Challenge Awards – Class of 2020

The PCF Challenge Award Winners – Class of 2020 recipients are:

2020 PCF Challenge Award

Principal Investigators: Rahul Aggarwal, MD (University of California, San Francisco), Lawrence Fong, MD, (University of California, San Francisco), Michael Evans, PhD (University of California, San Francisco), Thomas Hope, MD (University of California, San Francisco)

Co-Investigators: David Oh, MD, PhD (University of California, San Francisco), Charles Craik, PhD (University of California, San Francisco), Li Zhang, PhD (University of California, San Francisco)

Project Title: ¹⁷⁷Lu-PSMA-617 as a Radioimmunotherapy for Prostate Cancer

Description:

• Immunotherapies are cancer treatments that activate a patient’s immune system to target and kill their cancer cells. Checkpoint immunotherapy has been extremely effective, even curative, in some patients with various cancer types, but has had efficacy in only a small number of prostate cancer patients thus far.  Strategies to enhance immunotherapy for prostate cancer are greatly needed.
• Radiation therapy (RT) has been shown to activate anti-tumor immune responses and may be synergistic in combination with immunotherapy.
• ¹⁷⁷Lu-PSMA-617 is in a promising new class of systemic radiation therapies, composed of a tumor-targeting molecule attached to a radioactive isotope, thus delivering radiation directly to tumor cells anywhere in the body.
• Rahul Aggarwal and team are studying whether and how ¹⁷⁷Lu-PSMA-617 may be synergistic with checkpoint immunotherapy.
• In this project, the team will study the effects of various types of radiation therapies alone or in combination with checkpoint immunotherapy in mouse prostate cancer models.
• A novel PET imaging technology to measure and visualize anti-tumor immune responses will be tested and validated in preclinical models.
• The team will study how ¹⁷⁷Lu-PSMA-617 alone or in combination with anti-PD1 checkpoint immunotherapy impacts the tumor microenvironment and anti-tumor immune responses using tumor and blood samples from patients on a clinical trial. The team will also investigate this in patients from trials testing combinations of checkpoint immunotherapy with radium-223 or stereotactic radiation (SBRT).  Whether any immune parameters correlate with patient outcomes and have potential as predictive biomarkers will be determined.
• If successful, this project will determine the optimal form of radiation therapy that can synergize with checkpoint immunotherapy to produce effective anti-tumor immune responses. The mechanisms by which this occurs will be identified, which may reveal novel therapeutic targets to enhance the efficacy of radio-immunotherapy in men with prostate cancer.

What this means to patients:  Dr. Aggarwal and team are investigating the potential for therapeutic synergy between various types of radiation therapy and immunotherapy, as well as the mechanisms by which this occurs.  The team is also developing biomarkers and novel PET imaging methods to measure anti-tumor immune responses.  This will enable optimization of radio-immunotherapy as an effective new therapeutic strategy for patients with prostate cancer.

2020 Movember – Distinguished Gentleman’s Ride – PCF Challenge Award

Principal Investigators: Arul Chinnaiyan, MD, PhD (University of Michigan), Marcin Cieslik, PhD (University of Michigan), Ulka Vaishampayan, MBBS (University of Michigan), Yuzhuo Wang, PhD (University of British Columbia)

Co-Investigators: Lanbo Xiao, PhD (University of Michigan), Abhijit Parolia, PhD (University of Michigan),  Yuanyuan Qiao, PhD (University of Michigan),  Jeremy Taylor, PhD (University of Michigan),

Project Title: Targeting Transcriptional Addiction in Prostate Cancer by Impeding Neo-Enhancer Accessibility

Description:

• The androgen receptor (AR) is the primary oncogenic driver in prostate cancer, and thus the primary therapeutic target. However, resistance to androgen deprivation therapy (ADT) and second-generation AR targeting agents like enzalutamide and abiraterone, and progression to metastatic castration resistant prostate cancer (mCRPC), is nearly inevitable. This is because prostate cancer cells commonly adapt mechanisms to maintain AR signaling, such as amplification and mutations of the AR gene.  It has recently been shown that epigenetic changes in the AR gene are also important drivers of the development of mCRPC.
• Epigenetics is the regulation of the 3D structure of DNA surrounding a gene and its regulatory regions, which causes the gene to be more or less accessible to gene expression machinery.
• SMARCA2 and SMARCA4 are two major epigenetic regulators that are commonly altered in CRPC, and are required for AR activity. Thus, SMARCA2/4 may be ideal therapeutic targets.
• Arul Chinnaiyan and team are studying the impact of targeting SMARCA2/4 as a novel treatment approach for mCRPC.
• The team has previously shown that a novel agent which causes the degradation of SMARCA2/4 has activity against CRPC cells with express AR, but not CRPC cells which do not have AR.
• In this project, the team will investigate the mechanism of action of the SMARCA2/4-degrader in AR-positive CRPC cells.
• The team will also investigate the efficacy of the SMARCA2/4-degrader alone and in combination with AR-targeting agents in pre-clinical models of CRPC.
• The team will identify candidate biomarkers that can identify patients who are more likely to benefit from treatment with the SMARCA2/4-degrader.
• Finally, the team will initiate a phase 1/2 clinical trial to test the safety and efficacy of the SMARCA2/4-degrader alone and in combination with enzalutamide in patients with mCRPC.

What this means to patients:  Despite recent advances, mCRPC remains an incurable disease state and new treatments are urgently needed.  Dr. Chinnaiyan and team have identified a set of epigenetic regulators, SMARCA2/4, that are important in the development of CRPC and have developed a novel treatment that can target these regulators.  If successful, this team will identify the mechanisms of action of this treatment, and establish efficacy in patients, which may improve outcomes for patients with mCRPC.

2020 John Black Charitable Foundation-PCF Challenge Award

Principal Investigators: Johann de Bono, MD, PhD (Institute of Cancer Research), Andrea Alimonti, MD (Institute of Oncology Research)

Co-Investigators:  Silke Gillessen Sommer, MD (University of Italian Switzerland), Christina Yap, PhD (The Institute of Cancer Research), Arianna Calcinotto, PhD (Institute of Oncology Research), Christina Guo, MBBS (The Royal Marsden NHS Foundation Trust), Bora Gurel, MD (The Institute of Cancer Research), Khobe Chandran, MBBS (The Royal Marsden NHS Foundation Trust), Suzanne Carreira, PhD (The Institute of Cancer Research), Nicolo’ Pernigoni, MSc (Institute of Oncology Research), Pasquale Rescigno, MD (The Institute of Cancer Research)

Project Title: Targeting the Host Microbiota to Reverse Therapeutic Resistance in Lethal Prostate Cancers

Description:

• The microbiome are the community of microorganisms that live in symbiosis on the human host, such as the on the skin and along the gastrointestinal tract.  These microbes are critical for many aspects of normal human biology, such as aiding in food digestion and educating the immune system.
• Perturbations in the microbiome, termed microbial dysbiosis, are associated with many diseases, including cancer.  Microbial dysbiosis appears to influence cancer progression and resistance to treatments, however the underlying biology of these effects is unclear.
• Dr. Johann de Bono and team are studying the role of intestinal microbiota in prostate cancer.
• In this project, Dr. de Bono and team will determine whether and how gut microbiota impact prostate cancer.
• The team will develop a clinical assay to detect ‘unfavorable’ microbiota.
• If successful, this project will determine the biology by which unfavorable microbes contribute to prostate cancer, and identify possible therapeutic strategies for reversing their impact.

What this means to patients:  Dr. de Bono and team are studying the biology of how ‘unfavorable’ gut microbes impact prostate cancer.  The team is also developing a test to identify patients with unfavorable microbes in order to better understand how these microbes impact outcomes, and how these microbes can be reduced with novel interventions.

2020 Janssen-PCF Challenge Award

Principal Investigators: Veda Giri, MD (Thomas Jefferson University), Susan Halabi, PhD (Duke University), Alexander Wyatt, PhD (University of British Columbia)

Co-Investigators: Rhonda Bitting, MD (Duke University), Christopher McNair, PhD (Thomas Jefferson University)

Project Title: PARPi Response Evaluation for Clinical Impact and Scientific Innovation in Oncology: The PRECISION Registry

Description:

• The PARP inhibitors olaparib and rucaparib are a new class of “precision medicines” that have recently been FDA-approved for metastatic castration-resistant prostate cancer (mCRPC) patients whose tumors have mutations in certain DNA repair genes. These include mutations that were either inherited (“germline”) or acquired in the tumor (“somatic”) in BRCA1, BRCA2, ATM, PALB2, CHEK2, and multiple other genes. Several additional PARP inhibitors are also being tested in clinical trials.
• However, inconsistent response rates, response durations, and magnitudes of response to PARP inhibitors have been seen in patients with different DNA repair gene mutations. For instance, 83% of patients with BRCA1/2 mutations respond, compared to 37% of patients with ATM Larger datasets spanning diverse practice and patient settings are needed to improve and generalize appropriate use of PARP inhibitors in patients with mCRPC.
• Veda Giri and team are developing “The PRECISION Registry,” an international, collaborative registry of clinical, genomic, and outcomes data from patients with DNA repair mutations who have been treated with PARP inhibitors. Data sources will include pharmaceutical company clinical trial data, off-study data from academic and clinical practices, non-pharmaceutical company trials, prostate cancer registries, and the Durham VA.
• This registry will be used to conduct a meta-analysis to collectively assess responses to PARP inhibitors in patients with different DNA repair gene mutations.
• Bioinformatics and genomic analyses will be conducted using genomic sequencing data to identify genomic modifiers and biomarkers of PARP inhibitor responses.
• If successful, this project will greatly improve clinical use of PARP inhibitors in patients with mCRPC, inform strategies to enhance responses to PARP inhibitors, and accelerate the development of new therapeutics and clinical trials.

What this means to patients:  Dr. Giri and team will create a large international registry of data from patients treated with various PARP inhibitors in order to develop a better understanding of how different genomic alterations render sensitivity or resistance to these treatments.  This will result in improved clinical use of these treatments and lead to new therapeutic strategies for patients with prostate cancer.

2020 John Black Charitable Foundation-PCF Challenge Award

Principal Investigators: Nigel Mongan, PhD (University of Nottingham)

Co-Investigators: Victoria James, PhD (University of Nottingham), Catrin Rutland, PhD (University of Nottingham), Emad Rakha, MD (University of Nottingham), Jennie Jeyapalan, PhD (University of Nottingham), Rupert Fray, PhD (University of Nottingham), Nathan Archer, PhD (University of Nottingham), Brian Robinson, MD (Weill Cornell Medicine), Francesca Khani, MD (Weill Cornell Medicine), Simone de Brot, PhD, DVM (University of Bern), Jenny Persson, PhD (Umeå University & Malmö University, Sweden)

Project Title: Epitranscriptomic Determinants of Androgen Deprivation Therapy Resistance in Prostate Cancer

Description:

• Androgen-targeted therapies such as enzalutamide are important treatments for advanced prostate cancer. Unfortunately, emergence of treatment resistance and progression to castration resistant prostate cancer (CRPC), appears inevitable. There is an urgent need for new approaches to prevent or reverse the development of CRPC.
• Tumors that develop resistance to androgen-targeted therapies often exhibit increased expression of full-length androgen receptor (AR) and shorter pathogenic variants, including ARv7, which lack the AR protein domain targeted by these treatments. AR-variants are thought to be key mediators of androgen-targeted therapy resistance. However, how their expression levels are regulated in CRPC remains unclear.
• Dr. Nigel Mongan and team are studying how androgen-targeted therapies induce expression of AR-variants. The team has previously found that RNA methylation plays a major role in regulating what form of a gene is expressed as a protein and its levels.
• In this project, the team will investigate whether androgen-targeted therapies alter RNA methylation, including that of AR RNAs.
• The team has identified several enzymes involved in RNA methylation that may be involved and will determine whether their levels correlate with prostate cancer progression and treatment resistance in patient samples.
• The biology of how these RNA modifying enzymes impact prostate cancer biology and treatment resistance will be investigated in mouse prostate cancer models.
• Whether RNA methylation may be promising as a therapeutic target will be determined.
• If successful, this project will determine if and how RNA methylation impacts prostate cancer biology and whether RNA methylation enzymes have potential as therapeutic targets.

What this means to patients:  Dr. Mongan and team are studying the novel field of RNA methylation in prostate cancer.  They will determine if and how RNA methylation alterations impact disease progression and treatment resistance.  Finally, they will determine the potential of targeting RNA methylation as a novel treatment for preventing or reversing CRPC, which may lead to re-appropriation of such treatments that are already being developed for leukemia.

2020 PCF Challenge Award

Principal Investigators: Peter Nelson, MD (University of Washington), Elisabeth Heath, MD (Wayne State University/Karmanos Cancer Center)

Co-Investigators: Bruce Montgomery, MD (Seattle Puget Sound VA/University of Washington), Jay Shendure MD, PhD (University of Washington), Ivana Bozic, PhD (University of Washington), Gavin Ha, PhD (Fred Hutchinson Cancer Research Center), Larry True, MD (University of Washington), Colm Morrissey, PhD (University of Washington), Wael Sakr, MD (Wayne State University/Karmanos Cancer Center),  Navonil De Sarkar, PhD (Fred Hutchinson Cancer Research Center)

Project Title: PC-REACTR: A Multidimensional Tumor Atlas to Overcome Prostate Cancer Therapy Resistance

Description:

• Though advances have been made in extending the survival of men with metastatic prostate cancer, this disease remains incurable as resistance to current therapies and disease progression inevitably occurs. In order to devise new treatment strategies that will avoid or overcome treatment resistance and result in long-term tumor control, it is necessary to have a better understanding of the variability and complexity of advanced prostate cancer.
• Dr. Peter Nelson and team will create a multidimensional tumor atlas to investigate tumor biology and predict improved treatment combinations that can overcome treatment resistance.
• A multidimensional tumor atlas will be created that will contain data on genomic alterations, gene expression, and imaging of the tumor microenvironment over time in patients treated with standard of care and emerging therapeutics for advanced prostate cancer. This atlas will be made available as an open-access resource for the scientific community.
• This “4-D” information will be used in mathematical models to identify the mechanisms by which prostate cancer becomes drug-resistant, and to predict new treatment approaches that can overcome resistance.
• These models will be used to design clinical trials directed toward overcoming therapy resistance for standard and experimental treatment modalities.
• This project will create a valuable data resource for the scientific community and will result in improved understanding of prostate cancer biology, treatment resistance, and the identification of new improved treatment strategies.

What this means to patients:  Advanced prostate cancer is an incurable disease, for which new treatment strategies are urgently needed.  Dr. Nelson and team will create a multidimensional prostate cancer databank as a resource for the research community and will identify the mechanisms by which prostate cancer becomes drug-resistant and propose clinical trials to test treatment strategies designed to overcome drug resistance.

Principal Investigators: Kenneth Pienta, MD (Johns Hopkins University)

Co-Investigators: Sarah Amend, PhD (Johns Hopkins University), Angelo De Marzo, MD, Ph.D (Johns Hopkins University), Peter Kuhn, PhD (University of Southern California), James Hicks, PhD (University of Southern California)

Project Title: Dissecting the Prostate Cancer Diaspora

Description:

• Once prostate cancer metastasizes, it is incurable and lethal. Each year, more than 29,000 men in the United States die from metastatic prostate cancer. New therapies to prevent and treat metastatic prostate cancer remain an urgent medical need.
• Dr. Kenneth Pienta and team are studying the mechanisms and processes of prostate cancer metastasis.
• Tumor metastasis is a complex process, and studying tumor cell migration alone is insufficient to understand the nuances of cancer spread. A diaspora (from the Greek diaspora meaning “scattering” or dispersion”) is the movement, migration, or scattering of people away from an established homeland. Dr. Pienta and team are using the concept of diaspora to describe cancer metastasis in terms of the forces which cause cancer cells to leave the primary tumor, as well as the environmental and cellular features (“seed and soil”) necessary in a new body site for a metastatic tumor to “take root” and grow there.
• The team previously identified the existence of Poly-Aneuploid Cancer Cells (PACCs) as a subset of circulating tumor cells (CTCs) that appear to be the critical cells that are actually able to metastasize: the majority of CTCs simply do not survive once they leave the prostate. PACCs are large, have high genomic content, and have increased capacity to migrate. PACCs live among the greater cancer cell population, but when the tumor experiences stress (such as hypoxia or treatment with chemotherapy, radiation therapy, or hormonal therapy), PACCs protect themselves by going into hibernation and stopping cell division. The therapy wipes out the dividing cells, but once the treatment is stopped, PACCs wake up and act as stem cells to spawn a new generation of “daughter” cancer cells. Interestingly, hibernating PACCs have somehow developed resistance to that therapy, which is passed on to the new daughter cells.
• In this project, the team will determine the numbers and biology of PACCs in prostate cancer tissues from patients at different clinical disease states.
• The team will validate that the development of therapeutic resistance in PACCs occurs through mechanisms of reversible quiescence (hibernation).
• The team will study the mechanisms and functional consequences by which PACCs undergo whole genome doubling, and reversibly leave the cell cycle, and then reenter the cell cycle when stress is removed, to repopulate the tumor cell population.
• If successful, this project will determine the biology of a major mechanism underlying tumor metastasis and therapeutic resistance.

What this means to patients: Dr. Pienta and team are investigating the mechanisms by which a novel, giant tumor cell subtype, Poly-Aneuploid Cancer Cells (PACCs), are able to act as the major cell type seeding prostate cancer metastasis and therapeutic resistance. This may lead to the identification of new therapeutic strategies for preventing prostate cancer progression, treatment resistance, and metastasis.

2020 Bristol-Myers Squibb-PCF Challenge Award

Principal Investigators: Dan Robinson, PhD (University of Michigan), Felix Feng, MD (University of California, San Francisco), Ajjai Alva, MD (University of Michigan)

Co-Investigators: Marcin Cieslik, PhD (University of Michigan), Jason Brown, MD (University of Michigan), Jonathan Chou, MD, PhD (University of California, San Francisco), Yi-Mi Wu, PhD (University of Michigan)

Project Title: The Role of Precision Therapy in the Treatment of CDK12 Altered Metastatic Prostate Cancer

Description:

• Checkpoint immunotherapy is a highly promising type of cancer treatment which has achieved long-term tumor regressions and potentially even cures in some patients with cancers such as melanoma and lung cancer. This type of treatment has not yet been optimized for the treatment of prostate cancer. Identifying prostate cancer patients who are likely to benefit from checkpoint immunotherapy is a critical unmet need.
• Dr. Dan Robinson and team have identified a subtype of prostate cancer that have mutated or deleted both copies of the CDK12 gene. CDK12-mutant prostate cancer have altered molecular features that may cause these tumors to be more easily detected and targeted by anti-cancer immune responses.   Early data from this team suggest that patients with CDK12-mutant prostate cancer may be more likely to respond to checkpoint immunotherapy.
• In this project, Dr. Robinson and team will investigate the genes and molecular features that are altered in CDK12-mutant prostate cancer and determine the mechanisms by which this alteration drives anti-cancer immune responses.
• The team will investigate the mechanisms by which immune responses are generated against CDK12-mutant prostate cancer, including how CDK12 mutations cause other tumor mutations, and which of these alterations is responsible for generating immune responses.
• The team will perform studies to identify genes that are required in CDK12-mutant prostate cancer and may function as therapeutic targets.
• Preclinical models will be studied to validate the efficacy and mechanisms of checkpoint immunotherapy in the treatment of CDK12-mutant prostate cancer.
• Whether combining CDK12 inhibitors with checkpoint immunotherapy may be an effective therapeutic strategy for CDK12-intact prostate cancer will be investigated in preclinical models.
• The team will conduct a phase II clinical trial (IMPACT) testing anti-PD1 (nivolumab) and anti-CTLA4 (ipilimumab) checkpoint immunotherapy in metastatic prostate cancer patients with CDK12-mutant tumors. The mechanisms of action and determinants of clinical response to checkpoint blockade in CDK12-mutant prostate cancer will be determined using clinical samples from patients in this trial.
• If successful, this team will establish a precision medicine paradigm for the use of checkpoint immunotherapy in prostate cancer.

What this means to patients:  Checkpoint immunotherapy is a highly promising type of cancer treatment, but has yet to be optimized in prostate cancer.  Dr. Robinson and team will investigate the efficacy and mechanisms by which checkpoint immunotherapy may work in CDK12-mutant prostate cancer and identify novel immunotherapy treatment strategies for advanced prostate cancer. This will result in the establishment of a precision medicine paradigm for checkpoint immunotherapy in prostate cancer.

2020 Movember – Distinguished Gentleman’s Ride – PCF Challenge Award

Principal Investigators: Phuoc Tran, MD, PhD (Johns Hopkins University), Kenneth Pienta, MD (Johns Hopkins University)

Co-Investigators: Ana Kiess, MD, PhD (Johns Hopkins University), Hao Wang, PhD (Johns Hopkins University), Alexander Wyatt, PhD (University of British Columbia)

Project Title: Radiolabeled Systemic Therapy with SABR for Castration Sensitive Prostate Cancer Oligometastatic Disease

Description:

• Oligometastatic prostate cancer is an advanced disease state in which men have fewer than five sites of metastasis, but are still thought to be potentially curable.
• Phuoc Tran has previously demonstrated that targeting sites of oligometastatic prostate cancer with stereotactic ablative radiation (SABR), a highly focused form of radiation therapy, is feasible and prolongs progression-free survival. However, SABR alone was not curative in most men, and patients often progressed due to outgrowth of tumor deposits, particularly in the bone, that were too small to be detected by molecular imaging at the beginning of the study.
• Tran and team are conducting two clinical trials in patients with oligometastatic prostate cancer testing whether combining SABR with other systemic radioactive treatments can improve outcomes of patients with oligometastatic prostate cancer. The RAVENs trial will test SABR alone vs. in combination with radium-223. The BLUE JAE trial will test SABR in combination with the PSMA-targeted radionuclide therapy, ¹⁷⁷Lu-PSMA.
• In this project, Dr. Tran and team will use samples from the patients on these trials to investigate whether the levels of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) associate with patient outcomes.
• Epithelial-mesenchymal transition (EMT) is a phenomenon in which tumor cells change their phenotype to acquire invasive and metastatic properties. Whether low expression of EMT markers is associated with an attenuated metastatic phenotype of oligometastasis and improved outcomes of patients in these trials will be investigated.
• Immune responses may improve the efficacy of radiation therapy. Whether specific T-cells repertoire at the start of therapy in these trials may impact clinical outcomes will be determined.
• Finally, the frequency of inherited mutations in DNA repair genes in men with oligometastatic prostate cancer will be determined.
• If successful, this project will improve the management and understanding of the biology of oligometastatic prostate cancer.

What this means to patients:  Oligometastatic prostate cancer is thought to be a potentially curable state of prostate cancer, in which five or fewer metastases are present. Dr. Tran and team will conduct two clinical trials in men with oligometastatic prostate cancer to test the efficacy of stereotactic ablative radiation (SABR), a highly focused form of radiation therapy combined with other systemic radioactive treatments, and will investigate tumor biology and biomarkers of outcomes in these patients. This may lead to a new, curative treatment paradigm for men with oligometastatic prostate cancer.

2020 Larry and Camille Ruvo-PCF Special Challenge Award

Principal Investigators: Paul Boutros, PhD, MBA (University of California, Los Angeles), Robert Reiter MD (University of California, Los Angeles), Huihui Ye, MD (University of California, Los Angeles)

Project Title: The Influence of Germline Variation on Prostate Cancer RNA Circularization

Description:

• Prostate cancer is one of the most heritable forms of cancer, and a number of heritable (“germline”) genomic alterations that increase risk for prostate cancer have been identified. For instance, patients with specific versions of DNA Damage Repair (DDR) genes such as BRCA2, have a much higher likelihood of diagnosis and of dying of their disease.  However, how germline genome features influence the prostate cancer initiation and progression remain unclear.
• Circular RNA are a recently discovered class of RNA that form covalent circular structures and have many different cellular functions, in normal processes as well as in diseases such as cancer. The role of circular RNA in prostate cancer remains largely unexplored.
• Boutros and team hypothesize that germline genomic features impact the circular RNA landscape and have a role in localized prostate cancer.
• In this project, the team will determine whether common (>5% population frequency) germline features influence the circular RNA landscape of localized prostate cancer, using samples from a biobank of prostate cancer patient tissues.
• Whether rare (<5% population frequency) deleterious germline alterations in DDR genes influence the circular RNA landscape of localized prostate cancer will be investigated.
• In addition, the team will determine how the circular RNA landscape of localized prostate cancer differs between patients of different ancestries.
• If successful, this project will uncover the ways in which a patient’s germline genome influences prostate cancer evolution via regulation of the unexplored landscape of circular RNAs. These studies will improve our understanding of how to prevent, diagnose, prognose and treat lethal prostate cancer.

What this means to patients:  Dr. Boutros and team will perform the first study of the way in which the germline genome influences the circular RNA landscape of prostate cancer.  These studies will greatly improve understanding of prostate cancer biology including in patients of different ancestries and lay the groundwork for the development of new risk prediction tools, prognostic biomarkers, and treatment opportunities.

2020 Robert F. Smith-PCF Special Challenge Award

Principal Investigators: Christopher Haiman, ScD (University of Southern California)

Co-Investigators: Ann Hamilton, PhD (University of Southern California), Scarlett Gomez, PhD (University of California, San Francisco), Rosemary Cress, DrPH (Public Health Institute), Aaron Thrift, PhD (Baylor College of Medicine), Antoinette Stroup, PhD (Rutgers, the State University of New Jersey), Jennifer Beebe-Dimmer, PhD (Wayne State University), Xiao-Cheng Wu, MD/MPH (Louisiana State University – Health Sciences Center), Kevin Ward, PhD (Emory University), Maria Schymura, PhD (Health Research, Inc./New York State Department of Health)

Project Title: Optimization and Clinical Assessment of a Polygenic Risk Model for Targeted Screening and Strategic Earlier Detection of Prostate Cancer in Men of African Ancestry: “SPEAR Test”

Description:

• Prostate cancer is one of the most heritable forms of cancer. Studies have identified genetic loci that contribute to about 50% of familial prostate cancer risk.  However, most of these studies have been performed in men of European ancestry, and polygenic risk score-based risk prediction is inadequate in other racial and ethnic populations. This means that men from other racial and ethnic populations will not receive the same benefit as men of European ancestry when such tests become available and offered by their physician to guide medical decisions, including whether to be screening and at what age.
• To improve risk prediction in multiethnic populations, multiethnic genetic studies on prostate cancer risk are needed.
• Christopher Haiman and team are conducting the ongoing NCI/PCF RESPOND study, a collaborative initiative to generate genetic data for >32,000 prostate cancer cases and >74,000 controls of African ancestry by 2024, in order to understand the biological contributors to prostate cancer risk in African American men.
• This Robert F. Smith-PCF Challenge Award will be used to enhance the population-based recruitment of African American men with incident prostate cancer in RESPOND. This will include support of recruitment and patient sample collection activities at established recruitment sites, and to establish new recruitment sites in RESPOND.
• If successful, this project will accelerate the completion of RESPOND study patient cohort enrollment and data collection, which will enable large-scale genomic studies on prostate cancer risk to be performed in the African American population.

What this means to patients:  Dr. Haiman and team are creating a database of genetic data on ~100,000 African American men, in order to identify prostate cancer genetic risk factors and develop a clinical “polygenic risk score” test to identify men at highest lifetime risk of prostate cancer, who should undergo enhanced prostate cancer screening at earlier ages.  This will reduce prostate cancer disparities in African American men by enabling earlier detection and treatment of prostate cancer, when the chance for cures are significantly higher.

2020 Ken Griffin-PCF Special Challenge Award

Principal Investigators: Joseph Vinetz, MD (Yale University), Geoffrey Chupp, MD, (Yale University)

Co-Investigators: Anne Spichler, MD, PhD (Yale University), Kailash Patra, PhD (Yale University), Aryeh Salovey, (Yale University), Alan Marroquin (Yale University), Reetika Chaurasia (Yale University)

Project Title: Targeting TMPRSS2 in Early COVID-19

Description:

• Recent work has established that the TMPRSS2 enzyme is both necessary and sufficient for infection of human host cells by SARS-CoV-2.  Preliminary studies have demonstrated that SARS-CoV-2 infection can be prevented in cells by the TMRPSS2 inhibitors, camostat and nafamostat.
• TMRPSS2 is a protein originally identified and studied in prostate cells, which has a significant role in prostate cancer initiation and progression.  This connection between prostate cancer and COVID-19 has resulted in a rapid and impactful shift of cancer researchers to focus on identifying solutions for the COVID-19 pandemic.
• Dr. Joseph Vinetz and team are conducting a clinical trial to test camostat mesylate, a TMPRSS2 inhibitor used for the treatment of pancreatitis in Japan, in patients who have recently tested positive for SARS-CoV2 infection. This drug has a strongly favorable safety record, and the FDA has approved the study.
• This two-stage trial will first test whether camostat reduces viral load in patients compared to placebo, and will then determine the impact of camostat vs. placebo on clinical outcomes including progression of disease symptoms, oxygenation and hospitalization.
• Dr. Vinetz and team will also perform correlative studies to evaluate the immune system biology of patients treated with camostat, and to confirm the impact of camostat on TMPRSS2 levels in patient samples.
• If successful, this project will result in a new effective treatment for preventing disease progression and poor outcomes in patients infected with SARS-CoV2.

What this means to patients:  Dr. Vinetz is conducting a clinical trial to test the efficacy of camostat, a TMPRSS2 inhibitor, on preventing disease progression and poor outcomes in patients that recently tested positive for SARS-CoV2 infection.  This approach, which harnesses an available drug with known safety data, and biological knowledge derived from prostate cancer research, may result in an effective new treatment for COVID-19.