Project 1 investigators, in collaboration with investigators across all Prostate Cancer Foundation-Stand Up 2 Cancer (PCF-SU2C) sites, led the study to develop a precision medicine framework for metastatic, castration-resistant prostate cancer (mCRPC) by obtaining a comprehensive landscape of cancer-related mutations in order to potentially incorporate this information for therapeutic strategies and/or enrolling subjects into appropriate clinical trials. The results of this study were recently published in Cell (Cell. 2015 May 21;161(5):1215-28).
Project 2 researchers enrolled 25 patients onto the cabozantinib (CABO) clinical trial and acquired CT-guided biopsies of bone metastases and validated multiple antibodies for Met, phospho-Met, Akt, and VEGFR2 and are currently validating phospho-VEGFR2. They continue to assess the efficacy of CABO in multiple prostate cancer cell lines and recently found that AR+ CRPC cell lines (VCaP, LNCaP and LNCaP-AR) do not express MET in the presence of active AR signaling, while AR- CRPC cell lines (DU145 and PC3) express high levels of MET. In vivo studies have been completed for subcutaneous xenografts in VCaP and LNCaP-AR models, where CABO showed modest but significant inhibition on tumor growth.
Project 3 investigators towards structure-based design and synthesis of highly potent and drug-like small-molecule inhibitors of BET bromodomain (BRD) proteins have resulted in a promising lead compound. They found that the candidate inhibitor, CF-53 targets cellular BRD4 proteins and potently and effectively inhibits AR and AR-ERG signaling pathway in AR+ prostate cancer cells. Preliminary data provide initial but promising evidence that CF-53 may have a promising therapeutic potential for the treatment of castration-resistance, AR+ prostate cancer.
Project 4 researchers led a number of studies evaluating prostate cancer-specific long non-coding RNAs (lncRNAs), PCAT-1 and SChLAP1 that promote prostate cancer progression. They recently published a study that implicated PCAT-1 in the regulation of cMyc in prostate cancer (Neoplasia. 2014 Nov 20;16(11):900-8). Earlier they reported that SChLAP1 expression is significantly prognostic for metastatic disease progression of prostate cancer. Recently, they showed that SChLAP1 could be detected non-invasively in urine which could be developed for clinical utility (Lancet Oncol. 2014 Dec;15(13):1469-80) and they developed a novel detection method, RNA in situ hybridization (ISH), to evaluate SChLAP1 in tissue specimens (Neoplasia. 2014 Dec;16(12):1121-7).
Advances in biomarker development: The University of Michigan Prostate SPORE has generated several advances in biomarker development during the current grant period through our SPORE-supported bench work. Two of the most notable are delineated below.
More than 1,000,000 men undergo prostate biopsy each year in the United States, most for "elevated" serum prostate-specific antigen (PSA). Given the lack of specificity and unclear mortality benefit of PSA testing, methods to individualize management of elevated PSA are needed. Greater than 50% of PSA-screened prostate cancers harbor fusions between the transmembrane protease, serine 2 (TMPRSS2) and v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) genes. We developed a clinical-grade, transcription-mediated amplification assay to risk stratify and detect prostate cancer noninvasively in urine. Translation of these discoveries has led to a partnership with Gen-Probe Inc., which has licensed the technology to develop the assay for clinical use. This test is now offered at the University of Michigan and is being CLIA -certified for broad use.
Dr. Cooney, in collaboration with Dr. William Isaacs from the Johns Hopkins SPORE, genotyped DNA samples from over 2500 men with and without prostate. Samples from this project were used in the identification of a novel rare mutation in HOXB13 detected in approximately 1% of all men with prostate cancer and 3% of men with early-onset and/or hereditary prostate cancer. It is anticipated that this mutation may be useful to facilitate the diagnosis of prostate cancer in a subset of men and studies are ongoing to confirm this hypothesis. In addition, a provisional application has been filed to develop this as a diagnostic test
Advances in treatment science: The University of Michigan Prostate SPORE has generated several clinical trials during the current grant period through our SPORE-supported bench work. Two of the most notable are delineated below.
Research in the Chinnaiyan laboratory revealed that PARP-1 is a downstream target of the ETS family and that inhibition of this pathway resulted in tumor inhibition in preclinical models. This has led to the development of a clinical trial NCI #9012 "A Randomized Gene Fusion Stratified Phase 2 Trial Of Abiraterone With Or Without ABT888 For Patients With Metastatic Castration-Resistant Prostate Cancer" with the primary objectives of 1) evaluating the role of ETS gene fusion as a predictive biomarker for response to hormone therapy (abiraterone) alone or hormone therapy plus PARP-1 targeted therapy (ABT-888) in patients with metastatic castration resistant prostate cancer and 2) evaluating whether the addition of PARP targeted therapy is superior to hormone therapy alone based on ETS gene fusion status. Maha Hussain is the PI of this trial and it will be performed by CTEP and the NO1 Phase II Clinical Trials Consortium.
Research in the Pienta laboratory led to the identification of the CCL-2 axis as a valid target for further development as a therapeutic in patients with bone metastases. Two clinical trials have been successfully completed. The first trial investigated the efficacy of CNTO888, an antibody to CCL2, in patients with castration resistant prostate cancer who had failed docetaxel. This multicenter trial with Dr. Pienta as the PI enrolled 47 subjects and is currently being analyzed. It represents successful vertical collaboration with a pharmaceutical company, Centocor. The second trial investigated the efficacy of MNL1202, an antibody to the receptor for CCL2, CCR2, in patients with bone metastases. This trial, with Dr. Pienta as the PI, enrolled 42 patients and was conducted in a vertical collaboration through SWOG and Millenium Pharmaceuticals. The data is currently being investigated but early analysis suggests that efficacy goals were reached. These clinical trials suggest that targeting tumor associated macrophages in the host microenvironment is a potentially valid therapeutic strategy that needs further exploration as a new paradigm for the treatment of prostate cancer and other solid tumors.
Effective use of Tissue Resources: The Tissue / Informatics Core has continued to maintain an extensive bank of prostate cancer tissues, serum , plasma, DNA and buffy coat and urine from 1092 needle biopsy specimens and 4260 specimens from radical prostatectomies, representing >300,000 total samples. The Core also has 4224 frozen and 5018 formalin-fixed tissue blocks from 60 patients with metastatic cancer obtained through our active Rapid Autopsy Program. Over 4000 samples have been shared with over 20 different investigators and institutions during this grant period. These tissue resources are all linked to clinical and pathologic databases containing outcomes data. The Prostate Cancer Biomedical Informatics Network (PCBIN, formerly Inter SPORE Prostate Biomarker Study (IPBS)), a consortium of 11 Prostate SPORE at various sites is engaged in the ongoing development and curation of databases and biorepositories to support translational prostate cancer research. Select de-identified clinical data elements corresponding to the procured specimen are uploaded into local caTISSUE Suite on a periodic basis. The data stored in caTISSUE databases can be accessed for analysis using caGRID portal by Prostate SPORE investigators. The merging of the clinical and pathologic databases by the Tissue / Informatics Core team to allow for the rapid analysis of biomarkers was a paradigm for the Prostate SPORE program and is now utilized by other SPORE institutions. The Tissue / Informatics Core was used as a model by UM to set up a University-wide Biospecimen Core that the SPORE hosts.
Establishment of the Michigan Oncology Sequencing Center: MI-ONCOSEQ: The clinical management of patients with cancer does not entail a "one size fits all" approach. In fact, studies of the genomic landscape of human cancers have demonstrated a multitude of genetic aberrations, a subset of which may be "actionable" with current drugs. Thus, the personalization of therapy for cancer will require molecular characterization of individual patients. Advances in next generation sequencing technology now raise the possibility of using sequencing in clinical oncology. This SPORE based Tissue / Informatics Core initiative, housed in the Michigan Center for Translational Pathology, is focused on using high-throughput sequencing to identify actionable or informative gene mutations in patients with advanced or refractory cancer. MI-ONCOSEQ integrates 3 major activities to accomplish personalized onco-medicine goals: 1) A "Clinical Genomic Study" will identify patients with advanced or refractory cancer who are eligible for clinical trials, consent them to the study, obtain biospecimens (tumor tissue, germline tissue), store clinical data, and assemble a multi-disciplinary Sequencing Tumor Board to deliberate on return of actionable or incidental genomic results; 2) "Sequencing & Analysis" will process biospecimens and perform integrative sequencing and analysis of tumors to identify and CLIA validate point mutations, copy number changes, rearrangements/gene fusions, and aberrant gene expression; 3) "Ethics & Psychosocial Analysis" will observe the Sequencing Tumor Board's process for deliberating on sequence results and the clinician and patient responses to results. Sequencing and analysis of patient samples and deliberation of results in STB have been initiated and are ongoing
Recruitment of Researchers to the Prostate Cancer Field: The University of Michigan is committed to the development of the next generation of clinical/translational researchers and recruitment of researchers of impact to the field of prostate cancer research remains a high priority. The last three years alone have seen the recruitment of Drs. Scott Tomlins (currently a Career Development investigator) and Rohit Mehra in Pathology, Drs. Alon Weizer, Todd Morgan (currently a Career Development investigator) and Ganesh Palapattu in Urology, Dr. Felix Feng in Radiation Oncology (currently a Career Development investigator) and Dr. Ajjai Alva in Medical Oncology. Past recruitments include Drs. Arul Chinnaiyan and Kathleen Cooney who both started as Career Development investigators and have established very successful careers in the field. In addition, pilot project awardees Shaomeng Wang, Ph.D., and Morand Piert, Ph.D. have been recruited as well as Will Roberts, M.D., who started as Career Development awardee. As evidenced here, the SPORE administration has been highly successful in, and continues to place a high value on the recruitment of new researchers to the field of prostate cancer.
Secured ARRA Supplement to Fund Summer Student Research Experience. The SPORE was successful in receiving an ARRA administrative supplement to support student employment in research labs during the summers of 2009 and 2010. This supplement created a fantastic opportunity to provide work experience to high school and undergraduate students and at the same time, accelerated the tempo of SPORE research. We funded a total of 24 student grants in seven laboratories over the two summers. This program was easily handled through our Developmental Research Program which has proven a successful process for soliciting, reviewing and selecting applications. Each student worked in the lab of a SPORE PI for approximately six to eight weeks and was supervised by senior lab investigators. This program was successful in at least three ways. First, it afforded another opportunity for collaboration across campus. Second, the students' work was of the highest quality and contributed towards progress in the laboratories, for example, by analyzing tumors at the end of experiments. Some of the student research work is being incorporated into manuscripts. Tristan Layfield, a 2010 summer grant recipient in the Dr. Mark Day lab, is a co-author on the paper, "Repression of Androgen Receptor Transcription through the E2F1/DNMT1 Axis." Finally, it provided an opportunity to attract young investigators to the field of prostate cancer research.
This program produced such tangible results that at the October 2010 Operating Committee meeting to discuss which DRP projects to fund for the 2010-2011 grant year, it was decided to fund three pilot projects and save the remaining $25,000 to fund student grants again during summer 2011.
Continued Success in Stimulating Research in Prostate Cancer through our Developmental Research Program (DRP): The DRP provides annual funding to support new research opportunities and collaboration. Funding for these projects is critical for sustaining a vigorous and robust research environment and for the continued success of the SPORE. The DRP remains a successful and valuable program. During this current grant cycle, we funded 16 pilot projects ($50K each), 4 seed grants ($10K each) and 35 summer student projects ($5K each). These DRP investigators succeeded in receiving over $4.2 million in subsequent peer-reviewed grant funding. The DRP has been a successful component of the Prostate SPORE since the program began in 1995. Since 1995, we have invested $3.5 million in our DRP funding a total of 83 investigators which has led to over $32 million in subsequent peer-reviewed funding and 114 published manuscripts.
Continued Success in Stimulating Career Development in Prostate: The Career Development Program (CDP) has sustained a long and successful track record of attracting new investigators to the field of prostate cancer research and helping launch them forward into successful careers. During the current period, CDP investigators have generated $2.1M in new grant monies. Since 1995, our CDP has invested $2.7 million in the program and supported 21 investigators. The CDP investigators have generated $13.7 million in subsequent grants over the same time period and produced 76 manuscripts. Six investigators have been supported to date during this grant cycle and they are each making significant contributions to the field of translational prostate cancer research. Currently we have two investigators whose projects end 11/30/12 and two investigators whose awards began 7/1/12. Present CDP investigators include Felix Feng, M.D., Nallasivam Palanisamy, Ph.D., Todd Morgan, M.D. and Scott Tomlins, M.D., Ph.D. Dr. Feng is an assistant professor of radiation oncology, who is investigating the ERG-PARP1 interaction axis as a modulator of radiation response and a potential radiosensitization target which may have a significant impact on future individualized therapy for ETS fusion-positive prostate cancer patients. Dr. Palanisamy is a research assistant professor at the Michigan Center for Translational Pathology (MCTP) and is studying the genetic basis of ETS negative prostate cancer as part of the emerging prostate cancer classification system. Dr. Morgan is a urologist focusing on isolating and characterizing circulating and disseminated tumor cells (CTCs/DTCs) present in men with early localized prostate cancer in order to understand the mechanisms of recurrence and metastasis following primary treatment. Dr. Tomlins, Assistant Professor of Pathology and Urology, is a physician scientist studying the molecular pathogenesis if prostate cancer with a focus on men who are diagnosed prior to age 55. Past awardees during this cycle include Sooryanarayana Varambally, Ph.D., a research associate professor with the Michigan Center for Translational Pathology (MCTP) and the department of pathology, and Steve (Zhaohui) Qin, Ph.D., currently an associate professor of biostatistics and bioinformatics at Emory University. Dr. Varambally studied small molecular inhibitors of EZH2 which would have a major impact on the treatment of metastatic prostate cancer disease. Dr. Varambally received an NIH R01 grant allowing his continued work on this project. Finally, Dr. Qin worked with Drs. Arul Chinnaiyan and Jindan Yu to develop an algorithm to facilitate improved analysis of ChIP-Seq data. Dr. Qin received an NIH R01 grant and is pursuing this work at Emory University.