Challenge Awards-Class of 2014

Movember-PCF Challenge Award ($1 Million)

Project Title: Periprostatic adipose inflammation: A targetable mediator of prostate cancer progression

Principal Investigator: Andrew Dannenberg, MD (Weill Cornell Medical College)

Co-investigators: Kotha Subbaramaiah, PhD (Weill Cornell Medical College), Xi Kathy Zhou, PhD (Weill Cornell Medical College), Howard Scher, MD (Memorial Sloan Kettering Cancer Center), Peter Scardino, MD (Memorial Sloan Kettering Cancer Center), James Eastham, MD (Memorial Sloan Kettering Cancer Center), Clifford Hudis, MD (Memorial Sloan Kettering Cancer Center), Lee Jones, PhD (Memorial Sloan Kettering Cancer Center), Ayca Gucalp, MD (Memorial Sloan Kettering Cancer Center), Neil Iyengar, MD (Memorial Sloan Kettering Cancer Center), Dilip Giri, MD (Memorial Sloan Kettering Cancer Center).

Description:

• Obesity is a risk factor for the development and progression of prostate cancer and obese patients develop more aggressive disease with poorer survival. The role of obesity in promoting cancer is largely through aberrant interactions with the immune system. Interactions with adipose (fat) cells cause immune cells to become chronically activated and produce molecules that promote tumor progression and growth. Understanding the biology by which obesity and chronic inflammation cooperate to promote prostate cancer will lead to new treatment strategies for patients.
• Dr. Andrew Dannenberg and team have observed that prostate cancer patients have inflammation in the fat tissue surrounding their prostates. They have observed a phenomenon termed “crown-like structures” (CLS) in which phagocytic immune cells surround dying fat cells and produce tumor-promoting molecules. CLS are linked to more aggressive disease in breast cancer patients. Using tissues from men who have undergone radical prostatectomies, whether CLS are linked to tumor aggressiveness and chronic inflammation in prostate cancer patients will be determined. Metabolites from blood samples from patients will be profiled to generate a prognostic tool that indicates the presence of CLS in prostate fat tissues.
• Whether a patient’s body mass index (BMI), level of exercise, and medication use associate with the presence of CLS will be determined. Finally, a clinical trial testing the impact of aerobic exercise on the presence of CLS in prostate cancer patients will be conducted.
• These studies will determine whether CLS are a mechanism by which obesity and chronic inflammation cooperate to promote prostate cancer, and lead to new treatment strategies for obese prostate cancer patients.

What this means for patients:
Obesity is a major cause of chronic inflammation which promotes the development and progression of malignancies. This project will explore the role of a distinct fat cell-immune cell interaction in prostate cancer progression, develop prognostic tools that predict these interactions, and explore the effect of exercise and lifestyle activities on this phenomenon. These discoveries will contribute to the knowledge of how obesity and inflammation promote prostate cancer, and lead to treatment strategies and lifestyle changes that prevent prostate cancer progression.

Movember-PCF Challenge Award ($1.5 Million)

Project Title: Targeted Niche Therapy (TNT) to cure metastatic Prostate Cancer

Principal Investigator: Kenneth Pienta, MD (Johns Hopkins University School of Medicine)

Co-investigators: Rick Jones, MD (Johns Hopkins University School of Medicine), Bruce Trock, PhD (Johns Hopkins University School of Medicine), Russell Taichman, DMD (University of Michigan), Michael Schweizer, MD (Johns Hopkins University School of Medicine)

Description:

• Metastasis of prostate cancer to the bone is the primary cause of prostate cancer mortality. The discovery of new therapies that target prostate cancer in bone is critical for obtaining cures for patients.
• Dr. Kenneth Pienta and team propose a bold strategy for the elimination of prostate cancer in bone. They plan to treat patients with a medication that will release tumor cells from the bone followed by systemic chemotherapy to kill the now loose and trafficking tumor cells.
• To determine if prostate cancer cells can be forced out of the bone, patients will be treated with a medication named AMD3100, an inhibitor of the CXCR4 protein which is thought to cause tumor cells to adhere to bone marrow, followed by docetaxel chemotherapy. The numbers and features of tumor cells that exit the bone and enter the circulation will be investigated from patient blood specimens.

What this means for patients: Bone metastasis leads to significant morbidity and can cause mortality of prostate cancer patients. This project will test a new paradigm – that drugs can be used to force prostate cancer cells out of the bone and into the circulation making them targetable by systemic chemotherapy. If successful, this project will lead to a new and novel treatment method for bone-metastatic prostate cancer.

Movember-PCF Challenge Award ($1.5 Million)

Project Title: PD-1 Blockade with T-Cell Activating Therapy to Treat Metastatic Prostate Cancer

Principal Investigator: Douglas McNeel, MD, PhD (University of Wisconsin)

Co-investigators: Glenn Liu, MD, Robert Jeraj, PhD, Brian Olson, PhD (University of Wisconsin), Laura Johnson, PhD (University of Wisconsin)

Description:

• Therapies that use the body’s immune system to attack cancer cells have demonstrated significant life-prolongation for melanoma, lung cancer and bladder cancer patients but are less active in treating prostate cancer in clinical trials to date. Combining immunotherapies might improve the efficacy of this treatment strategy for prostate cancer.
• Dr. McNeel and colleagues are testing a novel combination prostate cancer immunotherapy in clinical trials that combines a T-cell re-activating therapy (anti-PD1), with a vaccine against a prostate cancer target, Prostatic Acid Phosphatase (PAP). The vaccine will increase the number of tumor killing-T cells, while anti-PD1 therapy acts to “take the foot off the brakes” of the immune response. The combination therapy is hoped to increase the ability of T cells to target and kill tumor cells expressing PAP.
• Dr. McNeel and team will evaluate the effect of the dual immunotherapy on tumor and immune responses in patients with metastatic castration-resistant prostate cancer (mCRPC). They will determine: (1)the safety and efficacy of the therapy; (2) mechanisms of therapeutic synergy; (3) whether expression of PD1 or its molecular partner, PD-L1, can be used as biomarkers that predict therapeutic response; and (4) the utility of a new molecular imaging technique, quantitative total bone imaging, in monitoring the treatment effect of this novel immunotherapy combination.

What this means for patients: Immunotherapies have led to deep and durable tumor responses in melanoma and other cancers but have failed to date to demonstrate a significant survival benefit for patients with mCRPC. If successful, this project will result in the generation of a powerful new immunotherapy treatment for patients with advanced prostate cancer, develop biomarkers that predict therapeutic response, and create a new molecular imaging technique to monitor patient response to many prostate cancer therapies.

Movember-PCF Challenge Award ($1 Million)

Project Title: Use of Selective GR Antagonists in Castration-resistant Prostate Cancer

Principal Investigator: Suzanne Conzen, MD (University of Chicago)

Co-investigators: Geoffrey Greene, PhD, Walter Stadler, MD, Russell Szmulewitz, MD, Diana West, PhD (University of Chicago)

Description:

• The androgen receptor (AR) is the primary driver of prostate cancer progression and survival and is a successful therapeutic target of many new life-prolonging treatments. However, tumors inevitably develop resistance to AR-targeting therapies and progress to lethal castrate-resistant prostate cancer (CRPC).
• Increased activity of the glucocorticoid receptor (GR), a protein relative of AR, acts as a mechanism of AR-targeted drug-resistance in some patients by turning on expression of many of the same tumorigenic genes which rescue tumor cells from the loss of AR function.
• Dr. Conzen and team will determine the efficacy and mechanisms by which several new GR-targeting agents act in combination with AR-targeting therapies to kill prostate cancer cells.
• Dr. Conzen has initiated clinical trials in CRPC patients to evaluate therapeutic synergy between AR and GR-targeting drugs (enzalutamide and mifepristone, respectively). Using circulating tumor cells from these patients, her team will evaluate whether inhibition of GR activity by mifepristone therapy will predict a therapeutic response in AR-targeted treatment-resistant patients.

What this means for patients: Castrate-resistant prostate cancer (CRPC) is often a lethal disease state in which tumors have developed resistance to AR-targeting therapies. If successful, this project will generate new drugs that inhibit a major mechanism of AR-drug resistance and leverage knowledge of how these drugs work to develop clinical biomarkers of therapeutic response.

Movember-PCF Challenge Award ($1 Million)

Project Title: The Novel CYP17 Lyase Inhibitor VT-464 for Patients with Advanced Prostate Cancer Resistant to Enzalutamide: Use of Predictive Biomarkers during Drug Development Process Is Essential for Improved Patient Management and Time to Drug Approval

Principal Investigator: Howard Scher, MD (Memorial Sloan Kettering Cancer Center)

Co-investigators: Elahe Mostaghel, MD, PhD (Fred Hutchinson Cancer Research Center), Mary-Ellen Taplin, MD (Harvard: Dana-Farber Cancer Institute), Richard Bambury, MD (Memorial Sloan Kettering Cancer Center) , Rana McKay, MD (Harvard: Dana-Farber Cancer Institute), Robert Montgomery, MD (University of Washington: School of Medicine).

Description:

• The recent addition of 5 new life-prolonging therapies to the treatment armament against castrate-resistant prostate cancer (CRPC) raises the bar for new agents entering the clinic in this therapeutic setting. Clinical trial design to demonstrate survival advantage, as mandated by the FDA, is confounded by crossover to many newly approved agents that alone prolong survival. Predictive biomarkers of treatment response are needed to create new efficacy endpoints for clinical trials and to more accurately select patients that will benefit.
• Dr. Howard Scher and team are developing a new clinical trials paradigm that will concurrently test the efficacy of new agents alongside the development of biomarkers predictive of response. These companion biomarkers will enable subsequent clinical trials with these agents to target patients most likely to benefit.
• The drug to be tested in this proof-of-principle clinical trials design schema is VT-464, which inhibits Cyp17, an enzyme involved in generating the androgens that fuel prostate cancer. VT-464 will be tested in CRPC patients progressing on enzalutamide, another androgen-axis inhibitor, which acts by an entirely different mechanism and may be synergistic with VT-464.
• Potential predictive biomarkers of response will be tested and validated in prostate cancer patients and further evaluated for their biological relevance in animal models. Biomarkers to be evaluated include tumor mutations associated with androgen axis drug-resistance mechanisms and changes in the numbers of (circulating) tumor cells measured in a patient’s blood.

What this means for patients: As more new drugs enter clinical trials and clinical practice, it is imperative to match patients with the most beneficial treatments available. If successful, this project will develop a new clinical trials paradigm that will speed the development of new drugs and create companion biomarkers that predict response. This will enable targeted patient accrual into subsequent clinical trials and the matching of patients to optimal therapies.

Movember-PCF Challenge Award ($1.4 Million)

Project Title: Development of Circulating Molecular Predictors of Chemotherapy and Novel Hormonal Therapy Benefit in Men with Metastatic Castration Resistant Prostate Cancer (mCRPC)

Principal Investigator: Andrew Armstrong, MD, MSc (Duke University)

Co-investigators: David Nanus, MD (Weill Medical College of Cornell University), Paraskevi Giannakakou, PhD (Weill Medical College of Cornell University), Emmanuel Antonarakis, MD (Johns Hopkins Sidney Kimmel Comprehensive Cancer Center), Jun Luo, PhD (Johns Hopkins University), Simon Gregory, PhD (Duke University), Susan Halabi, PhD (Duke University), Scott Tagawa, MD, MSc (Weill Medical College of Cornell University), Daniel George, MD (Duke University), Himisha Beltran, MD (Weill Medical College of Cornell University), Jason Somarelli, PhD (Duke University), Giuseppe Galletti, MD, PhD (Weill Medical College of Cornell University), Ryan Dittamore, PhD (Epic Sciences).

Description:

• Precision medicine involves the analysis of an individual’s tumor biology, to optimally design patient treatment plans. The discovery of biomarkers predictive of drug-response will allow assignment of patients to therapies most likely to benefit them and avoid unnecessary treatments and morbidities.
• Dr. Armstrong and team will identify potential predictive biomarkers of response and resistance to abiraterone, enzalutamide, and taxane-chemotherapy in mCRPC patients.
• Potential predictive biomarkers will be determined by assessing the biology and genomic features of circulating tumor cells and circulating tumor DNA obtained from successive blood samples drawn from patients undergoing therapy.
• The androgen receptor (AR) is the primary driver of prostate cancer growth and survival and is the main molecular target today for the treatment of prostate cancer. Shorter variant forms of AR (AR-Vs) can be highly active and drive tumor growth even in the presence of current AR-targeting agents. A major focus of this project will be to examine if the presence of AR-Vs can predict drug response and resistance.
• These studies will contribute to the development of a precision medicine approach for CRPC patients.

What this means for patients: The future of oncology practice involves the genetic analysis of an individual’s tumor to select therapies most likely to benefit them. This project will determine predictive biomarkers of response and drug resistance to the major therapies available for mCRPC patients — abiraterone, enzalutamide, and taxane-chemotherapy and will inform precision medicine strategies for prostate cancer patients.

Movember-PCF Challenge Award ($1 Million)

Project Title: Charting the Epigenomic Landscape of Advanced Prostate Cancer in Human Tissue

Principal Investigator: Matthew Freedman, MD (Broad Institute of MIT and Harvard)

Co-investigators: Mark Pomerantz, MD (Harvard: Dana-Farber Cancer Institute), Myles Brown, MD (Harvard: Dana-Farber Cancer Institute), Henry Long, PhD (Harvard: Dana-Farber Cancer Institute), Mary-Ellen Taplin, MD (Harvard: Dana-Farber Cancer Institute), Rana McKay, MD (Harvard: Dana-Farber Cancer Institute), Zoltan Szallasi, MD (Harvard: Boston Children’s Hospital), Fugen Li, PhD (Harvard: Dana-Farber Cancer Institute), Michaela Bowden, PhD (Harvard: Dana-Farber Cancer Institute), Massimo Loda, MD (Harvard: Dana-Farber Cancer Institute).

Description:

• The androgen receptor (AR) is the primary driver of prostate cancer and regulates the expression of genes required for tumor growth and survival. Understanding the differential effects of the AR in normal prostate vs. prostate cancer will enable discovery of new pathways involved in the development of malignancy.
• Dr. Matthew Freeman and team will map the AR “cistrome” – the genes regulated by AR, in clinical specimens from prostate cancer patients.
• The AR cistrome will be examined during the progression of prostate cancer from early stage tumors to those that have acquired resistance to the AR-targeting therapies abiraterone and enzalutamide. Genes involved in disease progression and acquired treatment-resistance will be discovered.
• The precise role of other proteins that cooperate with AR to regulate target genes during the progression of prostate cancer will be investigated.
• These studies will lead to the discovery of new predictive biomarkers for optimal therapy and potential drug targets to prevent prostate cancer progression and drug-resistance.

What this means for patients: The androgen receptor (AR) is the primary driver of prostate cancer and acts by turning on expression of many genes involved in tumor growth and survival. This project will define the genes regulated by AR and its cancer-promoting partners that are important in disease progression and treatment-resistance. These discoveries may lead to the development of new therapies and predictive biomarkers to optimize treatment for prostate cancer patients.

The Safeway Foundation-PCF Challenge Award ($1 Million)

Project Title: Systemic Treatment for Metastatic Prostate Cancer by a Novel Small Molecule Targeting RNA Polymerase I

Principal Investigator: Marikki Laiho, MD, PhD (Johns Hopkins University)

Co-investigators: Charles Bieberich, PhD (University of Maryland Baltimore County), Angelo De Marzo, MD, PhD (Johns Hopkins: John Hopkins Medical Institutions), Srinivasan Yegnasubramanian, MD, PhD (Johns Hopkins: John Hopkins Medical Institutions), Sarah Wheelan, MD, PhD (Johns Hopkins: John Hopkins Medical Institutions), Paul Sirajuddin, PhD (Johns Hopkins: John Hopkins Medical Institutions).

Description:

• Discovering and targeting molecules and mechanisms that prostate cancer cells depend on is critical for the development of novel therapies that extend the lives of patients.
• Dr. Laiho and team have found that prostate cancer cells have a significantly increased need for protein synthesis and the RNA Polymerase I molecule that governs these processes and have identified a molecule, BMH-21, that inhibits RNA Polymerase I.
• Efficacy and treatment protocols will be tested for analogs of BMH-21 in mouse models of aggressive prostate cancer. Novel platforms will be developed to examine the functional activity of RNA Polymerase I and therapeutic responses to BMH-21.
• The precise role of other proteins that cooperate with AR to regulate target genes during the progression of prostate cancer will be investigated.
• BMH-21 may also inhibit prostate tumor growth by inhibiting the activity of the androgen receptor (AR), a primary driver of prostate cancer, and by altering the epigenetic state of cells. The mechanisms and consequences of BMH-21 treatment on these activities will be determined.

What this means for patients: Discovering new targets for prostate cancer therapy is a critical need. If successful, this project will define the mechanisms and preclinical efficacy of a therapeutic agent that targets protein synthesis in prostate cancer cells and will lead immediately into the initiation of clinical trials.

The Safeway Foundation-PCF Challenge Award ($1.5 Million)

Project Title: The NEXT Project: Network Enriched Crossover Trials

Principal Investigator: Charles Ryan, MD (University of California, San Francisco)

Co-investigators: Eric Small, MD (University of California, San Francisco), Josh Stuart, PhD (University of California, Santa Cruz), Pamela Paris, PhD (University of California, San Francisco), Jack Youngren, PhD (University of California, San Francisco), Won Kim, MD, (University of California, San Francisco), Rahul Aggarwal, MD (University of California, San Francisco), Li Zhang, PhD (University of California, San Francisco), Ted Goldstein, PhD (University of California, Santa Cruz), Robert Baertsch, PhD (University of California, Santa Cruz).

Description:

• Precision medicine involves the prescription of treatments based on the unique biology of an individual’s tumor. Understanding how various molecular alterations integrate to promote tumor biology will inform better selection of appropriate medications for an individual patient.
• Dr. Ryan and team will evaluate alterations in the genomes of tumors from castrate-resistant prostate cancer (CRPC) patients enrolled in ongoing clinical trials to define biomarkers that predict treatment responses and resistance. These biomarkers will be used to guide enrollment of patients into subsequent clinical trials and will signal the need for a different treatment strategy.
• Biomarkers will be developed to predict: (1) development of resistance to second-generation AR-targeting drugs (enzalutamide or abiraterone); (2) which patients will benefit from cross-over to another agent; (3) responsiveness to non-AR pathway-targeting drugs; and (4) sensitivity to chemotherapy.

What this means for patients: Precision medicine is the future of clinical practice. Genomic analysis of an individual’s tumor will be used to select the optimal treatment during the continuum of clinical progression of prostate cancer. If successful, this project will define and validate genomic biomarkers that predict tumor responses to various drugs and will guide more effective therapy throughout the course of an individual’s disease.

PCF Challenge Award ($1 Million)

Project Title: Proposal Title: Targeting Genomic Instability in SPOP Mutant Prostate Cancer

Principal Investigator: Christopher Barbieri, MD, PhD (Weill Cornell Medical College)

Co-investigators: Johann de Bono, MD (Institute of Cancer Research/Royal Marsden Hospital); Mark A. Rubin, MD (Weill Cornell Medical College and NewYork-Presbyterian Hospital); Michael M. Shen, PhD (Columbia University Medical Center); Antonina Mitrofanova, PhD (Columbia University Medical Center); Gunther Boysen, PhD (Institute of Cancer Research/Royal Marsden Hospital); Michael A. Augello, PhD (Weill Cornell Medical College).

Description:

• Prostate cancer is a heterogeneous disease and can be classified into various subtypes by the mutations that drive disease development and progression. Understanding the biology by which various mutations drive prostate cancer will lead to the generation of new therapies that target prostate cancer subtypes.
• Mutations in the SPOP gene represent one molecular subtype, comprising ~10% of prostate cancers.
• Dr. Barbieri and team will determine if SPOP mutations promote prostate cancer by causing genetic instability and allowing the accumulation of additional oncogenic mutations due to an inability to repair damaged DNA. This might render SPOP-mutant tumor cells more sensitive to therapies that cause DNA-damage or block other DNA-damage repair pathways. Tumor cells with SPOP-mutations versus a subtype of tumors characterized by rearrangements in the ERG gene will be compared for sensitivity to drugs targeting the DNA damage-repair gene, PARP1.
• SPOP mutations occur early in the natural history of prostate cancer. It is not known if SPOP mutations play a role only in the initiation of prostate cancer versus later phases of disease progression. The role of SPOP at different times throughout prostate cancer development and progression will be examined using genetically engineered prostate cancer mouse models where SPOP can be deleted from prostate cells or tumors at any time.
• Finally, whether SPOP mutations render tumors more sensitive to PARP1-inhibitors will be tested in prostate cancer clinical trials.

What this means for patients: Understanding the biology of different prostate cancer molecular subtypes will lead to the development of more effective and personalized treatment strategies. This project will determine the role of SPOP mutations in prostate cancer and test whether SPOP mutations confer enhanced sensitivity of tumors to PARP1-inhibitors.

PCF Challenge Award ($1 Million)

Project Title: Identifying Early Biomarkers of Anti-Androgen Treatment Resistance and Lethal Prostate Cancer

Principal Investigator: Christopher Maher, PhD (Washington University)

Co-investigators: Felix Feng, MD (University of Michigan); Scott Tomlins, MD, PhD (University of Michigan); Nima Sharifi, MD (Cleveland Clinic); Elaine Mardis, PhD (Washington University); Joseph Evans, MD, PhD (University of Michigan); Jingqin Luo, PhD (Washington University).

Description:

• Over 80% of men who die from prostate cancer were diagnosed at a stage when clinicians could only detect localized disease. Patients are commonly treated with radical prostatectomy, but approximately 30% will relapse, indicating that in some patients, tumor cells had already metastasized at the time of surgery. This emphasizes a critical need for discovering biomarkers that identify which patients will go on to develop lethal disease.
• Dr. Maher and team will use next-generation genomic analysis techniques to identify biomarkers that predict the development of lethal prostate cancer in patients early during the course of their treatment. Biomarkers that predict resistance to drugs targeting the androgen receptor (AR), a critical driver of prostate cancer growth and survival, will also be determined.
• This study will employ prostatectomy specimens and clinical data from a unique and valuable Cooperative Group trial cohort of prostate cancer patients who presented with localized disease and underwent prostatectomy but later relapsed and were treated with either radiation therapy (RT) or RT + the AR-targeting therapy, Bicalutamide. Importantly, this study cohort has over 10 years of clinical follow-up data.
• These studies will provide new understandings on the biological mechanisms of prostate cancer, lead to the development of prognostic tests that predict lethal and treatment-resistant prostate cancer and identify promising new molecules and pathways that can be targeted for prostate cancer therapies.

What this means for patients: The development of biomarkers that predict disease progression and responses to therapies are critical for optimizing the treatment of prostate cancer patients. If successful, this study will identify early biomarkers that predict progression to lethal disease and resistance to AR-targeting therapies. This will enable the development of new treatment strategies and new treatments for prostate cancer patients.

PCF Challenge Award ($1 Million)

Project Title: Exploiting an Actionable Germline Biomarker of Castration-Resistant Prostate Cancer

Principal Investigator: Nima Sharifi, MD (Cleveland Clinic)

Co-investigators: Jorge Garcia, MD (Cleveland Clinic); Jason Hearn, MD (Cleveland Clinic); Eric A Klein, MD (Cleveland Clinic); Manish Kohli, MD (Mayo Clinic); Cristina Magi Galluzzi, MD, PhD (Cleveland Clinic); Donald Tindall, PhD (Mayo Clinic)

Description:

• The androgen receptor (AR) pathway is the fuel for prostate cancer growth and survival and is a primary therapeutic target. Resistance to AR-targeting therapies is common and patients eventually progress to a lethal, untreatable disease state. Multiple mechanisms can underlie AR-therapy resistance, including an overproduction of androgens which allows AR to become more easily activated.
• Dr. Sharifi and team are studying whether mutations in 3βHSD1, an enzyme involved the metabolic pathway converting androgen precursors into androgens, predispose patients to AR-targeting therapy resistance.
• An inherited mutation in 3βHSD1 leads to higher activity of 3βHSD1, greater output of androgens in CRPC patients, and associates with poor clinical outcome. Whether 3βHSD1 mutations also enhance androgen metabolism in yet untreated patients will be determined by measuring androgen biosynthesis pathway metabolites in patient tumor and serum specimens and correlating levels with 3βHSD1 genotype.
• These findings will be translated into an FDA-approved prognostic 3βHSD1 genotyping test.
• The androgen synthesis inhibitor, abiraterone acetate (AA), works by blocking the androgen biosynthesis pathway upstream of 3βHSD1 and therefore AA treatment may negate the effects of 3βHSD1 mutations. Two clinical trials will be initiated to determine if patients with 3βHSD1 mutations are more sensitive to 1) abiraterone treatment or 2) to combination therapy of androgen-deprivation therapy + abiraterone.

What this means for patients: Patients who develop resistance to AR-targeting therapies will likely progress to a lethal disease state. If successful, this project will develop a FDA-approved prognostic test that identifies a subset of patients with inherited mutations that predispose to AR-targeted therapy resistance and determine the efficacy of abiraterone as an alternative treatment approach for these high-risk patients.

PCF Challenge Award ($1 Million)

Project Title: Validation of Radiomics-Based Imaging Biomarkers for Guiding Therapy in Patients with mCRPC

Principal Investigator: Robert Jeraj, PhD (University of Wisconsin Carbone Cancer Center)

Co-investigators: Glenn Liu, MD (UW Carbone Cancer Center); Scott Tomlins, MD, PhD (University of Michigan Medical School); Scott Perlman, MD (University of Wisconsin-Madison); Urban Simoncic, PhD (University of Wisconsin-Madison)

Description:

• Once metastatic cancer develops, tumors can be located at many sites throughout the body and each tumor may exhibit a unique response to therapy. The development of imaging methods to assess metastatic tumor burden and treatment responses is critical for guiding clinical decision making.
• Dr. Jeraj and team will develop a quantitative total body imaging (QTBI) method that assesses individual metastatic tumor responses to treatment with enzalutamide, a therapy targeting the androgen receptor (AR).
• Patients being treated with enzalutamide will be followed using QTBI to create imaging signatures that predict response or resistance to enzalutamide.
• Imaging signatures will be compared with molecular biomarkers of resistance and response by obtaining biopsies of the most resistant and most responsive tumors from each patient and performing analyses to identify the associated genomic alterations.
• Finally, whether this QTBI method can predict the time to progression on enzalutamide will be determined by comparing the fraction of resistant lesions identified by imaging with standard PSA, radiographic and clinical measures of disease progression.

What this means for patients: The future of molecular imaging methods extends beyond simply monitoring disease status in patients. If successful, this project will generate a biologically-validated imaging method that assesses resistance and response of individual metastatic tumors to treatment and is able to predict time to disease progression on the AR-targeting therapy enzalutamide. This methodology will allow clinicians to optimize patient treatment plans and will speed the development of new therapies.

PCF Challenge Award ($1 Million)

Project Title: Eliminating Lethal Micrometastic Prostate Cancer Through High Intensity Short Duration AR Suppression

Principal Investigator: Mary-Ellen Taplin, MD (Harvard: Dana-Farber Cancer Institute)

Co-investigators: Rana Mckay, MD (Dana-Farber Cancer Institute); Eli Van Allen, MD (Dana-Farber Cancer Institute); Peter Nelson, MD (University of Washington, Fred Hutchinson Cancer Research Center); Cyrus Ghajar, PhD (University of Washington, Fred Hutchinson Cancer Research Center); Ken Pienta, MD, PhD (Johns Hopkins University); Ashley Ross, MD, PhD (Johns Hopkins University)

Description:

• Current prostate cancer patient treatment protocols often comprise sequential therapies that target the androgen receptor (AR) pathway which prostate cancer cells are addicted to for growth and survival. Androgen deprivation therapy (ADT) is given initially, but once tumors develop resistance, patients may go on to receive the more potent AR-targeting therapies enzalutamide or abiraterone, to which they also inevitably become resistant.
• Dr. Taplin and team are leading clinical trials testing a high-intensity AR-inhibition strategy that combines three AR-targeting therapies (LHRH antagonist + abiraterone + enzalutamide) in previously untreated high-risk prostate cancer patients. Delivery of high-intensity AR-inhibition at a time when tumor cells have fewer genomic alterations and have not yet adapted to a lack of androgens may prohibit the evolution of treatment-resistance and progression to untreatable lethal disease.
• Whether high-intensity AR-inhibition better eliminates detectable disseminated tumor cells (DTCs) and reduces tumor recurrence compared with less intense AR-inhibition therapy (subtracting enzalutamide or abiraterone) will be determined. DTCs that survive treatment will be assessed for acquired mutations and genes expressed to determine mechanisms of resistance to high-intensity AR-inhibition. Finally, to determine if metastatic environments contribute to the resistance of tumor cells to high-intensity AR-inhibition, bone marrow and lymph node biopsies will be examined for gene expression, location of tumor cells, and the levels of androgens that can feed tumor growth.

What this means for patients: Designing treatment strategies that prohibit tumor cells from progressing to an aggressive treatment-resistant disease state is critical. This project will determine the efficacy of a high-intensity AR-inhibition strategy and discover tumor cell mechanisms of resistance. If successful, this project will result in new treatment paradigms that extend the lives of prostate cancer patients and may actually cure some with otherwise lethal disease.

PCF Challenge Award ($1 Million)

Project Title: Early Detection of Neuroendocrine Prostate Cancer Transformation Using Circulating Genomic Signatures

Principal Investigator: Himisha Beltran, MD (Weill Cornell Medical College)

Co-investigators: Gerhardt Attard, MD, PhD (Institute for Cancer Research); Francesca Demichelis, PhD (University of Trento); Alessandro Romanel, PhD (University of Trento); Kenneth Hennrick, MD (Weill Cornell-NewYork Presbyterian)

Description:

• A subset of treatment-resistant metastatic CRPC patients will express markers of neuronal development which are thought to correlate with lethal prostate cancer. These tumors have evolved to no longer rely on the androgen receptor (AR) to grow and survive.
• Diagnosis of this subset of tumors is difficult and they can coexist with classical adenocarcinoma and other cancer cell phenotypes.
• Dr. Beltran and team will generate a noninvasive genomics method for the assessment and early detection of neuronal markers of prostate cancer. Tumor cell DNA is continually shed into the circulation and can be obtained by blood draws. Circulating tumor DNA obtained from blood of patients diagnosed with this subset of prostate cancer expressing neuronal markers will be comprehensively analyzed to determine DNA alterations in these cells compared with adenocarcinoma.
• The genetic alterations that arise during the development of the lethal tumor cell clone during resistance to the AR-targeting therapies, abiraterone acetate or enzalutamide will be identified. Genomic alterations will be correlated with clinical data to identify the best prognostic indicators of AR-therapy resistance and clinical outcome.
• These studies will be performed in a specialized clinical laboratory setting that will generate a highly standardized blood-based method for noninvasive early diagnosis of lethal prostate cancer.

What this means for patients: Understanding and targeting mechanisms of tumor cell drug-resistance is critical for extending the lives of prostate cancer patients. If successful, this project will identify genomic alterations that allow tumor cells to develop neuronal markers and gain resistance to AR-targeting therapies. This may lead to new methods to diagnose and treat patients with this lethal disease phenotype.

Janssen-PCF Special Challenge Award ($500,000)

Project Title: Osteocrines in Therapy Resistance of Prostate Cancer Bone Metastasis: Evaluation of Strategies to Overcome Therapy Resistance from Tumor-Educated Bone Microenvironment

Principal Investigators: Christopher Logothetis, MD (The University of Texas MD Anderson Cancer Center), Gary Gallick, PhD (The University of Texas MD Anderson Cancer Center)

Co-investigators: Sue Hwa Lin, PhD (The University of Texas MD Anderson Cancer Center); Eleni Efstathiou, MD, PhD (The University of Texas MD Anderson Cancer Center); Maria Karlou, PhD (University of Athens School of Medicine); Veronika Te Boekhorst, (The University of Texas MD Anderson Cancer Center)

Description:

• The bone is by far the most common site of prostate cancer metastasis and represents a painful and eventually therapy-resistant and lethal form of this disease.
• Dr. Logothetis and team are studying how prostate cancer cells hijack the bone setting in order to resist therapy and will develop therapeutic combinations to successfully kill bone metastases.
• Metastatic prostate cancer cells secrete factors that promote new bone formation. The newly formed bone cells are hypothesized to then provide factors called osteocrines that allow prostate cancer cells to survive and thrive in the bone environment.
• The team will identify osteocrines produced by bone cells that promote resistance to bone metastasis-targeting therapies including cabozantinib and docetaxel. The mechanisms by which osteocrines promote therapy resistance in prostate cancer cells will be determined with a specific focus on the role of integrins. Integrins are receptor molecules for several osteocrines, and prostate cancer cells may express integrins to receive survival signals from osteocrines.
• Pre-clinical mouse models of human prostate cancer will be used to test whether blocking osteocrines or integrins will overcome therapy resistance.
• Finally, a clinical trial using DI17E6, an αvβ3 integrin inhibitor, in combination with cabozantinib or other therapies, will be initiated to test whether blocking osteocrines can increase the efficacy of bone-targeting therapies in prostate cancer patients with bone metastases.

What this means for patients:
Prostate cancer most commonly metastasizes to the bone and progresses to a lethal untreatable disease state. Dr. Christopher Logothetis and team are studying the factors produced by bone cells that contribute to the ability of prostate cancer cells to grow within the bone environment and develop resistance to therapies. If successful, this study will identify new therapeutic targets for the treatment of metastatic bone lesions which will be tested in clinical trials.

Janssen-PCF Special Challenge Award ($500,000)

Project Title: Targeting and Mechanistic Insights Underlying N-Myc Driven Neuroendocrine Prostate Cancer

Principal Investigator: David Rickman, PhD (Weill Cornell Medical College)

Co-investigators: Bernard Eilers, PhD (University of Wuerzburg); Mark Rubin, MD (Weill Cornell Medical College); Himisha Beltran, MD (Weill Cornell Medical College); Olivier Elemento, PhD (Weill Cornell Medical College); Myriam Kosai, MD (Weill Cornell Medical College)

Description:

• Prostate tumors that express neuronal developmental markers can arise after the treatment of advanced prostate cancers with androgen deprivation therapy and are associated with an extremely poor prognosis and resistance to androgen receptor-targeting therapies.
• Dr. Rickman and team are studying the roles of two proteins, N-MYC and Aurora-A, in prostate tumors with neuronal features and the clinical relevance of targeting these genes as a therapeutic strategy in these patients.
• N-MYC is an oncogene that collaborates with Aurora-A to promote tumor growth. Both N-MYC and Aurora-A are overexpressed in prostate tumors following the acquisition of neuronal features, leading to the hypothesis that these proteins work together to drive this tumor phenotype.
• The mechanisms by which N-MYC and Aurora-A drive prostate tumors with neuronal features will be determined by examining the genes that they regulate together and the effect of inhibiting Aurora-A on the function of N-MYC.
• Usp proteins are hypothesized to be involved in interactions between N-MYC and Aurora-A. The team will test whether any Usp proteins are required for N-MYC functions in order to identify alternate molecules that can be therapeutically targeted to block this oncogenic pathway.
• Finally, samples from a clinical trial evaluating the efficacy of the Aurora-A inhibitor MLN8237 will be examined to validate the clinical relevance of N-MYC/ Aurora-A in human prostate tumors with neuronal features. Whether N-MYC activity in tumors correlates with the presence of the neuronal phenotype, clinical responses to MLN8237, and lack of responses to the androgen receptor-targeting therapies, abiraterone or enzalutamide, will be determined.

What this means for patients:
Prostate tumors that express markers of neuronal development represent a highly aggressive, treatment-resistant subtype of prostate cancer that can arise after androgen deprivation therapy. Dr. Rickman and team are studying the role of two genes, N-MYC and Aurora-A, in regulating the phenotype of these tumors, and how to therapeutically target these genes. If successful, this study will lead to new understandings of how this subtype develops and credential new treatment strategies for patients with this aggressive prostate cancer subtype.

Carl Icahn – PCF Challenge Award ($1.5 Million)

Project Title: Enhancing Prostate Cancer Immunotherapy through Epigenetic Reprogramming for Optimal Activation of Specific Effector T-cells

Principal Investigator: Charles Drake, MD, PhD (Johns Hopkins University)

Co-investigators: Stephen Baylin, MD (Johns Hopkins University), Vasan Yegnasubramanian, MD, PhD (Johns Hopkins University), William Nelson, MD, PhD (Johns Hopkins University), Michael Haffner, MD, PhD (Johns Hopkins University), Angelo De Marzo, MD, PhD (Johns Hopkins University), Charles Bieberich, PhD (University of Maryland, Baltimore County)

Description:

• Immunotherapies that target immune-system inhibiting molecules called “checkpoint inhibitors” such as PD-1 can lead to complete and durable tumor regression in subsets of patients with multiple types of solid tumors, but have not been successful in prostate cancer. Identifying methods to enhance the efficacy of checkpoint blockade immunotherapy is critical.
• Epigenetic therapies are a class of therapies that can reprogram gene expression profiles in cells and may result in enhanced immune system functions.
• Dr. Drake and team are studying whether epigenetic therapies can reprogram the immune system in a way that promotes anti-tumor immune activity and will allow checkpoint blockade immunotherapy to become effective in prostate cancer patients.
• The effect of epigenetic therapies on expression of genes involved in recognition by the immune system will be determined in prostate cancer cells. Additionally, the effect of epigenetic therapies on the gene expression profiles and the functions of immune cells will be determined in mouse models of prostate cancer. These studies will indicate if epigenetic therapies can reprogram tumor and/or immune cells to promote anti-tumor immune responses.
• It will also be determined whether epigenetic therapies can prevent or reverse immune system tolerance against tumor cells. Tolerance is a natural autoimmunity-preventing program that tumor cells hijack.
• Finally, the combination of checkpoint blockade immunotherapy (anti-PD-1) and epigenetic therapy will be tested in preclinical prostate cancer models.

What this means for patients:
Enhancing the efficacy of immunotherapies may lead to the development of long term clinical responses in prostate cancer patients. Dr. Drake and team will determine whether epigenetic therapies have the potential to render prostate cancer patients responsive to checkpoint blockade immunotherapy. If successful, this project will lead to a new combination therapy with curative potential.

All-Star Killer T-Cell Special Challenge Award ($1.6 Million)

Project Title: Phase I Study of PSMA-TGFβR DN CAR Modified T-cells in Patients with Advanced Castrate Resistant Prostate Cancer

Principal Investigator: Carl June, MD (University of Pennsylvania)

Co-investigators: Naomi Haas, MD (University of Pennsylvania), Marcela Maus, MD, PhD (University of Pennsylvania)

Description:

• CAR T-cells are immune cells collected from a patient’s own blood and genetically engineered to recognize specific molecules expressed by tumor cells. When re-infused into the patient, these cells seek and kill tumor cells expressing the targeted molecule and can provide life-long tumor surveillance. This strategy has led to cures in lymphoma patients and has significant promise for the treatment of prostate cancer patients.
• Dr. Carl June and team are developing CAR T-cells that recognize and kill prostate cancer cells that can also resist immune suppression mechanisms.
• Patient T-cells will be transduced with a chimeric antigen receptor (CAR) gene engineered to recognize the prostate cancer-specific protein PSMA and with a dominant-negative receptor molecule for the immune-suppression protein TGF-β. When the CAR T-cells come into contact with a prostate cancer cell that expresses PSMA, the CAR molecule will bind to PSMA and send a signal to activate the T-cell to kill the tumor cell. When the CAR T-cell encounters TGF-β in the environment, the dominant-negative receptor will prohibit any normal TGF-β receptors expressed by the T-cell from suppressing T-cell activity.
• The efficacy and safety of this therapy will be tested in advanced castrate resistant prostate cancer patients in a phase 1 clinical trial. Patients will also be assessed for the functionality and continued persistence of the CAR T-cells over time, and whether CAR T-cell therapy influences other anti-tumor immune responses including antibody responses.
• Post-treatment biopsies will be obtained from some patients and evaluated to determine expression of PSMA by tumor cells and infiltration of the tumor with both CAR T-cells and unmodified T-cells.
• Finally, the levels of circulating tumor cells (CTCs) will be measured over time to determine if CTC levels reflect the efficacy of CAR T-cell therapy.

What this means for patients:
CAR T-cell immunotherapy has demonstrated profound tumor-killing activity in lymphoma patients. Dr. June and team will create a CAR T-cell immunotherapy for prostate cancer patients and test it in clinical trials. If successful, this project will generate a powerful new therapy for the treatment of prostate cancer patients.