereditary prostate cancer, and these families have provided family/medical history as well as DNA samples. The PCGP families were initially used for linkage studies to localize candidate prostate cancer susceptibility genes (HPC1, HPCX, HPC20). Dr. Cooney’s laboratory has also performed sequence analyses of many candidate prostate cancer genes, including RNASEL and MSR1. In 2003, they completed and published a genome-wide linkage scan (GWS) for prostate cancer using 175 PCGP families in which the most significant evidence for linkage was observed on chromosome 17 near BRCA1. This observation led the team to new studies focusing on candidate genes on 17q that may be important for prostate cancer susceptibility. They have screened over 90 chromosome 17-linked families for BRCA1 mutations and located only one deleterious mutation in a family with both prostate and ovarian cancer. An extended linkage analysis conducted in collaboration with Johns Hopkins University including 95 new multiplex prostate cancer families and 9 additional microsatellite markers resulted in a maximum LOD score of 2.99 at approximately 81-82 cM for all 453 pedigrees. Inclusion of the new markers significantly reduced the size of the candidate region and, interestingly, analysis of families (n = 147) that had four or more prostate cancer cases and an average age of prostate cancer diagnosis < or = 65 years results in a maximum LOD score of 5.49 at 78 cM with a 1-LOD support interval of 10 cM. Additional studies are ongoing to define the relevant genes in this region that contribute to prostate cancer susceptibility.

Their SPORE-sponsored research project focuses on the creation of a set of brother pairs discordant for prostate cancer within the PCGP for family-based association studies. They currently have a set of over 1200 brothers with and without prostate cancer that have been used for pilot studies of single-nucleotide polymorphisms (SNPs) in or near candidate genes. As part of this research, they are performing a survey of unaffected men who have brothers with prostate cancer to gain an understanding of prostate cancer screening practices, risk perception/concern, and use of complementary and alternative medications.

Dr. Cooney’s laboratory actively participates in the International Consortium for Prostate Cancer Genetics (ICPCG) sponsored by the National Cancer Institute. A combined GWS using data from over 1200 prostate cancer families has been published suggesting several other candidate regions for study in addition to chromsome 17q. This grant has been successfully renewed and additional collaborative projects are planned.

Long Dang, M.D., Ph.D.

The goal of Dr. Dang’s research is to target mechanisms by which tumors escape angiogenic inhibition. Cancer development relies on the dynamic balance between cancer epithelial cells and the tumor vasculature. Thus, antiangiogenic therapy is a rational and promising approach against tumor growth and progression. However, subsets of tumors do not respond to antiangiogenic therapy. An understanding of the biological basis of these resistant tumors may provide effective strategies to overcome them. They thus sought to investigate the mechanisms that control tumor angiogenesis and affect the success of antiangiogenic therapy.

To begin, they created a simple and translatable model of angiogenesis inhibition in human cancer cells. Vascular endothelial growth factor (VEGF) is a dominant and ubiquitous growth factor in tumor angiogenesis. Of clinical relevance, anti-VEGF therapy was recently introduced into clinical practice. While results with anti-VEGF therapy are certainly compelling, therapy with anti-VEGF antibodies has not been shown to lead to durable remission and tumors eventually regrow.

Using targeted homologous recombination, they engineered a series of human cancer cell lines with genetic disruption of VEGF. These cell lines are isogenic with their parental cells, with the exception of permanent, complete, and specific ablation of VEGF. They reasoned that the mechanisms that mediate the growth of these experimental tumors with VEGF disruption would reflect the mechanisms by which clinical tumors became refractory to anti-VEGF therapy. They found that disruption of VEGF in experimental tumors led to two distinct outcomes. In the first consequence, tumor vessels remained grossly intact despite VEGF ablation, thus exhibiting a “vessel-persistent” phenotype. The second consequence was characterized by significant vessel drop-out and prolonged suppression of tumor growth, followed by the eventual enlargement of tumors. These tumors have thus escaped effective angiogenic inhibition, through mechanisms involving “tumor-cell resistance”.

A growing concern with effective antiangiogenic therapy is tumor reactive resistance: the resulting increase in intratumoral hypoxia may drive the selection of cells that are less dependent on the vasculature, cells which in turn may be more malignant. Furthermore, hypoxia also induces hypoxia-inducible factor-1 (HIF-1) activity which then turns on genes important in cell survival and angiogenesis. Through gene knockout experiments, we recently reported that the combination of VEGF and HIF-1a gene inactivation in HCT116 human colon cancer cells was synergistic in inhibiting tumor growth. In HCT116 cells, HIF-1 is important in the induction of glycolysis genes; and hence the inactivation of this gene affects glucose metabolism through glycolysis, ATP production, DNA synthesis, and cell growth.

Future directions in Dr. Dang’s laboratory will focus on how glycolysis is important in cancer progression and cancer cell survival to antiangiogenic therapy. They will also focus on how to convert tumors with “vessel-persistent” phenotype to tumors with “vessel dropout” phenotype upon VEGF withdrawal.

Dorraya El-Ashry, Ph.D.

Breast cancer presents as either estrogen receptor α (ERα) positive or ERα-, and the presence of ERα correlates with a better prognosis and response to hormonal therapy while the absence of ERα  correlates with more aggressive and metastatic phenotypes, no response to hormonal therapies, and overexpression of growth factor receptors (GFRs) such as EGFR or c-erbB-2.   Dr. El-Ashry’s laboratory focuses on understanding the interaction between ERα signaling and GFR signaling in breast cancer progression. They discovered that the overexpression of c-erbB-2 or EGFR directly induces the ERα- phenotype via the resultant hyperactivation of MAPK.  Importantly, this MAPK induced down-regulation of ERα is reversible via abrogation of MAPK activity.  Using genomic approaches, they were recently able to ascribe a major role for upregulation of MAPK activity in the biology of ERα- breast cancer and have identified some MAPK substrates that may be important for this biology.  Key substrates of EGFR and c-erbB-2 signaling specifically in breast cancer cells are also be established as this is important for investigating interactions between ERα and GFR signaling pathways that may be responsible for initiating the generation of tumor cells that are either ERα+ or ERα-.  The El-Ashry laboratory has ideal models to determine why high expression of ERα and EGFR/c-erbB-2 are mutually exclusive in breast cancer and thus the mechanisms that underlie the generation of the ERα+ versus ERα- phenotype.  Most exciting is the very recent finding that inhibition of MAPK in ERα- breast tumors can result in re-expression of ERα in some of them.  This re-expression of ERα in ERα- breast cancer cell lines via inhibition of MAPK activity was also able to restore anti-estrogen sensitivity.  These findings have tremendous implications for future therapeutics.  In fact, a pilot clinical trial is being planned with Drs. Schott and Hayes.  While this work was originally funded by the American Cancer Society and the Susan G. Komen Foundation, it is currently being funded by a major NIH grant as well as an additional Susan G. Komen Foundation grant.

Scott D. Gitlin , M.D.

Research in Dr. Gitlin's laboratory is primarily focused on the study of the role of viruses in causing malignancies. The main emphasis is on understanding the transcriptional regulation of the human T-lymphotropic virus type I (HTLV-I) retrovirus, the function of the HTLV-I Tax1 trans activating protein on viral and cellular gene expression, and the interaction of Tax1 with the ets cellular proto-oncogene. Specifically, he is attempting to define the mechanism(s) by which HTLV-I Tax1 regulates gene expression from the HTLV-I long terminal repeat (LTR) and by which Tax1 interacts with its host cell, events thought to be primarily involved in cellular transformation and the formation of disease (adult T-cell leukemia/lymphoma; tropical spastic paraparesis/HTLV-I-associated myelopathy) following HTLV-I infection. Previously, he has demonstrated a cooperative (synergistic) interaction of Tax1 with the cellular proto-oncogene Ets1 on regulating gene expression from the HTLV-I LTR, as well as from the P2 promoter of the parathyroid hormone-related protein gene. This cooperative interaction appears to involve the additional interaction of Tax1 and Ets1 with other cellular proteins on the promoter/enhancer and may contribute to our understanding of how HTLV-I infection leads to the development of disease. His investigations have also included identification of the functional domains of the Ets1 proto-oncogene and its intracellular mechanisms of regulating transcription. He has identified and characterized the effects of the Gli2/THP protein (a member of a family of proteins involved with development) on transcriptional control of the HTLV-I LTR and has contributed to an analysis of Tax1-cellular protein complexes. This latter analysis has led to the identification of Tax1-associated cellular proteins that are capable of mediating transcriptional and cytoskeletal related pathways. In addition, Dr. Gitlin’s laboratory has used transgenic mice to evaluate novel, molecular genetic approaches to treating and preventing disease caused by HTLV-I Tax1. Additional studies in this laboratory have attempted to develop a new murine model for studying the pathogenesis of adult T-cell leukemia/lymphoma which will allow the evaluation of gene therapy and other novel approaches to treating this disease.

Besides HTLV-I, collaborative efforts with other laboratories focus on studies investigating the role of the Human Herpesvirus 8 (Kaposi's sarcoma herpesvirus) and the Epstein Barr virus in causing human cancers. Also in progress are collaborative studies of the HIV-2 retrovirus which are aimed at understanding the regulation of promoter transcription and viral replication as well as studies to identify endogenous viruses that may contribute to oncogenesis.

Carolyn J. Hoban, D.Sc.

Dr. Hoban recently joined UM to contribute to the basic research on pathogenesis of primary sarcoma subtypes (Ewing’s sarcoma, chondrosarcoma, chordoma, osteosarcoma) and mechanisms underlying growth of cancer cells in bone.  The goal is to characterize common pathways in tumor types that proliferate in bone and identify druggable targets within the tumor or bone microenvironment.  One research project is to compare sarcoma pathways to those implicated in the growth of prostate cancer cells in bone, in collaboration with Dr. Pienta. Her wider laboratory focus is on investigating mechanisms of response and resistance to drugs used to treat sarcoma.  She is developing animal models of human sarcoma and cell lines to investigate novel drugs and combinations for translation into our sarcoma clinical research program.  In addition, Dr. Hoban is an Executive Officer for Southwest Oncology Group (SWOG), a national network of clinical oncology trials.   As executive officer of Translational Medicine Committee, she reviews correlative scientific research integrated into clinical research protocols across all tumor types.  She has oversight of the SWOG Tumor Bank activities, and serves on the NCI Group Banking Committee to share best practices, standard procedures for specimen collection, update informed consent guidelines, and facilitate innovative collaborations.  In SWOG, she is also liaison to the Early Therapeutics program where Phase I clinical studies are developed; and the Cancer Control and Prevention Program where chemoprevention studies are developed. 

Dr. Hoban’s research focuses on pathogenesis and progression of human sarcoma in a translational approach to identify therapeutic targets in tumor types that grows in bone.  The goals of the preclinical work is to establish animal models (xenograft) and cell lines of sarcoma derived from soft tissues and bone.  Comparative studies on additional tumor types that metastasize to bone will help us to identify mechanisms of cancer progression and nominate candidate pathways for drug target validation and clinical trials.

Patrick Hu, M.D., Ph.D.

Dr. Hu’s laboratory uses the nematode C. elegans as a model system to study evolutionarily conserved signal transduction pathways that are dysregulated in cancer and diabetes, with the eventual goal of generating hypotheses that can be tested in mouse models of human disease. They are currently focusing on an insulin-like growth factor (IGF) signaling pathway that regulates development, metabolism, and longevity in C. elegans. In humans, dysregulation of IGF signaling has been implicated in the pathogenesis of prostate, breast, and colorectal cancer. This pathway is structurally and functionally conserved between humans and C. elegans, indicating that novel discoveries about this pathway in C. elegans may be relevant to the pathogenesis of common human malignancies.

Madhuri Kakarala, M.D., Ph.D.

Madhuri Kakarala practices general oncology with a specific interest in male and female breast cancer at the Ann Arbor VA Hospital.  Her research focuses on translational investigation of nutritional interventions for cancer prevention as measured by novel biomarkers for early detection and efficacy testing.  Specifically, she is studying the effect of polyphenols on breast stem cell in-vitro self renewal and differentiation.  She is also working on a Phase I pharmacokinetic and toxicity clinical trial using these polyphenols in humans.

Ivan Maillard, M.D., Ph.D.

Ivan Maillard is a physician-scientist who investigates the interaction of blood-forming stem cells with their environment, using the mouse as a model organism. His research program focuses on the mechanisms that regulate the maintenance of blood-forming stem cells at different stages of development, as well as their capacity to expand in specific circumstances. Beyond this fundamental research, he is also a practicing physician taking care of patients with hematological malignancies.

Research in the Maillard laboratory is devoted to the following main topics: 1) investigate the interaction of hematopoietic stem cells (HSC) with their microenvironmental niche, particularly in fetal sites of hematopoiesis; 2) study the epigenetic regulation of HSC function during situations of hematopoietic recovery and 3) understand the role of Notch signaling in the regulation of T cell homeostasis and differentiation. They are using cellular and molecular approaches to achieve these goals.

Dr. Maillard’s laboratory previously investigated the role of Notch signaling, a highly conserved cell-cell communication pathway, in the regulation of HSC homeostasis and at various stages of T cell development. Using a potent and specific dominant negative inhibitor (DNMAML) to block Notch-mediated transcriptional activation, they found that canonical Notch signaling is dispensable for the homeostasis of adult HSCs, but absolutely required at the earliest stages of T cell development. In contrast, disruption of Notch signaling during mid-gestation led to dysregulation of the HSC pool in the fetal liver, with evidence of initial activation followed by loss of long-term HSCs. Importantly, these effects were mediated by a non-cell autonomous effect of DNMAML on the microenvironment, and not by loss of Notch signaling in hematopoietic progenitors. DNMAML expression resulted in disruption of microvascular elements in the fetal liver. Therefore, they hypothesize that microvascular structures are an essential component of the HSC niche in fetal tissues and that the integrity and function of the microvascular endothelium are regulated by Notch signaling. To investigate these hypotheses, they study the interaction of fetal HSCs and microvascular structures using a combination of genetic and cellular approaches. Our ultimate goal is to identify the critical elements of the HSC niche. In the future, they plan to evaluate if elements of the HSC niche operate in other contexts, such in cancer stem cell niches.
In addition, they are interested in the regulation of mature T cell homeostasis and differentiation by Notch signaling. Using the DNMAML system in collaboration with Dr Y. Zhang (Hematology-Oncology), they are investigating the molecular and cellular mechanisms underlying the activity of Notch signaling in different types of T cell responses.

Sami Malek, M.D.

The Malek laboratory focus is on basic and applied questions in leukemia and lymphoma.  All projects in the laboratory are supported by clinical translational trials that allow for specimen procurement from patients, clinical follow-up data gathering and basic science approaches.  All research data that are generated can, in principle, be linked in the future to clinical outcome parameters.  Project 1 in the laboratory is a search for genes and gene mutations that cause or contribute to chronic lymphocytic leukemia (CLL).  Experimental approaches taken included high density chip based SNP screens for genomic regions of amplification or copy loss/LOH in CLL genomes and direct exon resequencing of candidate target genes.  Dr. Malek’s laboratory has identified genomic complexity as a marker for aggressive disease and they are expanding this concept to more patients and targeted therapy. Current focus is integration of genomic profiles with expression profiles.  Project 2 involves studies into Myelodysplastic syndromes/Acute Myelogenous Leukemia (MDS/AML) pathogenesis and is supported by two clinical trials.  The objectives are to find genetic and epigenetic markers for MDS to AML progression as well as AML relapse or progression determinants.  Project 3 is a follicular lymphoma project in collaboration with Charlie Ross, MD and is a search for genomic aberrations in follicular lymphoma (FL) using high-density SNP-chip based analysis.  These data have been reported in CCR. Going forward they wish to correlate genomic changes with clinical outcome through collaboration with clinical FL specialists and a new clinical FNA-based trial.  Project 4 involves identification of markers for activity and resistance to Mdm2 inhibitors in CLL.  This dataset has reached initial completion and has been submitted for publication

Sofia D. Merajver, M.D., Ph.D.

Laboratory research: Dr. Merajver’s laboratory has discovered genetic alterations that contribute to an especially malignant phenotype of breast cancer called inflammatory breast cancer (IBC). They have isolated and characterized two markers specific for inflammatory breast cancer: a novel transforming oncogene RhoCGTPase and a tumor suppressor gene termed LIBC (WISP3), which is a low affinity IGF-binding protein. They are conducting basic studies to demonstrate the function of these genes in cell systems and animals, in collaboration with Dr. Celina Kleer, and are pursuing potential new therapeutic targets for intervention, based on modulating their function, in collaboration with Drs. Shaomeng Wang and Mary-Ann Mycek.  In collaboration with Dr. Amr Soliman, the Merajver and Kleer labs are involved in characterizing the molecular genetics and environmental epidemiology of IBC in North Africa, a region of high incidence of this aggressive cancer.  They have determined, for the first time, the true incidence of IBC in Egypt to be 15%.

Another major effort in the laboratory has focused on the study of the role of copper in angiogenesis, in collaboration with Dr. Theodoros Teknos and M. Islam.  Dr. Merajver and colleagues have developed animal models suitable to understand the role of copper deficiency in controlling tumor angiogenesis. This work has contributed to the translation of a major copper chelator, tetrathiomolybdate, as an anti-cancer agent. In collaboration with Dr. Quintin Pan, the laboratory is involved in studies of mechanisms of NFκB-mediated chemotherapy resistance in head and neck cancer.  Their recent collaborative work showing that tetrathiomolybdate inhibited metastasis, published in Molecular Cancer Therapeutics was selected for wide web-based distribution as a significant advance in 2007.

The laboratory has embarked on the study of RhoC signaling in single live cells utilizing laser spectroscopic techniques and mathematical modeling.  This work is aimed at uncovering the time-dependent behavior of signaling molecules such as the GTPases which are involved in on-off cycles.

Breast Cancer Genetics Research-Family collection: Dr. Merajver’s breast and ovarian cancer family collection has contributed to the isolation of the BRCA1 and BRCA2 gene and to the ascertainment of germ-line mutations in male breast cancer patients and families. The family collection is presently focused on collaborative investigations of the effect of tamoxifen chemoprevention in BRCA carriers and the cancer risks conferred by variants of uncertain significance in BRCA1 and BRCA2. Dr. Merajver and colleagues are studying polymorphisms and mutations in new candidate tumor suppressor genes and their relationship to breast cancer risk.

Kenneth J. Pienta, M.D.

The Pienta laboratory’s research focus is on gaining insight into the biologic mechanisms underlying prostate cancer metastasis.  These insights have been used to identify novel targets for the treatment of advanced prostate cancer, thus successfully moving bench research into the clinic in the form of Phase II and Phase III clinical trials. 

This research has been developed based on a comprehensive theory of metastasis focusing on the cellular traits necessary for the cancer cell to leave the primary tumor environment (emigration), survive in the circulation (migration), and develop in a secondary site (immigration). Dr. Pienta has developed several therapeutic strategies based on this theory, including targeting cell motility, cell – endothelial attachment, and bone microenvironment – prostate cancer cell interactions.  The laboratory is now focusing on tumor – microenvironment.  The role of tumor associated macrophages (TAMs) in the promotion of cancer growth is being studied.  The laboratory has developed a new therapy for treating prostate cancer by targeting TAMs through the inhibition of monocyte chemoattractant protein-1.

The laboratory is actively defining the lethal phenotype of metastatic cancer and designing therapies to decrease the morbidity and mortality associated with tumor burden.  By using an antibody to inhibit the chemokine CCL-2, the laboratory has decreased tumor burden and increased survival in preclinical models of prostate cancer.  This therapy is going into the clinic in 2008.

James M. Rae, Ph.D.

Dr. Rae’s primary research interest is in breast cancer with a focus on identifying the subset of estrogen receptor positive breast cancer patients who will respond to hormonal therapy.  His work involves two major lines of investigation; one is predicting patient response using a pharmacogenetics approach, while the other involves identifying and characterizing genes critically involved in hormone induced breast cancer growth.  His work in pharmacogenetics, the study of genetic variability in the way patients respond to medications, involves studies with tamoxifen and aromatase inhibitors and the use of genetic testing to identify patients unable to respond to therapy. Dr. Rae is part of the NIH-funded COnsortium on BReast cAncer pharmacogenomics (COBRA).  COBRA was organized in the early 2000s to study the pharmacogenomics of endocrine therapy of breast cancer and includes a multi-discliplinary team of laboratory, clinical and statistical investigators from the University of Michigan, Indiana University, and Johns Hopkins. The consortium recently found that an active metabolite of tamoxifen is made by a liver enzyme (CYP2D6) that is absent in ~10% of Caucasians due to genetic variants and that patients with specific CYP2D6 mutations have worse clinical outcomes than normal control patients.  Dr. Rae’s other main focus is the identification and characterization of genes uniquely responsible for hormone stimulated growth.  These genes have the potential of being prognostic and predictive markers for hormonal treatment as well as therapeutic targets in their own right. His group has identified several genes believed to be critically involved in estrogen stimulated growth of breast cancer and their detailed characterization of these genes suggest that they may play a role normal mammary gland development, are clinical markers for hormone response, and represent new potential therapeutic targets in breast cancer.

David Reisman, M.D., Ph.D.

Advances in cancer therapy arise not only from using drugs in novel ways but also by developing drugs that target specific molecular defects within cancers.  It is now possible to develop highly specific therapeutic interventions targeted at unique molecular alterations that can impact a patient’s clinical course with much less toxicity.  To this end, Dr. Reisman’s laboratory has discovered that the BRM gene, a key subunit of the SWI/SNF chromatin remodeling complex, is reversibly suppressed in a spectrum of human tumor types. As the BRM gene is involved in a number of critical growth inhibitory and cellular adhesion pathways, it is not surprising that the loss of BRM acts synergistically with carcinogens to promote tumor development in animal models.  Their research has revealed that the BRM gene is not mutated in cancer cells that lack its expression, but rather it is epigenetically suppressed.  They have also found that certain small molecular inhibitors known to block the function of histone deacetylase proteins are effective in restoring BRM expression.  As many of these compounds are currently in clinical trials, it may be feasible to target the re-expression of BRM in certain patients. BRM may also serve as a biomarker that will permit physicians to determine the specific subsets of patients who are likely to respond to this class of drugs. Continuing to study how the loss of BRM impacts cancer development will allow Dr. Reisman and his colleagues to understand and implement novel and needed strategies that exploit this molecular alteration.  They have also discovered additional evidence that certain individuals are at substantially increased risk for loss of BRM expression. These individuals may thus have a higher risk of developing cancer or may be susceptible to developing more aggressive tumors. By identifying those patients who carry this risk, we will be able to develop for them a specific therapy that restores BRM expression.  To translate this research to clinical practice, his laboratory is 1) pursuing drug discovery programs to identify novel agents that activate BRM; 2) using in vitro and in vivo studies to determine the most relevant pathways and genes that are impacted by BRM loss and, therefore, allow them to understand the clinical potential of re-expressing this gene; and 3) determining the role of BRM loss in the initiation and progression of cancer.

Theodora S. Ross, M.D., Ph.D.

Huntington Interacting Protein 1 (HIP1) is linked to neurology by virtue of its interaction with Huntington, the protein mutated in Huntington’s disease.  It was originally linked to neoplasia by our discovery of the oncogenic HIP1/PDGFbR fusion protein that resulted from a t(5;7) chromosomal translocation in a patient with chronic myelomonocytic leukemia. The protein structures of HIP1 and HIP1-related (HIP1r) suggest that they function in the actin cytoskeleton, clathrin trafficking and phosphatidylinositol turnover/signaling.  One part of the laboratory focuses on understanding the transforming biology of HIP1/PDGFbR and is in the process of generating and analyzing HIP1/PDGFbR conditional knock-in mice.  Using these mice, Dr. Ross’s laboratory is in a unique position to define common pathways of leukemogenesis by fusion tyrosine kinases in vivo.  These knock-in mice will be used to rigorously test the tumorigenic stem cell hypothesis in the setting of realistic expression of a human oncogene, to understand mechanisms of transformation by HIP1/PDGFbR and to make sense of therapeutic resistance to tyrosine kinase inhibitors (e.g. Gleevec) or further downstream signal transduction pathway inhibitors (e.g. Rapamycin).

The studies from Dr. Ross’s laboratory of HIP1/PDGFbR have led them to investigate the HIP1 and HIPr proteins, which are interesting in their own right.  Their roles in tumorigenesis and normal physiology are a major focus of the laboratory where they have employed cancer cells, mice and humans in our experimental work. They have found that HIP1 is overexpressed in epithelial cancers such as colon, prostate and breast cancer.  They have evaluated the clinical implications of this in prostate cancer patients and found that HIP1 expression is a strong marker of tumor progression.  HIP1 is also overexpressed in lymphomas and anti-HIP1 antibodies in the serum mark the presence of cancer (lymphoma and prostate cancer).   Further studies of HIP1 and serum anti-HIP1 antibodies as useful cancer markers for clinical management are in progress.

Understanding how HIP1 contributes to tumorigenesis is also a primary goal of the lab. They have shown that its expression is necessary for some normal and cancer cells to survive in vivo, that it directly transforms fibroblasts and that the transformed cells have altered levels of multiple growth factor receptors.  In addition HIP1 knockout mice have a general “cell loss” or degenerative phenotype as evidenced by hematopoietic defects, testicular degeneration, spinal defects, diminished prostate tumorigenesis and cataracts.  Although HIP1r knockout mice have no apparent phenotype, compound HIP1r;HIP1 deficient mice have a drastic acceleration of the HIP1 deficient phenotype and the double deficient mice are, as a result, afflicted with severe hypolordosis and weight loss followed by death at 4 months of age.  These findings indicate that HIP1 and HIP1r compensate for one another and are necessary for survival or proliferation of cells from diverse tissues.

Max Wicha , M.D.

Dr. Wicha’s laboratory is studying the biology of stem cells in the normal mammary gland and breast cancers. These studies involve the isolation and characterization of normal and malignant mammary stem cells and changes in these key cells during carcinogenesis. His laboratory has demonstrated that breast cancers are driven by a small subcomponent of cancer stem cells. These cells are not only important in carcinogenesis but may account for resistance of cancers to therapeutic agents. Based on these concepts, Dr. Wicha’s laboratory is working with clinical investigators to design clinical trials that specifically target breast cancer stem cells. Based on the work in breast cancer, Dr. Wicha’s laboratory is also investigating stem cells in other human malignancies including colon cancer and lung cancer. The overall goal is to develop an integrated program studying the biology of cancer stem cells and developing therapeutic approaches to target these cell populations.

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Tumor Immunology and Inflammation

Ronald J. Buckanovich M.D., Ph.D.

Dr. Buckanovich’s laboratory, established at the University of Michigan in July 2006, studies ovarian tumor vasculature and angiogenesis in ovarian cancer. In 2007 we identified over 70 ovarian tumor vascular markers (TVMs). Several ovarian TVMs are uniquely expressed in ovarian cancer. This tumor specific expression suggests that TVMs represent ideal biomarkers for ovarian cancer screening and diagnosis. As tumor vasculature is necessary for a tumor to grow beyond several millimeters, TVMs could be detected at the earliest stages of tumor development. Similary, tumor specific expression of TVMs and their direct exposure to blood, suggest that TVMs are also ideal immunotherapeutic targets.

A second major interest of the laboratory revolves around the role of a recently identified myeloid cell present in ovarian cancer. These cells, turned vascular leukocytes (VLCs), express both myeloid and vascular markers and appear to be critical for tumor angiogenesis. We have demonstrated that VLCs are critical for angiogenesis in ovarian cancer. We have identified immunotherapeutic targets expressed by VLCs and we have begun planning for a clinical trial to determine the efficacy of anti-VLC immunotherapeutics in women with refractory ovarian cancer.

Finally, our laboratory is studying the role of ovarian tumor vascular cells in regulating anti-tumor immunity. As T cells need to interact with and transit through vascular cells to enter into tumors, we hypothesize that vascular cells represent an important gatekeeper and regulator of antitumor immunity. If antitumor immune cells are not granted entry into the tumor they cannot be effective. We have demonstrated that vascular cells from tumors lacking infiltrating T cells express increased levels of the protein ETRB and confirmed that ETRB negatively regulates T cell migration into ovarian tumor islets. We are testing the efficacy of ETRB antagonist, on intratumoral T cell trafficking, ovarian cancer cell proliferation, and tumor progression in a murine model of ovarian cancer. A clinical trial to test the efficacy in humans is being planned.

Kemp B. Cease, M.D.

Dr. Cease’s research program is pursued in close collaboration with Dr. Jon Oscherwitz, a Research Assistant Professor in the Division. The laboratory is currently examining the immunologic structure-activity properties of tandemly repeated epitopes, with an emphasis on their utility in vaccines and immunotherapeutics. We have demonstrated enhanced immunogenicity of these structures for both T cell and B cell responses, and have shown that this is an intrinsic immunological property of the tandem repeat architecture.

B cell malignancies represent the current focus of the laboratory's research to develop effective strategies and paradigms for cancer immunotherapy. Recent laboratory work has focused on the induction of active immune responses directed at cell surface molecules found on malignant B cells. Prototype vaccines have been developed that actively induce immunity capable of protection of mice from an otherwise lethal challenge with a murine lymphoma. It is hoped that this line of research will demonstrate a clinically viable strategy for utilizing the tandem repeat immunogens for active immunity against cancer.

The primary research focus of Dr. Kaminski's research group is on radioimmunotherapy, especially as it applies to the treatment of B-cell lymphoma.  Several clinical studies have been completed which have shown a high degree of efficacy of 131-I-labeled anti-CD20 antibody anti-B1 (I-131 tositumomab or Bexxar) in patients with chemotherapy-resistant and rituximab-resistant low-grade or transformed low-grade lymphoma.  These studies have led to FDA approval of this treatment in 2003, which takes only one week to complete.  A study performed at the University of Michigan by Dr. Kaminski’s group also investigated the use of Bexxar as frontline therapy for patients with advanced-stage follicular lymphoma, an incurable disease.  Ninety-five percent of patients responded and 75 % had complete remissions, and only half of the patients have had a recurrence at a median of 8 years of follow-up.  The success of this treatment is leading to additional studies aimed at determining the optimal timing of radioimmunotherapy in the management of follicular lymphoma.  The above clinical studies have provided tissue and blood samples for further investigations into the mechanisms of action of radioimmunotherapy, including immunologically-mediated anti-tumor effects, radioimmunotherapy-induced apoptosis, molecular mechanisms of susceptibility and resistance to radioimmunotherapy, and the effects of radioimmunotherapy and low-dose rate irradiation on human hematopoiesis.  The molecular detection of minimal residual disease in patients treated with radioimmunotherapy also remains a focus of interest.  In collaboration with colleagues in Nuclear Medicine, new techniques are being explored to more precisely measure radiation doses to tumors and normal tissues.  Finally, the use of radioimmunotherapy in other B-cell malignancies such as multiple myeloma is beginning to be explored.   These studies are being supported by grants from GlaxoSmithKline and other private sources.

Jon Oscherwitz, M.D.

Dr. Oscherwitz’s research laboratory focuses on the development and testing of novel subunit vaccines for the induction of humoral and cellular responses against various disease-related antigens.  Specifically, their studies in various disease models, including B cell lymphoma, Alzheimer’s disease and Anthrax, are linked by the need to better understand the relationship between antigen structure and immunogenicity.  Previous research in this laboratory established that the representation of peptide epitopes as tandemly repeated sequences can significantly potentiate both the magnitude of antibody responses, as well as the likelihood that the induced antibodies will be reactive with the native proteins from which their sequences are derived.  They are currently utilizing this approach in the development of vaccines targeting cell-surface antigens in murine B cell lymphoma, where their current focus is on the development of active immunity against murine CD20.  They have also designed and are testing vaccines which selectively target the amyloid beta protein which is believed by many to have a causal role in the development of Alzheimer’s disease.  These studies utilize mice which are transgenic for the 42 amino acid human amyloid peptide.  The generation of immunity to this sequence presents us with unique challenges to stimulate humoral but not cellular immunity so as to avoid potentially deleterious effects associated with autoimmunity.  Finally, the development of novel, molecularly-targeted vaccines against current and potentially reengineered strains of anthrax is a major focus of this laboratory.  The availability of crystal structure for the protective antigen and lethal factor which together form the Anthrax lethal toxin, enable discrete targeting of potentially new and important epitopes within these molecules for the development of new Anthrax vaccines.  These studies are being pursued in concert with collaborators at the University of Pennsylvania, who are studying the delivery of our vaccines using recombinant adeno-associated virus.

Bruce G. Redman, D.O.

Dr. Redman serves as the Chair of the University of Michigan Comprehensive Cancer Center Data and Safety Monitoring Committee. Dr. Redman is an advisor to the Food and Drug Administration as an ad hoc member of the Oncology Drug Advisory Committee for the treatment of melanoma and kidney cancer. Dr. Redman is also a member of the National Advisory Council for Complementary and Alternative Medicine (NACCAM) at the National Institutes of Health (NIH). During the last year, Dr. Redman continued his on-going clinical research evaluating novel immunotherapeutic approaches to the treatment of cancer, particularly melanoma and kidney cancer. This clinical research involves the use of dendritic cell based strategies for which Dr. Redman is the sponsor of an IND. Dr. Redman is also a sponsor of an IND for the adoptive immunotherapy of kidney cancer. In addition, his clinical research continues to involve the evaluation of novel immuno-therapeutic molecules in Phase I, II and III trials for industry. Dr. Redman also continues as an Executive Officer of the Southwest Oncology Group, the largest cooperative cancer clinical trials group in the United States.

Robert F. Todd, III, M.D., Ph.D.

In April 2007, Dr. Todd was appointed as Interim Chair of the Department of Internal Medicine and took a leave of absence from his prior administrative post as Chief of the Division of Hematology/Oncology, a position which he had held for 14 years.  During the time of  Dr. Todd’s tenure as Division Chief, (1) over 74 faculty were recruited to the division (with excellent retention), more than doubling the size of the division from 25 to nearly 70; (2) 29 faculty were promoted (including several who advanced from assistant to full professors); (3) research activity expanded with a nearly six-fold increase in extramural research support (from $8 million to $47.3 million), including a ten-fold increase in federal direct costs (from $2.9 million in 1993 to $30.3 million in 2006 [inclusive of the SWOG grant]); (4) clinical activity increased as reflected by a nearly four-fold increase in ambulatory clinic visits from 11.6 thousand visits in 1993 to 41.8 thousand visits in 2007; (5) An Adult/Pediatric Hematopoietic Stem Cell Transplant Program  was created which currently performs over 200 allogeneic and autologous transplants per year; (6) An NIH-funded subspecialty training program was successfully renewed for 5 years, which attracts top trainee candidates at a national level(with graduates who pursue academic careers at a rate >50% at roughly twice the national average); (7) the financial status of the Division continued to improve with an operating margin of $3.6 million in FY06 (net patient care revenue of $9.9 million) which, prior to 2001, had been in deficit (prior to the establishment of a new financial model which involves margin-sharing on net chemotherapy revenues); and (8) national recognition for oncology care has risen as reflected by a top twenty  ranking in the US News and World Report for most of the past 10 years.

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Hematopoiesis and Bone Marrow/Stem Cell Transplantation

Yasser Khaled, M.D.
           
Dr. Khaled’s current research interest is the application of hematopoietic stem cell transplantation in the treatment of multiple myeloma.  His efforts include:  the development and adoption of a risk stratification strategy for hematopoietic stem cell transplantation in multiple myeloma; development of protocols to explore the role of unrelated hematopoietic stem cell transplantation in biologic high risk patients, and the creation of innovative conditioning regimens for autologous transplantation in standard risk patients with multiple myeloma.

Oleg Krijanovski, M.D., Ph.D.

Dr. Krijanovski’s research focuses on a phase II clinical trial using histone deacetylase inhibitor SAHA for prevention of clinical acute GVHD in collaboration with Dr. Pavan Reddy. This project represents a translational research   attempting to transition  to the bedside an experimental data obtained at our BMT laboratory that SAHA significantly inhibits experimental GVHD while preserving graft-versus-leukemia effects of allogeneic transplant.

John Levine, M.D.

The major focus of Dr. Levine’s scholarly activity is bone marrow transplantation. Within this rather broad area, his specific areas of interest are cellular immunotherapy for malignancies and diagnosis, treatment, and prevention of acute GVHD. He is developing novel approaches for the treatment and prevention of leukemia and lymphoma relapse following allogeneic bone marrow transplantation. In addition, he conducts related other research in the realm of bone marrow transplantation as well as play important supporting roles in a variety of other projects. His major projects are detailed as follows. 
Etanercept for the prevention of acute GVHD in high-risk patients: Dr. Levine is the Principal Investigator for a clinical trial that adds etanercept to standard GVHD prophylaxis for patients at high-risk of developing acute GVHD. The goal of this study is to reduce the rate of severe GVHD and day 100 mortality by 50%. This study is part of the BMT Program Project Grant awarded in 2004. As of May 2006, this study has enrolled 30 out of a planned 80 subjects. 
Etanercept for the treatment of acute GVHD: Dr. Levine is the Principal Investigator for a clinical trial of etanercept for the treatment of acute GVHD. This trial builds on their pilot trial data (published in BBMT, 2005). They have now treated almost 50 patients with moderate to severe acute GVHD with a combination of standard high-dose steroid therapy plus etanercept. Preliminary results with this combination therapy show a complete response rate of around 80% compared to the usual CR rate of 40% observed with steroids alone. 
Reduced Intensity Conditioning and DLI to exploit GVL effects: Dr. Levine has been conducting a phase II trial of reduced intensity conditioning, brief but intense immunosuppression, and prophylactic donor leukocyte infusions for patients with hematological malignancies.  This trial enrolled its first patient in late 2003. So far 30 patients have entered the study, the IRB recently allowed for an additional 20 patients to enroll in order to get better confidence intervals around actuarial survival. One-year survival for the first 30 patients is 64%. 
Day 7 TNFR1 levels predict for GVHD and survival: Dr. Levine has maintained primary responsibility for overseeing the comprehensive integrated clinical-laboratory database for the BMT Program.  They have collected more than 7000 clinical research samples on over 600 patients. From this enormously rich biologic resource, he designed and analyzed experiments that he hopes will shed light on the role of inflammatory cytokines in the prediction, treatment, and prevention of GVHD in bone marrow transplant patients. Preliminary findings, presented at the ASBMT meeting in February, demonstrated that TNF levels, measured as early as one week after transplant, are predictive of the development of moderate to severe acute GVHD, transplant-related mortality, and survival at 1 year in patients undergoing myeloablative allogeneic transplants.

Shin Mineishi, M.D.
           
Dr. Shin Mineishi joined the program in 2005 to become the Clinical Director of the Adult Bone Marrow Transplant Program.  Since his arrival, he has devoted himself to build the infrastructure for clinical trials, as well as to strengthen the Program for improved patient care. Dr. Mineishi chairs many clinical conferences to discuss management of clinical cases. His research focus has been on reduced-intensity allogeneic stem cell transplantation, and he is now developing several clinical protocols on various disease categories.  Dr. Mineishi serves as the site PI for several BMT trials being coordinated through the BMT Clinical Trials Network and is the PI of the multi-center clinical trial of scleroderma autologous transplant.
In FY07 Dr. Mineishi prepared a few new clinical trials to study new conditioning regimens for transplant for leukemias and lymphomas, and also he participated in the development of new clinical studies in CML, myeloma and cord blood transplant in adults. These studies are to start enrollment in FY08.

Edward Peres M.D.

Dr. Edward Peres joined the University of Michigan Blood and Marrow Transplantation Program in 2006. His research focuses on studying the utilization of umbilical cord blood as the source of hematopoietic stem cell transplant in adult patients. Prior to Dr. Peres’ arrival at the University of Michigan, cord blood transplantation had not been offered to adult patients.  During the past year, three cord blood transplants were performed in adult patients. Dr. Peres serves as the local PI on the double cord blood protocol and is developing a protocol for adult patients utilizing double cord blood transplants in patients who would not otherwise have a donor. Other research interests include trying to reduce treatment-related mortality in patients undergoing transplantation by utilizing the graft-versus-leukemia effect. 

Research Highlight:
Dr. Peres’ clinical research focuses on the use of umbilical cord blood stem cells in adult transplantation. This fall, he will open a trial to test the efficacy of double cord blood transplantation in patients who would otherwise not have an acceptable donor for transplantation.

Pavan Reddy, M.D.
           
Allogeneic bone marrow transplantation is the most potent form of immune therapy against a number of malignant diseases by its graft-versus-leukemia/tumor (GVL) effect. However, acute graft-versus-host disease (GVHD), the major complication of allogeneic BMT is tightly linked to the GVL effect. The immunobiology of GVHD and GVL responses are complex. Host dendritic cells and donor T cells, along with the cytokines, are critical for regulating immune responses.  Dr. Reddy’s laboratory is focused on understanding the role of dendritic cells and the inter-play of cytokines in the biology of GVHD/GVL by utilizing well-characterized mouse models of allogeneic BMT.  His laboratory has previously shown that a single cytokine, interleukin-18 (IL-18), can modulate GVHD/GVL responses through differential mechanisms (published in the Journal of Experimental Medicine and Blood).  Future studies are being planned to examine the cellular and molecular pathways that are responsible for these differential mechanisms of action by IL-18. Studies from his laboratory have also demonstrated that several pro-inflammatory cytokines, together, are sufficient for causing GVHD even in the absence of direct CTL.  Dr. Reddy’s laboratory has recently demonstrated that host antigen presenting cells (APCs) are critical for the induction of GVL after allogeneic BMT, which has resulted in a recent publication in Nature Medicine. Studies are in progress to evaluate the role of APCs in modulating the allo-antigen specific and tumor antigen specific responses after allogeneic BMT.  He has also discovered that histone deacetylase inhibitors are potent suppressors of the secretion of multiple pro-inflammatory cytokines and can also regulate the function of antigen presenting cells as well as T cell functions. Preliminary results from these studies were published in PNAS.  Dr. Reddy and his laboratory are now in the process of dissecting the mechanisms of immune modulation by alteration of histone acetylation in dendritic cells and the effect of such modulation on GVHD/GVL.

Gregory Yanik, M.D.

Dr. Yanik is currently involved in 3 areas of active research within the Blood and Marrow Transplant Program at the University of Michigan: (a) Graft Versus Host Disease (GVHD), (b) Neuroblastoma Clinical Trials Program (Pediatric Hematology/Oncology), and c) Acute Myelogenous Leukemia. 
Graft Versus Host Disease: Dr. Yanik is focused on developing novel treatment strategies for the management of chronic GVHD and Idiopathic Pneumonia Syndrome (IPS), a form of acute lung injury associated with GVHD.   He is the director of our Extracorporeal Photopheresis (ECP) facility, one of the largest ECP programs in the country. The use of ECP as adjunct therapy for the treatment of both chronic and acute graft versus host disease has become established both within their program and nationally. Under his leadership the past 2 years, the ECP program has grown three-fold.  Clinical trials utilizing ECP for the prevention of acute and chronic GVHD are being developed, based upon their preliminary work. 
National Trials: Idiopathic Pneumonia Syndrome (IPS) affects approximately 15% of allogeneic transplant recipients, associated with an 85% mortality rate. Preclinical work from our transplant program has shown that the lung is a target organ of GVHD, with the lung injury mediated by pro-inflammatory cytokines, including TNFα.  Dr. Levine and his colleagues have recently pioneered the use of a TNF binding agent, etanercept, for the management of IPS.  He is the lead author on the manuscript detailing their phase I/II clinical experience, the manuscript to be published this year.  He is currently the principal investigator of two large national trials investigating the role of etanercept in the treatment of IPS.  The first trial is sponsored by the BMT CTN (Clinical Trials Network), composed of the 16 leading transplant centers in the US.  This phase III trial will serve as the definitive trial for the use of etanercept in this clinical setting, and is scheduled to open in June 2006. The second trial, a phase II pediatric trial, opened April 2006 through the Children’s Oncology Group (COG) and Pediatric Blood and Marrow Transplant Consortium (PBMTC). Both trials are funded by the NHLBI, with salary support for his leadership of each trial. 
Acute Myelogenous Leukemia: Dr. Yanik is the lead investigator for their AML transplant program. They recently designed (and submitted to the Cancer Center PRC) a clinical trial investigating the management of AML in patients > 55 years in age. This work combines the efforts of the Adult Hematology Program (Dr. Harry Erba, Dr. Moshe Talpaz) and our Blood and Marrow Transplant Program.  This is the first joint trial between these individuals, the first of a combined AML translational therapy program.

Yi Zhang, M.D., Ph.D.

Dr. Zhang’s laboratory investigates the molecular mechanisms that regulate the generation and maintenance of memory T cells and pathogenic memory T cell-mediated inflammatory diseases, such as graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation and autoimmune diseases. Using experimental animal models, we have recently demonstrated that pathogenic memory T cells are responsible for the persistence and progression of GVHD.  These alloreactive memory T cells develop via a previously uncharacterized population of antigen-experienced postmitotic CD44loCD8+ T cells that have greater capability than naïve and mature memory T cells to self-renew and to proliferate. Furthermore, this postmitotic CD44loCD8+ T cell population can generate all subsets of memory and effector T cells. Their longevity, ability to self-renew, and multipoentiality define these cells as being T memory stem cell-like cells. Several stem cell regulatory pathways, such as Notch, Wnt/GSK-3, SOCS3 and Polycomb group proteins are associated with the generation and maintenance CD8+ memory T cell pools.

Taking advantage of gene knock-out approaches, small interferencing RNA (siRNA) delivered by retroviral vectors, and selective inhibitors of chemical compounds, we are characterizing how these stem cell regulatory pathways regulate: (1) the self-renewal and long-term survival of memory T cells, (2) the acquisition of effector functions mediating tissue injury, and (3) the capability of memory T cells to resist immunosuppressive treatment. Building on the extensive experience on memory T cell biology, hematopoietic stem cell biology and dendritic cell biology, other research in this program focuses on decoding the memory machinery that controls the memory functions of T cells. The long term goal of these studies is to develop new methods for regulating memory T cell responses in GVHD, as well as in many other diverse clinical settings, including allo-graft rejection, autoimmune diseases and tumors.

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Molecular Coagulation

Paula L. Bockenstedt, M.D.

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Clinical Pharmacology and Experimental Therapeutics

Asra Ahmed, M.D.

In Fiscal year 2007, Dr. Ahmed expanded her clinical responsibilities and continues to see patients at the Comprehensive Cancer Center.  In addition, she established a Hematology Clinic at the University of Michigan Satellite Center in Canton and she assumed the leadership role of the hematology clinic at the Ann Arbor Veterans Affairs Hospital.  Dr. Ahmed has a clinical interest in benign hematology, and continues to participate in the Myeloma and Lymphoma programs at the University of Michigan.

Ammar Al-Zoubi, M.D.

Dr. Al-Zoubi continues a major focus on the evaluation and management of patients with myeloproliferative disorders. He also focuses on primary systemic amyloidosis, cytopenias, and benign hematological conditions.  He was a contributor to Dr. Jakubowiak’s effort to establish the Myeloma program, and continues to evaluate and manage patients with myeloma. He is planning to develop clinical trials to address new treatment and management strategies for patients with myeloproliferative disorders with Dr. Talpaz.

Laurence H. Baker, D.O.

During the previous twelve months Dr. Baker’s laboratory has continued to explore several exciting avenues of translational and pre-clinical research in the field of soft tissue and bony sarcomas. Although sarcomas comprise only 1-2% of the total number of neoplasms diagnosed in North America and Europe, they disproportionately affect the adolescent and young adult population.  And, although chemotherapy has markedly increased favorable outcomes, the emergence of resistance to chemotherapy drugs is now recognized as the biggest problem affecting the clinical outcome for these tumors. They continue to examine several signal transduction pathways relevant to sarcoma.

The most exciting studies involve the IGF (insulin-like growth factor) pathway.  Deregulated IGF signaling through the type 1 receptor (IGF-1R) appears to be specifically relevant to sarcomas including Ewings family of sarcoma, osteosarcoma, rhabdomyosarcoma and others. Dr. Baker’s laboratory has identified not only the frequency of increased expression of IGFR-1, but more importantly, reported on the activated receptor frequency by histology.  This work correlated with clinical phase I studies of moab to IGFR-1. They have referred several patients to Texas for these studies, including a patient that was a sentinel event that precipitated much enthusiasm.  This 49 year old man who was in 4th relapse for PNET and had two prior thoracotomies to remove metastasis responded within one week of therapy and has entered a complete remission (pathologically confirmed within 6 weeks; this remission has now lasted over 8 months.  This year they will contract IGF signaling in pediatric and adult patients with the Ewings family of tumors to determine if there is a qualitative or quantitative difference among these two populations.  In addition, they will examine relevant combination therapy in a xenograft model of Ewings; specifically, they will examine issues of dose and schedule for two combinations IGF1R moab + rapamycin and IGF1R moab + doxorubicin. Both these combinations will enter the clinic in 2007-08. 

A second pathway was to explore epithelial growth factor receptor and two specific sarcoma histotypes: synovial sarcoma and malignant peripheral nerve sheath tumors (MPNST).  Using a tissue microarray of human specimens from their tumor bank of these two tumor types, they explored EGFR expression, activation and mutational analysis with outcome.  They also predicted results of an ongoing SWOG study with an EGFR small molecule (erlotinib) to be negative. This again underscores that clinical trials should, whenever possible, have pre-clinical evidence in support of a trial rather than just a literature search of expression.

Douglas Blayney, M.D.

Dr. Blayney is the Medical Director for Cancer Center Clinic Operations. He also serves as chair of the Clinical Operations Committee and the Cancer Center Pharmacy and Therapeutics Committee, and is co-chair of the CareWeb Ambulatory Care Advisory Committee.   He is a clinical lead for implementation of UM-Carelink (formerly the Orders Management Project or OMP), a University Health System initiative for computerized physician order entry.  During the past year, the Cancer Center successfully opened an offsite infusion expansion in Canton, added nine infusion beds and additional clinic space in the Cancer Center building on campus. The clinical operations continued on budget, had net revenues of 96M$, and had continuing high patient satisfaction scores during the fiscal year 2007.  He serves on the OMP Steering Committee, the Clinical Leadership Group, and the Medication Management team.  In addition, he has a research interest in collating the repositories of existing clinical data into a form useful for operations improvement, clinical outcome measures and patient safety.  He is collaborating with the Cancer Center Bioinformatics core in this effort.  Dr. Blayney is the founding Editor-in-Chief of the Journal of Oncology Practice, the newest journal published by the American Society of Clinical Oncology (ASCO).

Dr. Blayney has a research interest in using existing clinical data repositories for monitoring patient safety, improving operations, and measuring clinical outcomes.  In collaboration with the Cancer Center Bioinformatics core, he lead three cycles of participation in the American Society of Clinical Oncology’s (ASCO) Quality Oncology Practice Initiative (QOPI) at UM, which was the first implementation of this quality measurement program at a large cancer center.  This work was presented at the ASCO 2007 Annual Meeting, and at the San Antonio Breast Cancer Symposium 2006.  Other quality improvement activities included implementation of a Quality assurance and improvement (QA/QI) review activity at the Cancer Center, the implementation of standardized chemotherapy administration orders, and the integration of a chemotherapy administration note into CareWeb, the current UM electronic medical record.   He also is a member of the Board of Directors of the National Cancer Center Network (NCCN), and concluded service on the Board of Directors of the ASCO Foundation.

Dr. Blayney is the site principal investigator for a multi-institutional study of bendamustine, an alkylating agent being developed for the salvage therapy of low grade lymphoma, and also for development of a platelet growth factor for support of salvage chemotherapy of lymphoma.

As Medical Director for Clinical Operations of the Cancer Center, Dr. Blayney's efforts and oversight resulted in continued growth of patient volumes and revenue.  The Cancer Center achieved budget targets and, for the first time in his tenure, had improved employee satisfaction scores.  Quality improvement efforts within the Cancer Center started to gain national attention.  The Journal of Oncology Practice continued to grow and attract readers and contributors.

Erica Campagnaro, M.D.

Dr. Campagnaro joined the University of Michigan Division of Hematology and Oncology as a Clinical Lecturer in July 2007.  Her clinical interests are in acute leukemia, lymphoma, and multiple myeloma.  She is attends the Multiple Myeloma Clinic and the Multidisciplinary Lymphoma Clinic.  Her research targets patients with non-Hodgkin’s lymphoma, including phase II trials investigating the utility of novel agents in the treatment of NHL, as well as a trial investigating the use of a newer functional imaging modality, diffusion-weighted MRI, in patients with diffuse large B cell lymphoma.

Rashmi Chugh, M.D. 
           
Sarcomas are cancers derived from connective tissue and span a wide range of histologic subtypes, clinical behaviors, and afflicted populations.  They comprise less than 1% of all cancers and given their rarity and complexity of multi-disciplinary management, are best handled by a tertiary care sarcoma center.  Our sarcoma multi-disciplinary treatment team is actively involved in research in all aspects of sarcoma care including systemic therapy, radiation therapy, and surgery.

Dr. Chugh’s particular research focus is on the development of new drug combinations in the management of this disease.  Unfortunately, systemic therapy for sarcomas is limited and only a minority of patients benefit from treatment. Her research involves conducting phase I trials of novel combinations of both standard cytotoxic therapy and targeted agents in this disease.  The combinations are chosen based on rational laboratory or clinical evidence of potential benefit, and are taken to the bedside for further evaluation.  Promising combinations will continue to be tested in her program in phase II trials,

Nicholas J. Donato, Ph.D.
Dr. Donato is a Research Associate Professor in the Department of Internal Medicine, Hematology/Oncology Division. He received his Ph.D. from the University of California, Riverside and is trained in biochemistry and pharmacology. The focus of his graduate training was in defining the regulatory processes involved in polyamine biosynthesis in mammalian cells with a particular focus on the rate-limited enzyme, ODC. He investigated the role of its post-translational modification in its localization and stabilization and examined the anti-tumor activity of irreversible ODC inhibitors. He initiated his post-doctoral training in Molecular and Cellular Endocrinology (Dr. Anthony Norman) and continued his post-graduate training at M.D. Anderson Cancer Center, exploring cell death pathways and mechanisms of sensitivity and resistance to apoptotic cytokines and chemotherapeutic agents. His research became focused on the role of tyrosine kinases and phosphatases in signal transduction and in examining their ability to serve as valid targets for cancer therapy. He received several NIH and DOD grants and was promoted to the rank of Associate Professor at M.D. Anderson Cancer Center. His research focus was then directed toward targeted therapy of leukemias and made important contributions in understanding the mechanism of action of tyrosine kinase inhibitors in chronic myelogenous leukemia (CML) and other leukemias. He was first to investigate tumor cell “addiction” to CML oncogenes and in defining the signaling patterns that underlie addiction. He was also first to identify and characterize a Src-related tyrosine kinase (Lyn) in imatinib resistance and was instrumental in the preclinical development and clinical introduction of second-generation kinase inhibitors useful in the treatment of imatinib-resistant CML (Dasatinib). This work was supported by grants from the NIH and Leukemia Lymphoma Society. He has published more than 60 research articles and his work in CML is highly cited.
Dr. Donato joined the University of Michigan Medical School faculty in October, 2006. His current laboratory studies focus on defining novel targets and agents useful in the treatment of hematological malignancies. He jointly developed a new class of compounds and described their unique mechanism of action (degrasyns) as suppressors of cytokine signal transduction and inhibitors of tyrosine kinases. This class of compounds induces specific trafficking of leukemogenic kinases and he is identifying key elements in this cascade. Degrasyns also destabilize c-myc through forced interaction of a unique c-myc domain with specific phosphotyrosyl-regulatory proteins. This research should lead to definition of novel metabolic cascades and identification of novel targets for cancer therapy.

William D. Ensminger, M.D., Ph.D.

Dr. Ensminger’s research efforts are directed toward the experimental therapeutics of gastrointestinal cancers. Preclinical investigations are focused on the development of novel treatments for cancer involving the liver. Based upon prior laboratory efforts, clinical studies are underway examining the integration of hepatic arterial fluorodeoxyuridine (FUDR) as a regional radiosensitizer administered on a rationally conceived schedule along with conformal radiotherapy in the treatment of primary and metastatic tumors confined to the liver. Recently introduced more effective systemic chemotherapies for colorectal cancer are being added to such improved hepatic regional therapy along with surgical resection in an attempt to increase the cure rate. Other studies strive to improve the efficiency of the radioprotective agent amifostine in preventing damage to normal liver from hepatic irradiation. Regional pharmacokinetics and administration are being examined in rat and dog models prior to anticipated clinical investigation. A major laboratory effort is concentrated on the development of suicide gene therapy for hepatocellular carcinoma. An adenoviral expression vector already in clinical trial for prostate cancer is being examined in human hepatocellular xenografts in nude rats. This is a replication competent double suicide gene expression vector converting flucytosine to fluorouracil and ganciclovir to ganciclovir monophosphate in infected tissues. Studies are underway determining how to deliver sufficient vector to liver tumors for therapeutic efficiency using hepatic arterial delivery and manipulations designed to increase extravasation and dwell time of the vector in the liver. It is anticipated that these laboratory efforts will ultimately result in clinical studies in primary liver cancers.

FY07 highlight: Dr. Ensminger has provided medical oncology input and support to the newly formed Liver Tumor Group which provides for a Liver Tumor Board and soon, for a new multidisciplinary Liver Tumor Clinic in the Cancer Center. Dr. Ensminger’s laboratory efforts in gene therapy and clinical efforts in focal chemoradiotherapy and yttrium microsphere therapy are focused on primary liver cancers.

Harry P. Erba, M.D., Ph.D.

Dr. Erba's interests are directed toward the development of a clinical research program for adult patients with acute and chronic leukemias and myelodysplastic syndrome.  Most patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are not cured by standard chemotherapy.  Although high dose chemotherapy followed by allogeneic hematopoietic stem cell transplantation is a curative option, most patients with AML and MDS are not candidates for this therapy due to advanced age, co-morbid illness, or the lack of a hematopoietic stem cell donor. Dr. Erba is interested in developing treatment programs for patients with AML and MDS that are more effective and less toxic than currently available chemotherapy.  He participated in the pivotal trial of gemtuzumab ozogamicin (Mylotarg) in adult patients with AML in first relapse.  Gemtuzumab is a humanized murine monoclonal antibody directed against an antigen, CD33, found on the surface of most AML cells.  This antibody is conjugated to a potent toxin that causes double-stranded DNA breakage and cell death.  He has recently completed trials of this immunoconjugate as a single agent or in combination with standard cytotoxic chemotherapy in elderly patients with previously untreated AML.  He is now investigating the combination of Mylotarg with Zosuquidar, an inhibitor of the multidrug resistance protein, in patients with relapsed AML.  He was the study coordinator for a national cooperative group trial of the oral farnesyl transferase inhibitor, tipifarnib, in the treatment of elderly patients with previously untreated acute myeloid leukemia, who are not eligible for chemotherapy.  He is involved in the evaluation of the oral FLT3 tyrosine kinase inhibitor, CEP701, in patients with relapsed AML that express FLT3 activating mutations.  He is the co principal investigator of an industry-sponsored multicenter phase II trial of single agent clofarabine in older AML patients.  He has participated in the multicenter phase II study of a novel topoisomerase II inhibitor amonafide in combination with cytarabine for adult patients with previously untreated secondary AML.  This study has led to a phase III trial of this combination versus standard induction chemotherapy in the same population.  He is the local principal investigator for clinical trials evaluating the novel, oral tyrosine kinase inhibitor, nilotinib (AMN 107, Novartis), in patients with CML and other bcr/abl positive diseases.  He collaborates with Dr Sami Malek in the Division of Hematology/Oncology to provide samples of peripheral blood and bone marrow from patients with AML, MDS and chronic lymphocytic leukemia for laboratory analysis of a variety of biomarkers.  He continues to organize the bimonthly Leukemia Conference.  He is a member of the National Comprehensive Cancer Network practice guidelines committees for myelodysplastic syndromes, CML, and acute myeloid leukemia.  He is on the Executive Committee of the Southwest Oncology Group.

Daniel F. Hayes, M.D.

Dr. Hayes, with his colleague, Dr. Sofia Merajver, is co-Director of the Breast Oncology Program in the UMCCC.  As such, he continues to lead translational and clinical research in breast cancer in the Division.  These efforts cover the gamut of the breast cancer spectrum, from prevention to metastases, including therapeutic and correlative studies. In this regard, Dr. Hayes is a nationally recognized expert in tumor marker studies.  In addition to his role as Chair of the Breast Cancer Translational Medicine Committee of the Southwest Oncology Group, he is also Chair of the North American Breast Cancer Intergroup (TBCI) Correlative Science Committee, and, with Robert Bast of the M.D. Anderson Cancer Center, he co-Chairs the Tumor Marker Guidelines Expert Panel convened by the American Society of Clinical Oncology (ASCO).

Highlights for this year include Dr. Hayes’ being named the first recipient of the Gianni Bonadonna Breast Cancer Award for achievements in translational research and mentoring.  In addition, he and his colleagues from TBCI have reported that HER2 over-expression and/or amplification is associated with response to paclitaxel adjuvant chemotherapy.  These results were reported in the New England Journal of Medicine in September, 20071.
Pharmacogenomics of Endocrine Therapies:Dr. Hayes maintains a fruitful collaboration with COBRA (the COnsortium to study pharmacogemomics of BReast cAncer Endocrine Treatment).  COBRA consists of investigators at UM as well as Indiana University and Johns Hopkins University and is funded by the National Institutes of Health to study pharmacogenomics of endocrine therapies for breast cancer, including tamoxifen and the aromatase inhibitors2.  We have competed a prospective study of tamoxifen, from which we have determined that patients with inherited CYP2D6 polymorphisms or who are taking CYP2D6 inhibitors may not activate tamoxifen and therefore may have worse outcomes than those with wild-type gene.  More recently, we have demonstrated that serum lipids are affected differently by tamoxifen in patients with wild type vs. variant estrogen receptors3, and we are now evaluating similar associations between genotypes and hot flashes, bone density changes, and other clinically relevant outcomes.  We are currently conducting a prospective randomized trial to study the pharmacogemics of two aromatase inhibitors (AIs): exemestane and letrozole, and we are opening several pilot studies to investigate various outcomes related to the AIs and genetic differences.  
Circulating Tumor Cells: Dr. Hayes has led a prospective, multi-institutional clinical trial investigating circulating tumor cells (CTC) in patients with metastatic breast cancer4-6.  Two additional studies have demonstrated that one time and serial CTC levels appear to be more accurate than standard radiographic response criteria for predicting long term survival for both women with measurable and non-measurable breast cancer7,8.   Coupled with preliminary results demonstrating the ability to monitor both HER2 expression by CTC and apoptosis of CTC, these findings are the basis for an ongoing prospective randomized clinical trial, led by Dr. Jeffrey Smerage of the BOP, within the Southwest Oncology Group to further determine the clinical utility of monitoring CTC in patients with metastatic breast cancer.  Dr. Smerage is also leading an ongoing UMCCC pilot study to further characterize these cells for expression of various markers, including HER2, apoptosis, and bcl-2.

Recently, Dr. Hayes’ laboratory has developed a murine xenograft model to permit more rapid evaluation and characterization of CTC. This model will facilitate translation of CTC studies to the clinic.

N. Lynn Henry, M.D., Ph.D.

Dr. Henry’s primary research interest is the treatment of breast cancer, with particular focus on the toxicity and pharmacogenetics of therapy. Researchers at the University of Michigan are key members of the NIH-funded Consortium on Breast Cancer Pharmacogenomics (COBRA), which is based at Indiana University. COBRA was created in 2000 to study the pharmacogenomics of tamoxifen, and has since expanded its focus to study aromatase inhibitor therapy.   The majority of this research program is focused on the aromatase inhibitors. COBRA is currently accruing patients to the Exemestane and Letrozole Pharmacogenomics trial, in which women are randomized to either a steroidal or a non-steroidal aromatase inhibitor and monitored for two years. The primary endpoint is change in breast density. Multiple other endpoints are being evaluated, including change in bone mineral density, lipids, and serum hormone concentrations. One key aspect of this study is an in-depth characterization of the musculoskeletal toxicity that occurs during aromatase inhibitor therapy. Study participants who meet pre-defined objective criteria undergo a structured evaluation by rheumatologists. Ongoing research is directed towards understanding the mechanisms underlying the development of these symptoms, as well as identification of effective interventions to either prevent or treat these symptoms. Some of this work is being conducted in collaboration with Daniel Clauw, MD, Angela Gupta, MD, and Jon Jacobson, MD.

A second primary area of research also involves aromatase inhibitor therapy, but is specifically focused on premenopausal women who develop chemotherapy-induced ovarian failure. Some women experience recovery of ovarian function while taking aromatase inhibitors, and increased circulating estrogen levels are opposite of the intended goal of therapy. It would be beneficial to predict a priori which women will recover ovarian function during therapy, as these women could be treated with a different initial endocrine therapy, but to date, no factors have been identified which are predictive of either recovery of ovarian function or maintenance of ovarian failure during treatment. In conjunction with Dr. Hayes, Dr. Henry developed a multicenter clinical trial to evaluate the use of aromatase inhibitors in this patient population in an attempt to identify clinically-useful predictors. This trial should begin accrual in late 2007. This work is being conducted in collaboration with MaryFran Sowers, PhD, and John Randolph, MD.

Maha Hussain, M.D.

Dr. Hussain is nationally and internationally recognized for her clinical and scientific research expertise in the area of genitourinary-oncology, particularly prostate and bladder cancers.   Her research efforts are focused on the development of novel treatment approaches for bladder and prostate cancer integrating biological and clinical advances into clinical translational trials. She currently serves as principal investigator of 5 ongoing investigator initiated national and international multicenter clinical trials which she designed amongst in addition to other clinical trials.  These include an intergroup phase III international trial sponsored by SWOG which test the efficacy of intermittent androgen deprivation in patients with stage D2 prostate cancer; three multi-center CTEP sponsored phase II trials evaluating the integrin inhibitor EMD121974 in the treatment of  patients with metastatic and non metastatic androgen independent prostate cancer and the  histone deacetylase inhibitor Suberoylanilide Hydroxamic Acid in prostate cancer patients failing first line chemotherapy; and a randomized phase II multicenter trial evaluating the role of antiangiogenic therapy in preventing disease relapse in patients with urothelial cancers following chemotherapy using SU11248 (sunitinib). Several other trials which she designed are in development and will activate before the end of 2007 including a randomized trial assessing the role of EGFR inhibition in addition to chemotherapy in patients with advanced urothelial cancers.  This trial will be conducted by the NCCN with the UM as the coordinating lead center.  Dr. Hussain is the PI of a grant from the Department of Defence to support clinical translational research in prostate cancer and is the UM PI for an N01 grant under the University of Chicago that supports early therapeutics development.  Amongst several invited national functions Dr. Hussain’s expertise lead to her invited leadership of the ASCO education committee (chair elect 2007-08, chair 2008-09), and appointment as the chair Oncology Drug Advisory Committee.

Andrzej Jakubowiak, M.D., Ph.D.

Dr. Jakubowiak is an Associate Professor of Medicine and Director of the Inpatient Hematology/Oncology service. His research interests are in the field of multiple myeloma, and he serves as Director of the Myeloma Program. During the past year, he continued his efforts to further develop clinical and translational research in multiple myeloma. He has been a local principal investigator in several studies investigating the role of new promising combinations with VELCADE and Revlimid, and new studies with Perifosine, a novel Akt inhibitor. The results from the recently completed single institution study investigating a combination of VELCADE, Doxil, and Dexamethasone (VDD) in newly diagnosed myeloma, show a superior response rate and high rate of complete responses and have been presented at the ASH Meeting 2006 and at the International Myeloma Workshop 2007. In addition, the study generated data for the development of clinical and laboratory prognostic models of response to VDD. By correlating clinical outcomes with levels of light chains, the study resulted in the development of a model predicting a very good response to Velcade-based regimens early in the course of therapy. In addition, laboratory evaluations revealed that expression of NOXA, which is involved in cell apoptosis, and gene expression profiles, can serve as predictors of response to this regimen. In a separate single institution project, he is investigating the role of targeted therapy against clonogenic myeloma cells using anti-CD20 radioantibody. The project involves a clinical trial with Bexxar supported by GlaxoSmithKline, and clonogenic studies supported by the grant from the Clinical Research Initiatives Program. The research potential of the Myeloma Program at the UMCC has been greatly enhanced after joining the Multiple Myeloma Research Consortium (MMRC) last fall, which includes 12 leading myeloma programs and leads the evaluation of the most promising novel anti-myeloma agents and regimens. As a result of the recognition of Michigan’s role in this consortium, the UMCC is currently leading a multi-center MMRC study of the novel 3 oral drug combination treatment of relapsed refractory myeloma with Perifosine, Revlimid, and dexamethasone. Dr. Jakubowiak received a research grant from the MMRC for correlative studies related to this project, which will be conducted at both UMCC and Dana-Farber sites. As part of the MMRC research efforts, the UMCC participated in the evaluation of a number of novel agents, including a new promising proteasome inhibitor PR-171, a new immunomodulatory drug CC-4047 similar to thalidomide and Revlimid, and huLuc68, a new very promising anti-myeloma humanized antibody.

Dr. Jakubowiak continues to Chair the Multidisciplinary Myeloma Clinic and the Myeloma Conference, which serve as an avenue for evaluation of new myeloma referrals and facilitate enrollment to clinical studies, new research, and integration of care between hematology and BMT.  At the national level, he is a member of the Protocol Review Committee at the MMRC and the member of the Myeloma Committee at the Southwest Oncology Group. He has continued to further develop collaboration with leading myeloma researchers outside of the MMRC and SWOG with the most active collaboration with the Dana-Farber Cancer Institute.

Highlights from the last year include Dr. Jakubowiak being promoted to Associate Professer, Appointed as Director of Inpatient Hematology/Oncology Service and Director of the Myeloma Program.

Gregory P. Kalemkerian, M.D.

Dr. Kalemkerian is a Professor and Co-Director of the Thoracic Oncology Program within the Cancer Center. His major research interest is the development of experimental therapeutic approaches for the treatment of lung cancer. Specifically, he has studied the cellular and molecular effects of retinoids and other natural products in small cell lung cancer and designed clinical trials based on his laboratory findings. His other academic interests include the epidemiology of lung cancer, with a focus on the effects of age, race, gender, and treatment on patient outcome. Clinically, Dr. Kalemkerian directs the U-M Multidisciplinary Lung Cancer Clinic and the Multidisciplinary Thoracic Oncology Conference, and has a variety of clinical trials available for patients with lung cancer and mesothelioma. Dr. Kalemkerian is also coordinating the development of a lung cancer research program with an emphasis on experimental therapeutics and the implementation of a clinical lung cancer database at U-M.

Lisa A. Kujawski, M.D.

Dr. Kujawski’s research efforts are focused on the investigation of novel therapeutic agents and strategies in the treatment of the acute/chronic leukemias and myelodysplastic syndromes (MDS).  She is particularly interested in the biological significance of the leukemic stem cell (LSC), and ways to manipulate this population through the use of novel treatment approaches, outside of hematopoietic stem cell transplantation. The LSC population has been best characterized in chronic myeloid leukemia (CML), and is believed to be the gatekeeper of disease. Traditional chemotherapy, as well as newer agents including imatinib mesylate (Gleevec), have not been successful in eliminating the LSC, making relapse an ongoing challenge.  In collaboration with Dr. Moshe Talpaz, Dr. Kujawski is the principal investigator for a clinical trial exploring whether the addition of the immunomodulatory agent interferon-alpha to imatinib mesylate (Gleevec) can effectively eradicate the malignant stem cell population in patients with CML, thereby offering the potential for cure.  The therapeutic impact on the LSC population has not been widely studied in CML, and this clinical trial offers a unique opportunity to do so. Promising results may lead to a shift in the treatment paradigm toward a more LSC-directed approach.

As part of the adult leukemia program, Dr. Kujawski collaborates with Dr. Harry P. Erba, through the enrollment and care of patients on several therapeutic clinical trials pertaining to the acute leukemias and myelodysplastic syndromes. She will also be the local principal investigator for a phase II clinical trial investigating the histone deacetylase inhibitor, vorinostat in the treatment of low-grade MDS, as well as, a phase I clinical trial investigating the combination of decitabine and vorinostat in the treatment of high-grade MDS and acute myeloid leukemia (AML).

Furthermore, Dr. Kujawski is interested in the biology and treatment of chronic lymphocytic leukemia (CLL) and is in the process of helping to build a clinical research program in this area.  From a translational science standpoint, she continues to collaborate with Dr. Sami Malek, investigating significant genomic changes in CLL, through the use of high-density SNP oligonucleotide arrays. Results thus far reveal the degree of genomic complexity determined by SNP analysis appears to serve as an important prognostic marker in patients with CLL.

Bryan Schneider, M.D.

Dr. Schneider's interests are directed toward the development of a clinical research program for lung and esophageal cancer.  He collaborates with Dr. Greg Kalemkerian and Dr. Susan Urba in the division of medical oncology (thoracic oncology) investigating novel therapeutic strategies for thoracic malignancies.  Lung cancer is the leading cause of cancer death in the United States with a 5-year survival rate of 15%.  Standard chemotherapy for advanced disease is moderately effective at best and new treatments are desperately needed.  Dr. Schneider’s focus is on investigator initiated therapeutic trials in advanced lung cancer.  The HDAC inhibitor suberoylanilide hydroxamic acid (Vorinostat) is currently being investigated in a phase I clinical trial for which Dr. Schneider is the primary investigator. Other new therapies such as the tyrosine kinase inhibitor sunitinib will also undergo clinical investigation soon.  Dr. Schneider’s other focus is on genomic profiling of lung and esophageal cancer in an effort to predict response to therapy.  He collaborates with Dr. David Beer and Dr. Andrew Chang in the department of thoracic surgery with the goal of utilizing genomic profiling of esophageal cancer to predict response to neo-adjuvant chemoradiation.  He will play an active role in the development/implementation of a clinical phase I program headed by Dr. Moshe Talpaz with the goal of bringing new anti-cancer agents to the university hospital to offer patients.

As a highlight, Dr. Schneider has a large clinic devoted to the treatment of thoracic malignancies: lung cancer, esophageal cancer, mesothelioma and thymoma.  His primary research interest is the development of new therapeutic approaches to these malignancies.  He will play a role in the new clinical phase I program and continue to investigate genetic profiling of thoracic malignancies to enhance therapeutic approaches.  

Anne F. Schott, M.D.

Dr. Schott divides her time between three professional tasks: she is a breast cancer clinician/educator, a breast cancer clinical researcher, and she serves as an Executive Officer of the Southwest Oncology Group (SWOG), a national clinical trials organization dedicated to making progress in the prevention and cure of cancer through clinical research. As Executive Officer of SWOG, Dr. Schott is responsible for facilitating the research agendas of the Breast, Lung, Head and Neck, Early Therapeutics, and Special Populations Committees. As breast cancer clinician and researcher, she is the principal investigator for a number of clinical trials for individuals with all stages of breast cancer.  Examples of these trials are listed here:

For Stage I and II breast cancer, she has recently published a study that examined the ability of various radiology studies (mammography, ultrasound, MRI) to accurately define the response to chemotherapy prior to breast surgery (neoadjuvant chemotherapy). This study defined the limits of conventional radiology imaging methodology in determining response to treatment. This line of investigation is followed with an ongoing study examining a new technology, diffusion MRI, in the same patient population. In another recent study of neoadjuvant chemotherapy in breast cancer patients, Dr. Schott examined the expression of thymidine phosphorylase and other enzymes as markers for response to a combination of capecitabine and docetaxel chemotherapies.   For Stage IV breast cancer, Dr. Schott recently published a study examining a new dosing scheme for a combination chemotherapy, capecitabine plus vinorelbine, and was the national study coordinator of a recently-completed SWOG study looking at a simple, all-oral combination chemotherapy consisting of capecitabine and cyclophosphamide.  She has opened another national clinical trial for patients with breast cancer spread primarily to bone, that uses a new agent called dasatinib for treatment. Finally, Dr. Schott is the lead investigator for a clinical trial in advanced breast cancer that will examine the effectiveness of new treatments directed at breast cancer stem cells, which will be done in collaboration with colleagues at Baylor University and Dana Farber Cancer Institute.

Dr. Schott’s translational research efforts have included a leadership role in the establishment of a prospective neoadjuvant tissue and clinical database that supports the laboratory efforts of her collaborators within the Breast Oncology Program of the UMCCC. Dr. Schott also spearheaded the collection of archival breast tissue before and after neoadjuvant therapy, for the development of a Tissue Microarray (TMA). The prospective tissue collection and archival TMA have already led to important new understandings in stem cell biology of breast cancers and will continue to be an excellent resource for biomarker discovery in breast cancer.

Scott Schuetze, M.D., Ph.D.

Sarcomas are a heterogeneous mix of bone and soft connective tissue tumors. Sarcomas occur in children, teenagers and adults. The majority of patients diagnosed with aggressive sarcomas are at significant risk of tumor spread which is often ultimately fatal. Few chemotherapy treatments are available for sarcomas and benefit a minority of patients. The causes of sarcoma resistance to standard chemotherapy have not been clearly delineated but altered tumor metabolism of drug is thought to play a role. Many sarcomas contain specific genetic changes that are important in the pathogenesis of the disease and may be amenable to disruption of the specific pathways that are critical to growth of the tumor. This concept has been substantiated in gastrointestinal stromal tumors that are treated with drugs which target the c-kit tyrosine kinase. Numerous compounds targeting tumor growth and death signals are in development.  A substantial proportion of Dr. Schuetze’s research effort is in the development, implementation and conduct of clinical studies of new targeted therapies in patients with advanced sarcomas. The Sarcoma Multidisciplinary Team is also actively involved in testing methods to identify sarcomas resistant to standard therapies and developing treatment protocols to overcome tumor resistance.

Because sarcomas are histologically complex tumors, it is often difficult to determine whether chemotherapy treatments are of benefit. New radiological tests that measure biologic properties of sarcomas may be of more use than standard radiological tests that measure tumor size and shape in evaluating the effects of standard chemotherapy or targeted therapy in sarcomas. The sarcoma team is actively involved in the development and evaluation of functional imaging methods to predict sarcoma response to treatment. They hope imaging methods will be identified that can select, early-on in the chemotherapy, the patients whom are likely to derive the greatest benefit from treatment. Patients who are unlikely to benefit from the specific chemotherapy would be spared toxicities from an ineffective regimen and could be considered for a different treatment plan.

Samuel M. Silver, M.D., Ph.D.

During the academic year 2006-7, Dr. Silver's efforts were devoted to the continued development of a community-based test project for the measurement of adherence to NCCN treatment guidelines in breast cancer to give both providers and guideline writer feedback about the practice of oncology in the community.  This was previously successfully implemented at St. Joseph Mercy Hospital.  BlueCross/BlueShield of Michigan funded an expansion of this effort to other hospital systems in Michigan; 5 new sites were launched in the summer of 2006, and 7 additional sites were initiated during the summer of 2007.  It is Dr. Silver’s belief that practice of guideline-based care will reduce costs while improving care.  Dr. Silver also continues his responsibilities as the Medical Director of the Medical Management Center (MMC) of the University of Michigan Health Care System.  The MMC provides: 1) Care management for complex, high cost, at risk, patients with chronic illnesses, 2) Disease Management Programs, 3) Data Analysis for the identification, monitoring, and feedback functions of managing chronic and high cost illnesses and 4) Innovative programs in association with payers for the management of chronic diseases.  Again we have received support from BlueCross/BlueShield of Michigan for the support of these programs

As a Highlight for FY07, Dr. Silver continued expansion of the Michigan Breast Oncology Quality Initiative, a project funded by BlueCross/Blue Shield of Michigan to measure adherence in community practices of NCCN treatment guidelines in breast cancer in order to give both providers and guideline writers feedback about the practice of oncology in the community.

Jeffrey Smerage, M.D., Ph.D.

Dr. Smerage’s primary area of interest is translational breast cancer research, with a specific interest in tumor markers and the development of novel methods to monitor biologic therapies.  Patients with epithelial tumors are known to have cancer cells circulating in the peripheral blood.  It has been recently demonstrated that women with metastatic breast cancer and who have elevated levels of circulating tumor cells (CTCs) are at very high risk for rapid progression and early death compared to women with low numbers of CTCs.  Even more interesting, is the finding that patients who have elevated CTCs after one cycle of a new therapy have an extremely short time to progression (median 1.5 months).  This implies that they are receiving ineffective therapy, and it suggests that these patients would be better served by switching to an alternate therapy early, rather than waiting for clinical evidence of progression.  Dr. Smerage is the Principal Investigator for SWOG S0500, which is a phase III randomized study in which patients with elevated CTCs at first follow-up will be randomized either to continue on current therapy or to switch early to alternate therapy.  For this work, Dr. Smerage was selected as a SWOG Young Investigator.

In addition, Dr. Smerage is developing methods to phenotype CTCs with a goal to use them as a surrogate marker to predict response and survival in clinical trials.  They are also being developed as a method to monitor target modulation in clinical trials of target-directed biologic therapies.  He has modified the CTC assay to allow the detection of apoptosis and Bcl-2 protein expression in CTCs.  This is now being further optimized using blood samples from women undergoing therapy for metastatic breast cancer.  Blood samples are being drawn at baseline, 1-3 days after starting therapy, and 3-4 weeks after starting therapy.  The current study will improve our knowledge of the dynamics of CTC numbers after initiating therapy as well as the timing and dynamics of apoptosis induction after the initiation of therapy.  After optimization, the new assay will be tested as a correlative endpoint in a therapeutic clinical trial to assess correlation with response, progression free survival, and overall survival.  The detection of Bcl-2 expression is intended to be used as a surrogate endpoint in clinical trials of novel anti-Bcl-2 agents.  Dr. Smerage was awarded a research grant from the Hope Foundation to support this work.

Because metastatic disease is believed to result from hematogenous spread, it is presumed that CTCs are involved in this process of metastasis.  However, not all patients with CTCs show recurrence or rapid progression.  Thus not all CTCs are equally capable of independent tumor formation.  It is currently hypothesized that “tumor stem cells” are the subpopulation responsible for metastatic tumor formation.  Dr. Smerage is part of a larger collaboration between investigators in the Breast Oncology Program, the Department of Engineering, and the UM Institute of Nanotechnology to develop novel methods to detect rare events such as CTCs, and more specifically, to detect the tumor stem cell subpopulation within the larger population of CTCs.

David C. Smith, M.D.

Dr. Smith's research efforts are focused on the development of new therapies for patients with genitourinary malignancies. He is the principal investigator on several trials designed to assess the efficacy of new chemotherapy combinations in patients with hormone-refractory prostate cancer. Recently completed trials include a phase II trial of docetaxel in combination with estramustine and zoledronate aimed at assessing the effect of these agents on markers of bone metabolism, an evaluation of a novel angiogenesis inhibitor in patients with asymptomatic hormone-refractory disease, a phase II trial testing the efficacy and toxicity of vaccine therapy, and a new oral combination chemotherapy. A newly opened trial of docetaxel and vaccine is now enrolling patients at the University of Michigan. Dr. Smith is also a study coordinator and active participant in a number of prostate cancer trials open in the Southwest Oncology Group.

In the area of bladder cancer, Dr. Smith is the principal investigator for a novel trial neoadjuvant paclitaxel, carboplatin, and gemcitabine for patients with locally advanced bladder cancer which has recently completed enrollment and will serve as the basis for further studies. He is also the local PI of a multicenter trial evaluating the novel vinca alkaloid vinflunine as second line therapy in bladder cancer.

These research activities are conducted in the setting of an active clinical practice and a collaborative Multidisciplinary Genitourinary Oncology Clinic which allows an extensive interaction with co-investigators from Urology, Pathology and Radiation Oncology.

Moshe Talpaz, M.D.

Dr. Moshe Talpaz is the first Alexander J. Trotman Professor of Leukemia Research, Professor of Hematology Oncology, Department of  Internal Medicine, and Associate Director for Translational Research in the Comprehensive Cancer Center at the University of Michigan Health System.   Dr. Talpaz completed his medical training at the Hebrew University and Hadassah Medical School in Jerusalem, Israel in 1971 and subse