Challenge Awards-Class of 2015

2015-2017 Movember Foundation-PCF Challenge Award ($1 Million)

Project Title: Targeting the MLL Complex for the Development of New Therapeutics for CRPC

Principal Investigator: Shaomeng Wang, PhD (University of Michigan) & Arul Chinnaiyan, MD, PhD (University of Michigan)

Co-investigators: Rohit Malik, PhD (University of Michigan), Angelo Anguilar, PhD (University of Michigan), Liu Liu, PhD (University of Michigan), Chao-Yie Yang, PhD (University of Michigan)

Description:

• The androgen receptor (AR) is the primary oncogenic driver of prostate cancer and a major therapeutic target. Patients ultimately develop resistance to AR-targeting therapies and progress to lethal castrate-resistant prostate cancer (CRPC).
• Often, CRPC is driven by the acquisition of genomic aberrations that confer continued activation of the AR pathway. Thus, new methods for targeting AR are necessary to treat this disease state.
• Dr. Wang, Dr. Chinnaiyan, and colleagues are studying the targeting of menin-MLL, a complex that interacts with and supports the oncogenic activities of AR. They found that blocking the interaction between menin and MLL disabled this complex from supporting AR and inhibited tumor growth. Better inhibitors and understanding of the mechanisms involved are needed for this class of compounds to become a viable treatment strategy.
• Highly potent and selective small molecule inhibitors of the menin-MLL interaction will be developed and tested for pharmacokinetic properties, toxicity, and anti-tumor efficacy in preclinical laboratory models in preparation for entry into clinical trials. In addition, the cellular effects of menin-MLL inhibitors will be studied in order to understand the mechanisms of action of menin-MLL inhibitors in prostate cancer.

What this means for patients:
Castrate-resistant prostate cancer (CRPC) is a lethal form of prostate cancer that arises when tumors develop resistance to hormonal therapies. Dr. Wang, Dr. Chinnaiyan and team are developing and testing new therapies to target the menin-MLL complex that regulates the activity of the androgen receptor (AR). If successful, this project will result in the generation of a new therapy that blocks AR activity in a novel way and will extend the lives of CRPC patients.

2015-2017 Movember Foundation-PCF Challenge Award ($1 Million)

Project Title: Integrative Genomics of Prostate Cancer Progression

Principal Investigator: Mark Rubin, MD (Weill Cornell Medical College), Scott Tomlins, MD, PhD (University of Michigan) & Ronglai Shen, PhD (MSKCC)

Co-investigators: Joanna Cyrta, MD (Weill Cornell Medical College)

Description:

• Cancer is a disease driven by the continued acquisition of genomic alterations that allow tumor cells to grow and divide abnormally, metastasize to other tissues, and develop resistance to therapies. Understanding the genomic alterations that confer each of these properties is critical for understanding disease evolution and designing optimal therapeutic strategies.
• Dr. Rubin and team are collecting archived primary prostate tumor samples from metastatic castration resistant prostate cancer (mCRPC) patients whose mCRPC tumor genomic and transcriptomic alterations have previously been characterized by the PCF-International Dream Team. Of the 500 patients assessed by the Dream Team, approximately 200 have primary tumor tissue available for this study.
• The genomes and transcriptomes of these ~200 primary tumor samples will be sequenced and compared with alterations in matched metastatic tumors from the same patient in order to identify molecular alterations that mediate drug resistance and progression to mCRPC in individual patients.
• Because of the continual acquisition of genomic mutations, tumors are heterogeneous and can be “multi-focal.” This results in multiple tumor clones with different disease potentials that arise independently. Multiple regions of the primary tumor will be analyzed by these methods in order to identify the tumor clone that ultimately results in mCRPC.

What this means for patients:
Despite significant progress made in characterizing the “genomic landscapes” of primary prostate cancer and metastatic castrate resistant prostate cancer (mCRPC), studies have not yet been performed to identify the molecular alterations that mediate progression from primary cancer to mCRPC in patients. Dr. Rubin and team will analyze matched primary tumor and metastatic castration resistant prostate cancer (mCRPC) specimens in order to identify these alterations. If successful, this project will identify molecular mediators and molecular pathways of prostate cancer progression that may serve as therapeutic targets and/or biomarkers that inform optimal therapies for individual patients.

2015-2017 Movember Foundation-PCF Challenge Award ($1 Million)

Project Title: Exploiting DNA Repair Vulnerabilities as a Precision Oncology Target in Metastatic Prostate Cancer

Principal Investigator: Peter Nelson, MD (University of Washington), Phillip Kantoff, MD (Harvard: Dana-Farber Cancer Institute) & Bruce Montgomery, MD (University of Washington)

Co-investigators: Heather Cheng, MD, PhD (University of Washington), Mary-Claire King, PhD (University of Washington), Eliezer Van Allen, MD, PhD (Harvard: Dana-Farber Cancer Institute), Ruth Etzioni, PhD (Fred Hutchinson Cancer Research Center), Colin Pritchard, MD, PhD (University of Washington)

Description:

• Inherited alterations in DNA-damage repair genes occur in ~8-10% of metastatic castrate resistant prostate cancer (mCRPC) patients, while another ~10-20% of mCRPC patients have tumors with acquired DNA-damage repair gene alterations. Alterations in these genes promote the development of aggressive prostate cancer but also serendipitously confer sensitivity to treatment with PARP-inhibitors and/or platinum chemotherapy (carboplatin).
• Dr. Nelson and team are identifying and characterizing DNA-damage repair gene alterations that occur in tumors from mCRPC patients.
• The genomes of mCPRC patients will be sequenced to identify inherited alterations in DNA-damage genes that promote prostate cancer and the frequency at which they occur.
• A Phase II clinical trial will be initiated to test the efficacy of docetaxel plus carboplatin in mCRPC patients harboring tumors with inherited or acquired biallelic inactivation of DNA repair genes.
• Inherited or tumor-acquired alterations identified in DNA repair genes with a previously unknown significance will be tested for sensitivity to PARP-inhibitors and platinum chemotherapy in laboratory models.
• Prostate cancer laboratory models that have been genetically engineered not to express the DNA-damage repair genes BRCA1, BRCA2 and ATM will be studied for sensitivity to carboplatin versus two different PARP inhibitors to guide the treatment of patients with similar alterations.
• Finally, methods will be developed to acquire and sequence the genomes of circulating tumor cells obtained from patient blood to create minimally invasive biomarker tests that can identify patients who have alterations in DNA damage repair pathways and should be considered for treatment with PARP inhibitors or platinum chemotherapy.

What this means for patients:
Precision medicine approaches for the treatment of prostate cancer patients require the identification of genomic alterations that confer sensitivity to specific treatments. Dr. Nelson and team are identifying and characterizing DNA-damage repair gene alterations that occur in ~20-30% of prostate tumors. If successful, this study will result in the development of biomarker tests that identify patients who should be treated with PARP inhibitors or platinum chemotherapy, and will enable population-based screening to identify individuals at increased risk for prostate cancer.

2015-2017 Movember Foundation-PCF Challenge Award ($1 Million)

Project Title: Altering the Natural History of Metastatic Prostate Cancer using Stereotactic Ablative Radiotherapy and Immune Stimulation

Principal Investigator: Phuoc Tran, MD, PhD (Johns Hopkins University), Adam Dicker, MD, PhD (Thomas Jefferson University), Charles Drake, MD, PhD (Johns Hopkins University), Kenneth Pienta, MD (Johns Hopkins University), Martin Pomper, MD, PhD (Johns Hopkins University), Theodore DeWeese, MD (Johns Hopkins University), & Mario Eisenberger, MD (Johns Hopkins University)

Co-investigators: Ashley Ross, MD, PhD (Johns Hopkins University), Hao Wang, PhD (Johns Hopkins University), Max Diehn, MD, PhD (Stanford University)

Description:

• Oligometastatic prostate cancer is a disease state in which only a few detectable metastatic lesions have developed in a treatment-naïve patient. Local treatment of the primary tumor and metastatic sites in combination with chemotherapy has resulted in long term survival benefits in patients with colorectal cancer and sarcomas. It is unknown if prostate cancer patients would benefit from a similar approach.
• Dr. Tran and team are studying the efficacy of treating prostate cancer patients who have 5 or fewer metastatic lesions with stereotactic ablative radiation (SABR), a radiation therapy regimen that delivers a highly focused, localized, high-dose of radiation in a hypofractionated protocol that is designed to minimize toxicity.
• A NCI-sponsored Phase II clinical trial testing the efficacy of administering SABR to all sites of disease in oligometastatic prostate cancer patients is being initiated.
• Radiation therapy is thought to stimulate the immune system by releasing tumor antigens that activate anti-tumor T cell responses. In additional Phase I and Phase II trials, the combination of SABR with a prostate cancer vaccine will be tested in oligometastatic prostate cancer patients for potential therapeutic synergy. The vaccine, ADXS-PSA, consists of a live, attenuated strain of Listeria monocytogenes that expresses a prostate tumor-associated protein (PSA) and generates robust anti-tumor immune responses in preclinical prostate cancer models.
• In these trials, circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) will be collected from patient blood and quantified at various time points before, during and after therapy to determine whether any of these measurements can serve as predictive biomarkers of patient outcome.
• To determine if these treatment regimens reflect anti-tumor immunity in the T cell population, the TCR gene will be sequenced from peripheral blood immune cells collected from these patients. The TCR gene encodes the protein that T cells use to identify targets and is unique to each T cell clone.

What this means for patients:
Oligometastatic prostate cancer may still represent a curable state of advanced prostate cancer if effective treatments can be developed. Dr. Tran and team are studying the effects of using stereotactic ablative radiation (SABR) with or without immunotherapy and developing non-invasive methods of disease monitoring. If successful, this project will lead to a new treatment regimen that extends the lives of oligometastatic prostate cancer patients.

2015-2017 Movember Foundation-PCF Challenge Award ($1 Million)

Project Title: CARAVAN: Checkpoint-Radiation-Vaccine Neoadjuvant Trial for Metastatic Prostate Cancer

Principal Investigator: Adam Dicker, MD, PhD (Thomas Jefferson University) & Lawrence Fong, MD (University of California – San Francisco)

Co-investigators: James Hodge, PhD, MBA (National Cancer Institute), Leonard Gomella, MD (Thomas Jefferson University), Jonathan Mann, MD (Thomas Jefferson University), Jean Hoffman-Censits, MD (Thomas Jefferson University), Albert Chang, MD, PhD (University of California – San Francisco), W. Kevin Kelly, DO (Thomas Jefferson University), Benjamin Leiby, PhD (Thomas Jefferson University), Nicola Mason, DVM, PhD (University of Pennsylvania), Ulrich Rodeck, MD, PhD (Thomas Jefferson University), Ruth Birbe, MD (Thomas Jefferson University)

Description:

• Radiation therapy (RT) or radical prostatectomy are the primary treatment strategies for men diagnosed with locally advanced prostate cancer. However, even with the addition of androgen deprivation (ADT) therapy, many patients experience recurrences and progress to lethal disease. Other therapeutic strategies are needed to extend the lives of these patients. .
• Drs. Dicker, Fong and team are investigating whether the addition of neoadjuvant immunotherapy regimens to RT will improve patient outcomes.
• A Phase I clinical trial (CARAVAN) will be initiated to test the addition of a combination of immunotherapies to RT prior to radical prostatectomy in prostate cancer patients with locally advanced disease. The immunotherapy combination consists of intratumoral injection of Pembrolizumab and Ipilimumab, and infusional administration of ADXS-PSA, a prostate cancer vaccine that activates immune responses against the PSA protein that is expressed by prostate cancer cells.
• Once the maximum tolerated immunotherapy combination with RT has been determined, a Phase II clinical trial will be initiated to test the efficacy of that regimen in men with oligometastatic prostate cancer (early metastatic prostate cancer where 5 or less metastatic lesions are present). Immune responses induced by this therapeutic combination will be assessed by comparing immune populations and the T cell repertoire present in blood and tumor specimens before vs. after treatment.
• Exosomes are microvesicles that are shed from various cell types including tumor and immune cells and contain proteins, DNA, and RNA. The molecular components of tumor and immune cell-secreted exosomes obtained from patient peripheral blood will be assessed to determine if they can serve as biomarkers of immune responses and/or clinical outcomes.

What this means for patients:
Immunotherapy may hold the potential to cure men with locally advanced prostate cancer and may synergize with radiation therapy (RT). Drs. Dicker, Fong and team are testing whether the addition of a combination immunotherapy regimen to neoadjuvant RT prior to radical prostatectomy will improve patient outcomes. If successful, this project will lead to a new therapeutic strategy for treating prostate cancer as well as biomarkers to identify men who should receive this treatment.

2015-2017 Movember Foundation-PCF Challenge Award ($1 Million)

Project Title: Targeting Aberrant AR-FL and AR-V Expression and Activity to Overcome Therapy Resistance in Metastatic Castration-Resistant Prostate Cancer

Principal Investigator: Haojie Huang, PhD (Mayo Clinic), Manish Kohli, MD (Mayo Clinic), Scott Dehm, PhD (University of Minnesota), Martin Gleave, MD (Vancouver Prostate Centre)

Co-investigators: Liewei Wang, MD (Mayo Clinic), Paul Rennie, PhD (Vancouver Prostate Centre), Liguo Wang, PhD (Mayo Clinic),

Description:

• The androgen receptor (AR) is a transcription factor that is activated by androgens and turns on expression of the growth and survival genes that drive prostate cancer.
  Therapies have been developed that target the activation of AR by androgens. However tumors commonly acquire therapeutic resistance by increasing the production of AR or androgens, by acquiring mutations in AR, or by producing alternate forms of AR (AR-variants) that do not rely on androgens to become activated. New strategies are needed to target AR in order to prevent therapeutic resistance and disease progression.
• Dr. Huang and team are studying a novel therapeutic paradigm in which the expression, DNA binding activity, and transcriptional activation of AR are simultaneously targeted to avoid treatment resistance and the development of castrate resistant prostate cancer (CRPC).
• The enhancer mRNA sequence of the PSA gene (PSA eRNA) is regulated by AR and controls the expression of a number of other AR-regulated genes by modulating the AR transcriptional complex. Whether expression of the PSA eRNA is associated with resistance to abiraterone acetate will be examined in metastatic tumor biopsies from CRPC patients enrolled in a clinical trial.
• The effect of targeting the PSA eRNA as a therapeutic strategy will be tested in CRPC preclinical laboratory models.
• Finally, the effect of co-targeting the expression, DNA binding activity, and transcriptional activation of AR will be tested in enzalutamide-resistant prostate cancer models. Small molecules that target the ability of AR to bind to DNA will be combined with molecules that target the PSA eRNA to block induction of genes by AR. In a second strategy, molecules that target both AR and AR-variants will be combined with deleting a major transcriptional control region of the PSA eRNA.

What this means for patients:
Resistance to androgen receptor (AR) targeting therapies are common and can result in drug resistance and progression to lethal castration resistant prostate cancer (CRPC). Dr. Huang and team are studying a new mechanism of targeting AR activity and determining whether combining this strategy with agents that target other aspects of AR activity will result in a more effective therapy. If successful, this project will result in a new, more potent therapy for the treatment of medically-resistant prostate cancer.

2015 PCF Challenge Award ($700,000)

Project Title: Metabolic Reprogramming in Prostate Cancer Therapy

Principal Investigator: : Dario Altieri, MD (The Wistar Institute)

Co-investigators: Lucia Languino, PhD (Thomas Jefferson University), Dmitry Gabrilovich, MD, PhD (The Wistar Institute), Maria Caino, PhD (The Wistar Institute)

Description:

• One hallmark of virtually all cancers, is a global reprogramming of metabolism. Metabolic changes may drive disease progression and metabolic factors may serve as therapeutic targets.
• Dr. Altieri and team are studying how metabolic changes affect tumor cell metastasis and are testing novel methods to target tumor cell metabolism for the treatment of prostate cancer.
• Mitochondria are the energy generating factories of the cell. The effect of targeting mitochondria on prostate cancer metastasis will be tested by treatment of preclinical prostate cancer models with molecules that block essential mitochondrial proteins.
• The potential for achieving therapeutic synergy by targeting mitochondria and the oncogenic PI3K pathway will be tested by combining mitochondrial-inhibitors with PI3K pathway-inhibitors in preclinical laboratory models.
• Mitochondria can be repositioned within the cell and the location of mitochondria is hypothesized to affect cellular functions. Whether the repositioning of mitochondria influences tumor cell metastasis will be tested in prostate cancer cell lines. Targeting mitochondrial repositioning in combination with targeting of integrin proteins that regulate metastasis by controlling cell-cell and cell-extracellular matrix interactions will be studied for potential therapeutic synergy.
• Finally, whether targeting mitochondrial metabolism can reverse resistance to anti-androgen therapy will be explored.

What this means for patients:
Tumor cells have highly altered metabolism indicating that targeting various aspects of metabolism may block tumor cell growth. Dr. Altieri and team are studying the role of metabolic alterations in tumor metastasis and testing novel methods to target aspects of metabolism in single and combination therapeutic strategies. If successful, this project will lead to new therapies to treat and prevent metastatic prostate cancer.

2015 PCF Challenge Award ($1 Million)

Project Title: Testing Targeted NK (TaNK) cell Therapy in Prostate Cancer

Principal Investigator: Ganesh Palapattu, MD (University of Michigan), Karen Knudsen, PhD (Thomas Jefferson University), David Smith, MD (University of Michigan)

Co-investigators: Philip Boonstra, PhD (University of Michigan), Felix Feng, MD (University of Michigan), Hans Klingemann, MD, PhD (Conkwest, Inc.), Bruce Redman, DO (University of Michigan), Rohit Mehra, MD (University of Michigan), William Kelly, MD (Thomas Jefferson University), Jean Hoffman-Censits, MD (Thomas Jefferson University)

Description:

• Cellular immunotherapy for cancer has focused on harnessing the significant target cell-killing abilities of T cells. T cells can be uploaded with chimeric antigen receptors (CARs), which are engineered molecules that equip T cells with the ability to specifically recognize tumor antigens and kill tumor cells. CAR T cells have shown great promise against lymphomas and are being tested in many solid tumors including prostate cancer.
• Natural killer (NK) cells have target cell-killing capabilities equivalent to T cells but have not been explored in cellular immunotherapy approaches.
• Dr. Palapattu and team are studying a novel prostate cancer immunotherapy approach in which NK cells are equipped with prostate-tumor recognizing CAR molecules.
• An NK cell line (NK-92) that maintains an activated state will be engineered to express a CAR molecule that recognizes the PSMA protein which is expressed specifically by prostate cancer cells. This cell line can be safely administered to patients “off-the shelf” instead of needing to manufacture cells uniquely for each patient as is necessary for cellular immunotherapy regimens utilizing T cells in order to avoid potential autoimmune complications.
• The efficacy of PSMA-CAR expressing NK cells will be tested in preclinical models of androgen-sensitive and anti-androgen therapy-resistant prostate cancer.
• A Phase I clinical trial testing the safety and efficacy of PSMA-CAR expressing NK cells in prostate cancer patients will be initiated. Whether PSMA-CAR expressing NK cells can activate other aspects of the immune system against tumors or against the NK cells will be evaluated in patients.

What this means for patients:
NK cells have been implicated in mediating natural anti-tumor immune responses, however NK cells have not been studied in cancer immunotherapeutic approaches. Dr. Palapattu and team will create and test the preclinical and clinical efficacy of NK cells engineered to express a “CAR” molecule that directs them to target and kill prostate tumor cells. If successful, this project will lead to a novel and powerful immunotherapeutic approach to treat prostate cancer.

2015-2017 PCF Challenge Award ($1 Million)

Project Title: T-cell Receptor Gene Therapy for Treatment of Lethal Prostate Cancer

Principal Investigator: David Baltimore, PhD (California Institute of Technology)

Co-investigators: Owen Witte, MD (University of California, Los Angeles), Lili Yang, PhD (University of California, Los Angeles), Michael Bethune, PhD (California Institute of Technology)

Description:

• Immunotherapy has resulted in long term, potentially curative responses in some patients with melanoma and other solid tumors, and with further development, holds much promise for the treatment of prostate cancer.
• Dr. Baltimore and team are studying how T-cells recognize prostate tumor cells in order create a T-cell gene therapy that has the potential to eliminate prostate cancer.
• T-cell receptors (TCR) are unique genes that are genetically different in every individual T-cell, and allow each T-cell to recognize a different protein antigen. Recognition of these antigens – usually uniquely expressed by pathogen infected-cells or other dangerous cells such as tumor cells, allows the T-cell to become activated and kill the target cell.
• T-cells that infiltrate prostate tumors will be studied in order to identify the sequences of T-cell receptor (TCR) genes that recognize prostate tumors and the tumor antigens that they recognize.
• The sequences of these TCRs will be used to make a gene therapy in which a patient’s T-cells are genetically modified with prostate tumor-targeting TCR genes. The activity and delivery of this therapy will be optimized using in vitro assays and mouse tumor models to evaluate the potential therapeutic efficacy of this immunotherapy approach.

What this means for patients:
Immunotherapy has demonstrated powerful effects in some patients with melanoma and other cancers, but needs further development in prostate cancer. If successful, this project will create a platform for a novel TCR gene therapy for the treatment of lethal prostate cancer that will lead to new clinical trials.

2015-2017 PCF Challenge Award ($1 Million)

Project Title: Optimizing First Line Treatment for Men with Castrate Resistant Prostate Cancer

Principal Investigator: William Kevin Kelly, DO (Thomas Jefferson University)

Co-investigators: Karen Knudsen, PhD (Thomas Jefferson University), Robert Den, MD (Thomas Jefferson University), Susan Slovin, MD, PhD (Memorial Sloan Kettering Cancer Center), Susan Halabi, PhD (Duke University), Ruth Birbe, MD (Thomas Jefferson University), Benjamin Leiby, PhD (Thomas Jefferson University)

Description:

• Determining whether an individual patient will benefit from a therapy is critical for extending patient lives and reducing unnecessary morbidities from ineffective treatments.
• Dr. Kelly and team will examine the utility of the retinoblastoma (RB) gene as a biomarker to determine if CRPC patients would benefit from receiving abiraterone vs. chemotherapy.
• Tumors that have lost the RB gene are hypothesized to be resistant to AR-targeting therapies but be more sensitive to chemotherapy. Conversely, treatments that activate RB, such as CDK4/6 inhibitors, are hypothesized to enhance the sensitivity of RB-expressing tumors to AR-targeting therapies.
• The response of patients in two clinical trials that stratify men to receive treatments based on whether or not their tumors have retained or lost the RB gene, will be examined. These trials will test abiraterone vs. abiraterone + cabazitaxel chemotherapy or abiraterone vs. abiraterone + a CDK4/6 inhibitor (LEE-001).
• The expression of RB and RB-pathway genes as well as AR-variants which may promote abiraterone-resistance will be correlated to clinical outcome in these trials. Whether or not RB, AR-variants or other genes mediate therapeutic resistance will be determined by examining gene expression and genomic mutations in tumor samples at the time of progression.
• Finally, data from several clinical trials will be examined to identify characteristics of patients that respond better to chemotherapy and to develop models that predict the optimal number of chemotherapy cycles for maximal benefit.

What this means for patients:
Identifying biomarkers that match patients with optimal therapies is a critical need. If successful, this project will identify biomarkers that predict whether a CRPC patient will be more likely to benefit from abiraterone vs. chemotherapy and will develop models that predict the optimal duration of chemotherapy administration. This will enable clinicians to optimally treat CRPC patients to maximize benefit and minimize unnecessary morbidities.

2015-2017 PCF Challenge Award ($1 Million)

Project Title: Optimizing the Use of Taxane Chemotherapy in Prostate Cancer

Principal Investigator: Hing Leung, MD, PhD (Cancer Research UK Beatson Institute)

Co-investigators: Eyal Gottlieb, PhD (Cancer Research UK Beatson Institute), Owen Sansom, PhD (Cancer Research UK Beatson Institute), Rob Jones, PhD (University of Glasgow and Beatson West of Scotland Cancer Centre), Emma Shanks, PhD (Cancer Research UK Beatson Institute), Gabriela Kalna, PhD (Cancer Research UK Beatson Institute), Prabhakar Rajan, MD, PhD (Cancer Research UK Beatson Institute), Rachana Patel, PhD (Cancer Research UK Beatson Institute)

Description:

• Developing methods to match patients with treatments that will most benefit them is a critical goal in prostate cancer patient care.
• Dr. Leung and team are studying prostate cancer patients treated with docetaxel chemotherapy in order to identify biomarkers that predict which patients will most benefit from chemotherapy and determine mechanisms of chemotherapy resistance.
• Gene expression and genomic mutations will be examined in tumor tissues from patients who were treated with docetaxel in the STAMPEDE clinical trial. Genes associated with good vs. poor outcome will be identified to develop a prognostic biomarker panel that predicts chemotherapy sensitivity and de novo chemotherapy resistance.
• In addition, the contribution of metabolic alterations to chemotherapy resistance will be examined by analyzing the metabolic profiles of prostate cancer cells and the effect of knocking down metabolic genes on the sensitivity of prostate cancer cells and tumors to docetaxel in preclinical models. Genes that enhance the death of prostate cancer cells when combined with docetaxel represent promising targets for the development of therapies that will synergize with chemotherapy.

What this means for patients:
Determining whether patients will benefit from chemotherapy is critical for devising optimal treatment strategies. If successful, this project will identify biomarkers that predict chemotherapy sensitivity and identify novel therapeutic targets for preventing chemo-resistance and achieving therapeutic synergy when combined with chemotherapy.

2015-2017 Distinguished Gentleman’s Ride – PCF Challenge Award ($500,000)

Project Title: MEK Inhibition as a Treatment for Metastatic Castrate Resistant Prostate Cancer

Principal Investigator: Matthew Rettig, MD (University of California, Los Angeles)

Co-investigators: Nicholas Nickols, MD, PhD (University of California, Los Angeles), Hong Wu, MD, PhD (Peking University), Robert Reiter, MD, MBA (University of California, Los Angeles), Jiaoti Huang, MD, PhD (University of California, Los Angeles), Ted Goldstein, PhD (University of California, Santa Cruz), Robert Baertsch, PhD (University of California, Santa Cruz), Nicholas Reese, MD (University of California, Los Angeles), David Elashoff, PhD (University of California, Los Angeles)

Description:

• Developing effective treatments for patients with metastatic castrate resistant prostate cancer (mCRPC) remains a critical unmet need as these patients have few to no remaining treatment options. Recent studies have found that the MAPK pathway is highly activated in some mCRPC tumors and correlates with worse disease outcomes. This suggests that the MAPK pathway may be an oncogenic driver of mCRPC and therefore a potential therapeutic target.
• Dr. Rettig and team are studying the effect of targeting the MAPK pathway in patients with mCRPC.
• In an off-label usage, an mCRPC patient who previously failed treatment with ADT, abiraterone, enzalutamide, Sipuleucel-T, and Radium-223, exhibited a marked response to Trametinib, an inhibitor of the critical MAPK pathway member MEK, with a >90% reduction in PSA for over 20 weeks.
• A phase II clinical trial will be conducted to test the efficacy of Tremetinib in patients with mCRPC who have failed treatment with enzalutamide or abiraterone.
• To validate the ability of Trametinib to inhibit MEK activity in patients, biopsies of tumors obtained pre- and post-treatment will be examined for changes in the activation status of ERK, a phosphorylation target of activated MEK. Whether Trametinib inhibits the expression of genes controlled by the MAPK pathway will also be examined.
• Genomic and gene expression analyses will be performed on the tumor biopsy samples in order to identify mechanisms of response or resistance to Trametinib. Specifically, the team will analyze mutations in MAPK genes and the activation status of the androgen receptor (AR) for any relationship with Trametinib responsiveness.

What this means for patients:
The MAPK pathway regulates growth and survival genes and may drive the progression of mCRPC. Dr. Rettig and team are studying the efficacy of inhibiting the MAPK pathway with Trametinib in mCRPC patients and the mechanisms that regulate treatment responsiveness. If successful, this project will lead to a new therapy for the treatment of highly aggressive treatment-refractory metastatic prostate cancer.

2015 Kelsey Dickson Team Science Courage Research Award ($500,000)

Principal Investigator: Paul Nghiem, MD, PhD (University of Washington), Peter Nelson, MD (University of Washington)

Proposal Title: Therapeutic Strategies Exploiting Synergies in Merkel Cell Carcinoma and Neuroendocrine Prostate Cancer: Targeting Immune Responses and Intrinsic Signaling Programs

• Studying mechanisms of different cancer types may reveal biology and treatments strategies that can be applied to other cancer types.
• Dr. Nghiem and team are studying the parallels between Merkel cell carcinoma (MCC), a highly aggressive neuroendocrine skin cancer, and the aggressive neuroendocrine subtype of prostate cancer (NEPC).
• Anti-tumor immune responses are critical to the survival of patients with MCC. This study will examine the mechanisms of response and resistance to immune-based therapeutics in MCC and determine if prognostic/predictive MCC immune markers are informative in NEPC
• A subset of MCC tumors contain mutations in the tumor suppressor genes RB1 and TP53, which are also associated with NEPC. Aberrations in other key oncogenes may also occur in both tumor types.
• This study will evaluate responses in preclinical models of MCC and NEPC to inhibitors of key oncogenic pathways altered in at least one of the tumor types to identify pathways that should be prioritized for clinical trials.
• Finally, deep molecular characterization of the genomic, gene expression and epigenomic landscapes of NEPC and MCC will be performed to define commonalities that may be viable therapeutic targets in these neuroendocrine tumors.

What this means for patients:
First-in-field study to compare two tumor types to find novel therapeutic targets. The study of Merkel cell carcinoma (MCC), a neuroendocrine skin cancer, may reveal biology and treatment strategies for neuroendocrine prostate cancer (NEPC) and vice versa. Dr. Nghiem and team will compare the biology and therapeutic responsiveness of MCC and NEPC. If successful, this project will identify shared mechanisms and treatment strategies for these aggressive cancer types.