University of Michigan Comprehensive Cancer Center
The Comprehensive Cancer Center was established in 1986, and ranked 6th nationally for grant funds from the National Cancer Institute in 2009.
A. Alfred Taubman Medical Research Institute
Established in 2007 by a grant from A. Alfred Taubman, the Taubman Medical Research Institute funds the Taubman Scholars in discovery science initiatives.
Breast Cancer Research Foundation
HER2 Regulation of Breast Cancer Stem Cells: An IL-6-mediated Inflammatory Loop Mediates Trastuzumab Resistance
Our laboratory previously demonstrated that HER2 plays an important role in the regulation of breast cancer stem cells in HER2 amplified breast cancer. We demonstrated that the molecular mechanism of this regulation was through Akt activation of β-catenin signaling. In our previous BCRF proposal, we extended these studies by proposing the hypothesis that HER2 also plays a fundamental role in the regulation of cancer stem cells (CSCs), in luminal breast cancers in a process that does not require HER2 amplification. In this present proposal we will determine if HER2 is selectively expressed in the CSC population and determine whether trastuzumab can inhibit the growth of non-HER2 amplified breast cancers in mouse xenografts.
Cerulean Pharmaceuticals Contract: Investigating the Role of CRLX101 in breast cancer xenografts
Cerulean has developed a novel nanopharmaceutical delivery system that it hopes will combine efficacy and tolerability to extend survival and improve patient quality of life. Therefore, we will investigate the efficacy of CRLX101 in combination with bevacizumab as a breast cancer therapy, specifically its influence on the cancer stem cell population within breast tumors. In addition, this study will assess the ability of CRLX101 to counteract the increase in the CSC population from hypoxia induced by antiangiogenic therapy.
Department of Defense
Breast Cancer Research Program IDEX Award: Targeting Breast Cancer Stem Cells Through Combined HER2 and Akt Blockade
We will utilize preclinical models and develop a phase I clinical trial to test the hypothesis that simultaneous inhibition of HER2 and Akt signaling will increase the efficacy of either agent alone in targeting the breast cancer stem cell population. This study brings together two principle investigators, Dr. Max Wicha, with expertise in breast cancer and stem cell biology and Dr. Patricia LoRusso, with expertise in Phase I developmental therapeutics. Dr. Wicha’s laboratory will perform the preclinical in vitro and xenograft model studies, as well as performing the bioassays for cancer stem cells and the pathways that regulate them in samples derived from clinical trials. Dr. LoRusso will lead the Phase IB clinical trials which will be performed jointly at the Karmanos Cancer Center and the University of Michigan Comprehensive Cancer Center.
Department of Defense
Breast Cancer Research Program Idea Award (Wicha/Liu) : A Novel Combination Therapy Targeting Triple Negative Breast Cancer
Recent studies indicate breast cancer is driven by cancer stem cells (CSCs) which are cancer-forming cells with stem cell properties: self-renewal driving cancer formation and differentiation contributing to cellular heterogeneity. Since CSCs mediate chemo-resistance and recurrence, more effective cancer treatments will require CSC targeting. It has been shown that CSCs are increased in chemo-resistant triple-negative breast cancer (TNBC). DNA damage is the underlying cause of mutations leading to cancer and studies show that DNA damage response and repair pathways regulate breast CSCs (BCSCs) and is partially responsible for therapeutic resistance. Despite the use of PARP inhibitors (PARPi) in the treatment of TNBC, our previous data show that PARP inhibition can kill bulk cancer cells, but spare BCSCs. We also found BCSCs have higher Rad51 expression than non-CSCs and 17AAG can down-regulate Rad51 in BCSCs of TNBC. Our hypothesis is that 17AAG and PARP inhibition are synergistic in TNBC, and that 17AAG might sensitize CSCs to PARP inhibition by decreasing Rad51. We will first lower down Rad51 in TNBC cells and assess the cell sensitivity to PARP inhibition. Then, we will determine whether 17AAG makes BCSCs in TNBC sensitive to PARP inhibition. These studies allow us to explore a novel combination approach to target both BCSCs and bulk cancer cells in TNBC.
Dompe Pharmaceuticals s.p.a
Dompe Research Agreement: Feasibility of Combining Reparixin with Gemcitabine and Cisplatin (or Carboplatin)
We seek to determine in a breast cancer animal model if reparixin in combination therapy slows primary tumour growth. We propose a tumor take experiment to investigate the potential use of Gemcitabine and Cisplatin and/or Carboplatin as chemotherapeutic agents in combination with reparixin treatment in mouse xenograft models. We have previously evaluated SUM159 cells and assessed sensitivity to reparixin and found them suitable for use in our in vivo modeling. For our in vivo experiments with reparixin administered to breast cancer-bearing mice, reproducing the clinical situation of foreseen clinical trials is our primary objective.
MedImmune Research Agreement: Targeting Different States of Breast Cancer Stem Cells
This research seeks to evaluate the clinical relevance of EMT/MET CSC and establish an imaging platform (ALDH+, CD44+) for the two state model for evaluating MedImmune treatment assets. In addition this proposal seeks to evaluate IL-6 in Her-2 resistant breast cancer stem cells. MedImmune would like to leverage the existing breast xenografts, isolate and characterize CSCs from these models to assess treatment response and create novel models utilizing primary human tissues to model disease resistance. This project should demonstrate clear clinical relevance of IL-6 inhibition, assess feasibility of using IL-6 as a biomarker and determine when IL-6 intervention would take place. Initially this project will use existing models to test treatment response and look at experimental resistance (by titrating PTEN), isolate and characterize CSCs and finally establishing new models of primary human resistance.
National Cancer Institute
Cancer Center Core Grant (Wicha)
The major goal of this project is Cancer Center core support. The core grant supports the senior leadership, programs and shared facilities of the Cancer Center. The Center provides the organizational framework to promote interdisciplinary research through the development of defined clinical, basic science and prevention programs in cancer research, and the development and support of shared resources.
National Institutes of Health
RO1CA129765 (Wicha): Stem Cell Self-Renewal and Mammary Carcinogenesis
The major goals are to elucidate the stem cell self-renewal pathways that are involved in carcinogenesis in sporadic and hereditary breast cancers. Specifically, we seek to elucidate the roles of BRCA1, HER2 and PTEN in the regulation of mammary stem cell self-renewal. To determine the mechanisms by which HER2, PTEN and BRCA1 regulate mammary stem cell function. To determine the effect of dysregulation of stem cell self-renewal and mammary development in humanized NOD/SCID mouse models. Finally we will detect and characterize stem cell populations during breast cancer initiation and progression.
National Institutes of Health
RO1CA101860 (Wicha): Regulation of Breast Stem Cells by the Microenvironment
This proposal investigates the isolation and characterization of human mammary stem cells and elucidation of the mechanisms that govern self-renewal and differentiation. The grant deals with normal mammary stem cell biology and regulation of these cells by the microenvironment. Specifically we plan to determine the effects of mammary fibroblasts and MSCs on breast stem cell self-renewal. In addition we will characterize the chemokine networks mediating the interaction of mammary stem cells within the microenvironment. We also propose to selectively target the IL-8/CXCR1 axis in BCSCs through CXCR1 blockade.
National Lung Cancer Partnership
Young Investigator Research Grant (Hassan): Blocking the Notch pathway inhibits the epithelial-mesenchymal transition (EMT) status in lung cancer and alters chemoresistance
In this proposal we seek to investigate the role of Notch inhibition in blocking EMT and induction of chemosensitivity.
National Institutes of Health
K08 (Hassan): Assessing the Notch pathway as a Therapeutic Target in Lung Cancer Adenocarcinoma
In this proposal investigate the specific role of the Notch pathway in lung cancer and its effect in lung cancer stem cells, both in vitro and in vivo.
Organogenesis Team Research Award (Wicha/Guan/Weiss): Regulation and Therapeutic Targeting of Breast Cancer Stem Cells
Using well-characterized transgenic mouse models, as well as human breast cancer cell lines and primary tissues, we propose to determine the role of miRNAs and tumor microenvironment, Snail (a key transcriptional repressor known to drive the normal EMT programs associated with development as well as the pathologic programs co-opted during neoplasia) as well as focal adhesion kinase (FAK) signaling in the regulation of EMT-MET CSC transitions and their roles in mediating tumor metastasis. These studies bring together three senior investigators with complementary expertise. Dr. Wicha’s expertise is in cancer stem cell biology and in breast carcinogenesis. Dr. Guan has expertise in mouse models of breast cancer and in the role of FAK in regulating breast cancer development. Dr. Stephen Weiss is an expert in tumor metastasis and the molecular regulation of Snail-dependent EMT programs. Studies supported by this proposal will be utilized to apply for a program project grant from the National Cancer Institute.
Susan G Komen Foundation
Promise Grant : Targeting Stem Cells in Triple-Negative Breast Cancer (TNBC) in Different Racial Populations
We hypothesize that Black African women have a greater percentage of ALDH-positive CSCs with a different molecular profile in TNBC compared to African American women who have a higher proportion of CSCs compared to Caucasian American women. Since TNBC is a heterogeneous disease whose frequency varies according to racial/ethnic identity, it is possible that the frequency of TNBC subsets (hence response to CSC targeted therapy) will also differ in accord with racial/ethnic identity. We hypothesize that we will be able to specifically target BCSCs in both established cell lines and xenografts of TNBCs utilizing inhibitors of Notch, Hedgehog, PARP/Chk and the IL-8/CXCR1 axis. We propose to develop a strategy to clinically target TNBC by attacking the pathways which drive self-renewal and survival in BCSCs.
Susan G Komen Foundation
Career Catalyst Award (Liu): A novel strategy to target breast cancer stem cells utilizing microRNA100
Recent evidence suggests that many cancers, including those of the breast, are maintained by a population of cancer cells that display stem cell properties. These “cancer stem cells” may also contribute to tumor metastasis, treatment resistance and relapse. This suggests that more effective cancer treatments will require the effective targeting of this cell population. Recently, miRNAs (small none-coding RNAs) have been reported to be able to suppress tumor growth and metastasis, some of which have been shown to regulate the cancer stem cell. Both miRNA93 and Let7 have been shown highly depleted in mammary stem/progenitor cells. We have found that expression of miRNA100 (mir100) in breast cancer cell lines reduces their stem cell populations suggesting a strategy for targeting breast cancer stem cells. We propose that mir100 may hold significant potential as a novel molecular therapy for breast cancer stem cells. Therefore, the role of mir100 will be determined. We will assess its role in the regulation of breast cancer stem cells and the fundamental mechanisms by which over-expression of mir100 in breast cancer cells will impair tumor growth and metastasis and make the cells more sensitive to chemotherapy. The proposed experiments will explore a novel therapeutic approach to target and eliminate cancer stem cell populations which have been strongly implicated in therapy resistance and recurrence of advanced tumors.
Susan G Komen Foundation
Career Catalyst Award (Korkaya): Targeting breast cancer stem cells by blocking both intrinsic (Akt) and extrinsic (IL-6) signaling pathways in metastatic mouse xenograft models
In order to study the mechanism of resistance, we have generated a mouse xenograft model of aggressive metastatic breast cancer. In this model, aggressive metastatic breast tumor cells secreted high level of cytokines (IL-6) resembling to aggressive human breast tumors. We also determined that these cytokines contribute to aggressive CSC phenotype. Currently available standard chemotherapeutic agents do not target breast CSCs in our mouse tumor xenograft models as in the metastatic human breast tumors. However, our studies strongly suggested that targeting intrinsic (PI3-K/Akt) or extrinsic (IL-6) signals significantly reduced the breast CSCs which are the resistant cell population. In this proposal, we aim to investigate the role of signals from tumor microenvironment in regulating breast CSCs and determine whether the inhibition of both intrinsic and extrinsic signals will effectively target aggressive breast CSCs in our mouse xenograft models. Provided that our results indicate better outcome in mouse xenograft models, we strongly believe that our studies can rapidly translate into clinic. The IL-6 inhibitor has been already approved by FDA and the European Union for rheumatoid arthritis and has been under preclinical studies for number of human malignancies as a single agent. Our approach will be unique in that we will simultaneously target the two most important signals which we believe contribute to the aggressive/metastatic phenotype.
Taubman Medical Research Institute
Senior Taubman Scholar Award (Wicha): Proposal to Develop a Program in Cancer Stem Cell Research
We propose to establish a new CSC research program at the NCRC that would bring together scientists and clinicians working in different aspects of cancer stem cell biology. We have already assembled research teams in all of the major cancer areas focused on isolating cancer stem cells in each cancer type. This will allow us to study the similarities and differences between these cancer stem cells. The program will develop a bank of tumors obtained from patients with various forms of cancer. In addition, it will establish animal models that will greatly facilitate stem cell research allowing us to identify targets in these cells that can be used to develop new therapies.
Breast Cancer Research Foundation (2011-12)
Regulation of Breast Cancer Stem Cells by Tissue Hypoxia
Work in our lab provided support for the cancer stem cell hypothesis. Cancer stem cells mediate tumor metastasis and resistive to cancer treatments. This proposal investigated agents such as the VEGFR antibody, bevaczumab, and the multi-kinase inhibitors, sunitinib and sorafenib, as cancer stem cell drugs. We tested both in vitro systems and using xenograft models. We determined the role hypoxia plays in cancer stem cell self-renewal and survival in vitro and how these anti-angiogenic agents effect the breast cancer stem cell population in tumor xenografts.
Department of Defense (2008-2012)
National Functional Genomics Center- A Center for Genetic Origins of Cancer at University of Michigan
This proposal sought to develop a comprehensive approach to genetics, proteomics and bioinformatics to elucidate the mechanisms driving tumorigenesis. We showed that cancer stem cells are the key cell population driving tumorigenesis, metastasis and treatment resistance. This proposal also developed novel colon cancer mouse models and bioinformatic approaches to decipher the molecular heterogeneity of cancer, to define the pathways that regulate self-renewal and survival of human cancer stem cells and to generate novel animal experiments.
National Cancer Institute (2010-2011)
Epigenetic changes and their impacts on breast cancer progression and initial susceptibility
The major goals of this proposal were to elucidate epigenetic methylation changes induced by carcinogenesis in sporadic and hereditary breast cancers. We carried out a comparative epigenomic analysis of mammary stem cells (MaSC) derived from parous and nulliparous women. In parallel, we analyzed these same cell types derived from rodent models of pregnancy-associated protection. We identified changes in the epigenome that correlate with protective hormone exposures as the foundation for long term studies to associate such changes with actual risk reduction in human patients.
National Cancer Institute (2009-2012)
Challenge Grant, Correlative Studies for a Phase I Dose-Escalation of the Sonic Hedgehog Smoothened GDC-0449 (NSC # 747691) Plus Pan-Notch Inhibitor RO4929097 (NSC # 749225) Administered in Patients with Breast Cancer
We conducted a Phase I open label study assessing the safety, tolerability, pharmacokinetic (PK) profiles, and pharmacodynamic (PD) biomarkers of RO4929097, a γ-secretase inhibitor (GSI) administered in combination with GDC-0449 in patients with breast cancer. This enabled us to validate the proposed schedule of administration and identification of pharmacodynamic (PD) markers for these agents.
Stand Up To Cancer (2009-2012)
American Association for Cancer Research
Personalizing Treatment of Triple Negative, Metastatic Breast Cancer
The SU2C grant brings together a worldwide team to focus on the development of novel therapeutics to test each of the molecular subtypes of breast cancer. Our goal was to focus on the role of breast cancer stem cells in mediating therapeutic resistance.
Dompé, one of Italy's leading biopharmaceutical companies, has a solid history of developing innovative drugs for illnesses of high societal impact. Dompé actively participates in a high-caliber network that covers the entire pharmaceutical pipeline, from research & development through production and distribution. Dr. Wicha’s pre-clinical research on one of Dompé’s compounds, reparixin, was the first to demonstrate a key role for this interleukin-8 (IL-8R) receptor inhibitor in breast cancer. Various labs have since demonstrated similar effects in other tumor models including prostate and bladder cancer. Dr. Wicha’s promising finding with his research models led to a pioneering CSC trial 2011.079 targeting the IL-8R, CXCR1, in metastatic breast cancer. This trial, “Phase Ib pilot study to evaluate reparixin in combination with chemotherapy with weekly paclitaxel in patients with HER-2 negative metastatic breast cancer (MBC)”, is currently open at the University of Michigan, Fox Chase Cancer Center and soon the University of Kansas. Recently, Dr. Wicha’s laboratory has undertaken additional pre-clinical studies to test the effect of reparixin in murine CSC xenograft models with other chemotherapeutic agents including gemcitabine, carboplatin and cisplatin. Dr. Wicha serves as a consultant for Dompé.
Cerulean has developed a novel nanopharmaceutical delivery platform that combines efficacy with tolerability, giving patients with advanced cancers hope for extended survival and improved quality of life. Cerulean nanopharmaceuticals target tumors by entering through abnormally large tumor blood vessel pores and gradually release payload inside the tumor over time. These nanopharmaceuticals penetrate tumor blood vessels, but are too large to enter healthy tissue. The nanopharmaceuticals disintegrate over time and thereby release the active drug from within the tumor cells. Dr. Wicha’s laboratory has recently initiated a study to investigate the efficacy of CRLX101 in combination with bevacizumab as a breast cancer therapy, specifically its influence on the cancer stem cell population within breast tumors. In addition, this study will assess the ability of CRLX101 to counteract the increase in the CSC population from hypoxia induced by antiangiogenic therapy
MedImmune, headquartered in Gaithersburg, Maryland, is the global biologics arm of AstraZeneca, and currently employees approximately 3,500 worldwide. In the Fall of 2011, the University of Michigan and MedImmune signed a new agreement to work together on a broad range of projects. The three-year strategic collaboration brings scientists from one of the nation’s top medical research institutions together with scientists from one of the world’s leading developers of biologic therapies. Dr. Wicha’s laboratory aims to translate his CSC scientific discoveries using promising MedImmune compounds into new candidates for treating cancer. One candidate of particular interest is an interleukin-6 receptor (IL-6R) inhibitor. We hope this relationship will lead to one or more early phase clinical trials investigating the role of MedImmune compounds in breast cancers.
Paganini Biopharma, Inc. has developed a human monoclonal antibody directed against a unique transmembrane target (EMP2) that efficiently eliminates breast cancer stem cells (BCSC). EMP2 is overexpressed in approximately 74% of triple negative breast cancers (TNBC). Dr. Wicha’s laboratory is testing their anti-EMP2 antibody, PG-101, in vitro using his TNBC lines as well as some of his TNBC xenograft models. Dr. Wicha also serves as a consultant for Paganini Biopharma, Inc.
DeNovo Sciences LLC, a small medical device startup in Plymouth Township, recently won a $500,000 first-place prize at the annual Accelerate Michigan Innovation Competition. The company has created a prototype micro fluidic chip about an inch square that has passed early tests to see if it can capture cells. It hopes to eventually refine the chip so that it can capture and detect cancer cells that are circulating in the blood before they find a landing site in the body and metastasize since most cancer deaths are caused by such metastasis. Denovo’s microfluidic circulating tumor cell (CTCs) isolation chip enables a researcher to isolate rare CTCs (1 to 10 cells per ml of blood) for down-stream molecular characterization and profiling. Since the CTC chip uses label-free capture, it has the advantage of flexibility in the use of antibody markers to identify the target cells. Dr. Wicha’s laboratory is working on a pre-clinical research collaboration with Denovo Sciences to analyze the chip’s ability to capture and identify the population of CSCs within a polyclonal population of breast cancer cell lines. Dr. Wicha hopes this research will lay the foundation for a more in depth clinical study in the near future to identify and characterize CSCs within breast cancer patient CTCs.
Jennerex, Inc. is a biotherapeutics company focused on design, development and commercialization of first-in-class, targeted oncolytic immunotherapy products for cancer. Jennerex product candidate, JX-929, is an engineered vaccinia virus strain with high potency plus enhancements for cancer selectivity and the ability to activate potent chemotherapy in tumors. JX-929 assaults cancer cells both by viral attack and cell lysis ("oncolysis"). Dr. Wicha’s laboratory is working closely with other UM PI’s including Dr. Chang and Dr. Li to test the oncolytic vaccinia virus in an immunocompetent syngeneic Balb/c host for its efficacy in preventing tumor growth and in treating established tumors using the murine mammary tumor 4T1. This research will also determine the sensitivity of ALDHhigh 4T1 CSCs to the oncolytic vaccinia viruses by testing direct oncolysis of the ALDHhigh 4T1 CSCs in vivo. Through the injection of firefly luciferase labeled CSCs, tumor growth will be determined by in vivo bioluminescence imaging using an IVIS200 system following intraperitoneal injection of luciferin substrate. It is hoped this agent will prove efficacious in tumor stem cell clearance and result in a CSC clinical trial in the near future.
Dr. Wicha’s laboratory is planning on collaborating with Spingotec to assess the potential therapeutic role of neurotensin in breast cancer stem cells. His laboratory will determine if neurotensin increases BCSCs by treating breast cancer cell lines in vitro over a course of concentrations and then measuring the frequency of CD44+CD24, CD44+CD24-EpCAM+ and ALDH+ cells by flow cytometry. This research also seeks to determine if neurotensin receptor 1 (NTR1) is expressed on breast cancer stem cells by simultaneous staining with anti-NTR1 antibody and Aldefluor, CD44, CD24, and EpCAM in breast cancer cell lines. In addition, we will assess if two NTR1 antagonists decrease breast cancer stem cells in breast cancer cell lines over a course of concentrations and times. Finally, this collaboration will combine NTR1 antagonists with docetaxel, paclitaxel and herceptin to determine if NTR1 antagonists prevent the known increase in breast cancer stem cells after chemotherapy treatment.
Genentech has been delivering on the promise of biotechnology for more than three decades, using human genetic information to discover, develop, manufacture and commercialize medicines to treat patients with serious or life-threatening medical conditions. Genentech is among the world's leading biotech companies, with multiple products on the market and a promising development pipeline. Genentech is very interested in moving forward studies with their IL-6 receptor antibody, toclizumab, in trastuzumab resistant breast cancer . Pat LoRusso at Karmanos Cancer Institute is the clinical lead for this study and Dr. Wicha’s laboratory plans to complete the correlative studies as they relate to CSCs. A new CSC trial is envisioned in an effort to overcoming trastuzumab resistance by blocking an inflammatory feedback loop using anti-IL6 antibody tocilizumab. Our recent paper published in Molecular Cell describes the pre-clinical studies which support this model. Based on this pre-clinical work, we are now working with Genentech to design a study using the IL6-R antibody tocilizumab to treat women with trastuzumab refractors HER2-positive breast cancer. We anticipate that this study will open next year.
OncoMed Pharmaceuticals was founded in August 2004, by Dr. Wicha and Dr. Michael F. Clarke who led the discovery of cancer stem cells, in solid tumors. Today OncoMed Pharmaceuticals is a biotechnology company dedicated to improving cancer treatment by developing monoclonal antibodies and other agents that target the biologic pathways critical to tumor initiating cells, also known as "cancer stem cells". OncoMed is leveraging its’ understanding of tumor initiating cells to discover and develop novel therapeutics that could provide important alternatives for the treatment of cancer. OncoMed has several clinical trials at the University of Michigan and elsewhere, using internally discovered and developed monoclonal antibodies including 2008.060 (OMP-21M18; DLL-4), 2010.106 (OMP-59; Notch 2/3) and 2011.041 (Frizzled). These antibodies each target pathways critical for cancer stem cells and will ultimately be tested in several common solid tumors. Additional details for these Phase I trials can be found at ClinicalTrials.gov. Dr. Wicha is a consultant for and holds equity in OncoMed Pharmaceuticals and formerly served on the Scientific Advisory Board.
Verastem, Inc., co-founded by Dr. Robert Weinberg, is a biopharmaceutical company focused on discovering and developing novel drugs that selectively target cancer stem cells. Cancer stem cells are an underlying cause of tumor recurrence and metastasis. Verastem is translating discoveries in cancer stem cell research into new medicines for the treatment of major cancers such as breast cancer. Verastem does not support Dr. Wicha’s pre-clinical CSC research; he currently serves as a member of Verastem’s Scientific Advisory Board.
Pfizer is committed to applying science and global resources to improve health and well-being at every stage of life. Pfizer has a leading portfolio of products and medicines that support wellness, prevention, treatment and cures for diseases across a broad range of therapeutic areas including cancer stem cells. In the past Pfizer has supplied various agents including their gamma secretase inhibitors for Dr. Wicha’s pre-clinical studies. Pfizer does not financially support Dr. Wicha’s research; he serves as a consultant for Pfizer.