Challenge Awards – Class of 2022

The PCF Challenge Award Winners – Class of 2022 recipients are:

2022 Movember-PCF VAlor Challenge Award

Principal Investigators: Isla Garraway, MD, PhD (University of California, Los Angeles; Greater Los Angeles VA Healthcare System), Kara Maxwell, MD, PhD (University of Pennsylvania),Corporal Michael J. Crescenz VA Medical Center), Kosj Yamoah, MD, PhD (Moffit Cancer Center), Timothy Rebbeck, PhD (Dana-Farber Cancer Institute; Harvard TH Chan School of Public Health), Brent Rose, MD (University of California, San Diego)

Co-Investigators: Daniel Lee, MD, MS (University of Pennsylvania), Nicholas Nickols, MD, PhD (University of California, Los Angeles), Michael Lewis, MD (Greater Los Angeles VA Healthcare System), Matthew Rettig, MD (University of California, Los Angeles), Saiju Pyarajan, PhD (Brigham and Women’s Hospital)

Project Title: The Rate Elements Skewing Outcomes Linked to Veteran Equity in PCa (RESOLVE PCa) Consortium: Multilevel Modeling to Predict Prostate Cancer Incidence and Aggressiveness

Description:

• Racial disparities in prostate cancer pose a significant public health problem. Understanding the complex factors that contribute to disparities is critical for solving them and improving the lives of patients with prostate cancer.
• In a study in over 70,000 patients with prostate cancer, Dr. Isla Garraway and colleagues found that despite similar screening, self-identified Black/African American patients had a significantly higher incidence of localized and metastatic prostate cancer compared to White/European American patients.
• The team is leveraging a mega-dataset of clinical, demographic, survey and genetic data from over 500,000 Veterans.
• In this project, the team will apply complex modeling approaches to parse out the genetic (polygenic risk score, rare variant alterations, ancestral markers) and non-genetic (self-identified race/ethnicity, social determinants of health, socioeconomic status, and environmental exposures) factors that contribute to disparities in prostate cancer incidence, aggressiveness, and outcomes.
• If successful, this project willdevelop a multi-level prostate cancer risk prediction model and create improved prostate cancer screening and treatment paradigms. 

What this means to patients:  Understanding the factors that contribute to prostate cancer disparities is a critical unmet medical need.  Dr. Garraway and colleagues will use a vast dataset with clinical, demographic, and genetic data from over 500,000 Veterans, to identify social and environmental vs. genomic/genetic factors that contribute to prostate cancer racial disparities and develop models for predicting risk and improving tailored patient screening and management strategies.

2022 Movember-Distinguished Gentleman’s Ride-PCF VAlor Challenge Award

Principal Investigators: Lorelei Mucci, ScD, MPH (Harvard T.H. Chan School of Public Health), Daniel George, MD (Duke University)

Co-Investigators: Dana Rathkopf, MD (Memorial Sloan Kettering Cancer Center), Konrad Stopsack, MD, MPH (Harvard T.H. Chan School of Public Health), Terry Hyslop, PhD (Duke University), Karen Autio, MD (Memorial Sloan Kettering Cancer Center), Deborah Enting, MD, PhD (Guy’s and St Thomas’ NHS Foundation Trust)

Young Investigators: Yiwen Zhang, PhD (Harvard T.H. Chan School of Public Health), Hannah McManus, MD (Duke University)

Project Title: IRONMAN: Enhancing Survivorship in Patients with Advanced Prostate Cancer

Description:

• Patients with advanced prostate cancer are at greatest risk of cancer death, but also suffer quality of life deterioration and adverse events due to the cancer and its therapies.
• Understanding the factors that impact survivorship outcomes, risk factors for adverse events, and unmet needs of patients, will allow the identification of opportunities and strategies for helping patients to thrive despite living with advanced prostate cancer.
• IRONMAN is a global registry that collects real-world clinical, demographic, and lifestyle data, as well as tissue and blood samples, from patients newly diagnosed with metastatic hormone sensitive or castration resistant prostate cancer.
• In this project, Drs. Lorelei Mucci, Daniel George, and team will leverage data from IRONMAN on over 1,500 patients with advanced prostate cancer, to study the relationships between clinical, demographic and lifestyle factors, with survivorship outcomes, with a focus on racial health disparities.
• How patient-reported quality of life domains such as cognitive function, sleep quality, pain, fatigue, and psychosocial health are associated with demographic, clinical, and lifestyle factors including physical activity, will be investigated, to identify factors that predict flourishing after diagnosis of advanced prostate cancer.
• The impact of patient demographic and clinical factors on treatment decisions, treatment disparities, and clinical outcomes will be investigated.
• “Biological aging,” which can be measured by analyzing the state of DNA, may be accelerated past a patient’s chronological age by hormonal therapy and comorbidities. The relationships between biological age and quality of life measurements, serious adverse events, and overall survival, will be investigated.
• If successful, this project will identify relationships between clinical, demographic, and lifestyle factors, and patient quality of life and outcomes. This will enable the identification of strategies for improving quality of life, extending survival, and reducing health disparities for patients with advanced prostate cancer.

What this means to patients:  Survivorship is a field of oncology which aims to understand and improve quality of life in patients living with or after cancer. Drs. Mucci, George, and team’s project focuses on understanding patients’ cancer experience and quality of life, their prognosis, and treatment disparities. These findings will inform practice, identify unmet needs, reduce disparities, and identify strategies for advanced prostate cancer patients to flourish.

2022 Michael & Lori Milken Family Foundation-PCF Challenge Award

Principal Investigators: Himisha Beltran, MD (Dana-Farber Cancer Institute)

Co-Investigators: Andres Acosta, MD (Brigham and Women’s Hospital), Jacob Sands, MD (Dana Farber Cancer Institute), Sheng-Yu Ku, PhD (Dana-Farber Cancer Institute)

Project Title: Mechanisms of Response and Resistance to DLL3-Targeted T Cell Engager Therapy

Description:

• Neuroendocrine prostate cancer (NEPC) is a rapidly progressive and highly lethal form of advanced prostate cancer. There are no approved therapies for NEPC and very few clinical trials have been dedicated to patients with NEPC.
• Beltran and colleagues have been studying NEPC biology to discover therapeutic targets and develop new treatments.
• Her team identified DLL3 as a protein that is on the surface of the vast majority of NEPC tumor cells and other neuroendocrine cancers such as small cell lung cancer (SCLC) but is not expressed in normal cells. The cancer specificity and optimal cellular location of DLL3 make it a promising therapeutic target for these difficult to treat cancers.
• Beltran and colleagues have observed promising preliminary safety and efficacy with the novel DLL3-targeting immunotherapy, HPN328, in a phase 1 trial in NEPC and SCLC. HPN328 is a tri-specific T cell engager, that simultaneously binds to DLL3 on tumor cells and to T cells, thereby bringing T cells into contact with tumor cells to kill them (its 3^rd arm binds to albumin in blood, which increases its circulation time).
• In this project, the team will develop methods to improve patient selection for DLL3-targeted therapies, using samples and data from patients on the phase 2 expansion trial. DLL3 levels, immune cells, and tumor gene expression and mutations will be evaluated in NEPC and SCLC patient tumor and blood samples, before and during HPN328 treatment, to identify patterns that correlate with treatment responses.
• Mouse models will be studied to understand the mechanism of action of HPN328 and potential treatment resistance mechanisms. Mouse models of NEPC and SCLC will be treated with HPN328.  The effects of differences in DLL3 expression, T cell activity, and tumor microenvironment, on treatment efficacy will be studied. Whether combining HPN328 with other immunotherapies may increase efficacy will also be investigated.
• If successful, this project will identify biomarkers for selecting NEPC and SCLC patients most likely to benefit from DLL3-targeting treatments and identify strategies for improving the efficacy of HPN328.
• The direct comparison of NEPC with SCLC will reveal biological similarities between these cancer types and enable knowledge from one field to be applied to the other, ultimately improving outcomes for patients with these aggressive cancers.

What this means to patients:  NEPC is a highly aggressive and lethal form of advanced prostate cancer with no approved therapies. Dr. Beltran and team are investigating a new immunotherapy for NEPC that may also have efficacy in SCLC. They will determine how to best select patients for this treatment and identify strategies to improve treatment efficacy.

2022 Stewart Rahr Foundation-PCF Challenge Award

Principal Investigators: Samuel Denmeade, MD (Johns Hopkins University), Robert Casero, PhD (Johns Hopkins University), Erika Pearce, PhD (Johns Hopkins University)

Co-Investigators: Laura Sena, MD, PhD (Johns Hopkins University), Angelo DeMarzo, MD (Johns Hopkins University), Hao Wang, PhD (Johns Hopkins University), David Sanin, PhD (Johns Hopkins University)

Project Title:  Hormonal Shock Therapy for Metastatic Castrate Resistant Prostate Cancer

Description:

• Prostate cancer cells maintain androgen receptor (AR) activity at a level optimal for growth and survival. Bipolar androgen therapy (BAT) is a promising experimental treatment that cycles patients between extremely high and extremely low levels of androgens; this causes prostate cancer cells to die, and those that survive by adapting to the new conditions are then sensitive to the next extreme shift in androgen levels. Unfortunately, only ~30% of patients benefit from BAT, and this treatment is not curative.  Methods to improve on this strategy remain needed.
• Samuel Denmeade and team have identified the polyamine pathway as a potential driver of BAT resistance and therapeutic target to improve on the efficacy of BAT.
• In this project, Denmeade and team will perform a clinical trial testing BAT in combination with the polyamine inhibitor DFMO, in sequence with enzalutamide, in patients with castration resistant prostate cancer (CRPC).
• Samples from patients on this trial will be studied to confirm the ability of DFMO to inhibit the polyamine pathway in tumors, and the impact of this treatment combination on tumor metabolism and gene expression.
• Whether and how this treatment impacts the anti-tumor immune response will also be studied using samples from this trial.
• If successful, this project will identify a promising new treatment strategy for CRPC and define the mechanism of action in patients.

What this means to patients:  Bipolar androgen therapy (BAT) is promising treatment strategy that requires further optimization for maximum patient benefit.  This project will test a new combination treatment strategy that targets the polyamine pathway to block treatment resistance and define the mechanisms by which this treatment blocks tumor growth in patients.

2022 John Black Charitable Foundation-PCF Challenge Award

Principal Investigators: Harveer Dev, MD, PhD (University of Cambridge), Simon Pacey, MD, PhD (University of Cambridge), Charlie Massie, PhD (University of Cambridge)

Co-Investigators: Hisham Mohammed, PhD (Knight Cancer Institute)

Project Title: First-In-Man PARP1-Selective Inhibitor in Lethal Prostate Cancer: Mechanisms of Action and Biomarkers of Therapeutic Response

Description:

• PARP-inhibitors are a new class of treatments that are approved for patients with metastatic castration resistant prostate cancer (mCRPC) with alterations in certain DNA repair genes, and are under investigation in broader patient groups and in combination with other therapies.
• Recent phase 3 clinical trials found that the combination of a PARP-inhibitor with next generation hormonal agents were efficacious in mCRPC patients regardless of whether they had DNA repair gene alterations.However, not all patients responded to this combination. It remains unclear how this combination therapy works in genomically ‘DNA repair proficient’ tumors and how to identify the patients most likely to benefit.
• Harveer Dev and team are studying the mechanisms of action of combining PARP-inhibitors with anti-androgen therapy in mCRPC.
• In this project, Dr. Dev and team will determine whether epigenetic patterns in tumor cell DNA can serve as biomarkers of response to PARP-inhibitor + anti-androgen combination therapy.  Whether these biomarkers can be detected in circulating tumor DNA will be determined, and the team aims to ultimately develop a liquid biopsy-based biomarker test to select patients for this treatment.
• Prostate cancer models will be used to determine the role of various DNA repair genes in response to various doses and timings of PARP-inhibitor + anti-androgen combinations, in order to identify optimal personalized treatment dosing strategies.
• Samples from patients treated with PARP-inhibitor + anti-androgens in clinical trials will be studied to determine how the treatment impacts tumor and immune biology.
• If successful, this project will elucidate the mechanisms of action of PARP-inhibitor + anti-androgen combination therapy, and result in the development of a blood-based biomarker test that can identify patients most likely to benefit from this treatment.

What this means to patients:  The combination of a PARP-inhibitor with anti-androgen therapy is a promising new treatment strategy for patients with mCRPC, that is currently under FDA-evaluation for approval.  Dr. Dev’s project will elucidate the biology of this treatment combination and develop a blood test to select which patients are most likely benefit from this therapy.

2022 Stupski Foundation-PCF Challenge Award

Principal Investigator: Christina Dieli-Conwright, PhD, MPH (Dana-Farber Cancer Institute)

Co-Investigators: Rebekah Wilson, PhD (Dana-Farber Cancer Institute), Alicia Morgans, MD (Dana-Farber Cancer Institute), Michael Rosenthal, MD, PhD (Dana-Farber Cancer Institute), Hajime Uno, PhD (Dana-Farber Cancer Institute), Matthew Vander Heiden, MD, PhD (Dana-Farber Cancer Institute)

Project Title: Debunking the Frailty-SarcopenIa-ADT Axis in MEtastatic Prostate CanceR with MultiCompenent Exercise: The FIERCE Trial

Description:

• Androgen deprivation therapy (ADT), the mainstay treatment for advanced prostate cancer, can cause a number of side effects, including decline in muscle mass and physical function, which exacerbates age-related conditions such as frailty and sarcopenia (a decrease in muscle mass, strength, and function). Frailty and sarcopenia are associated with worse outcomes and shorter survival in patients with prostate cancer.
• Patients who received ADT are 3 times more likely to develop frailty compared to patients who never received ADT and 2 times more likely to develop sarcopenia compared to men without cancer.
• Exercise plays a key role in resolving or preventing these ADT-related side effects and improving muscle mass, fitness, and strength.
• Multicomponent exercise incorporates resistance and aerobic training combined with functional movements (e.g., balance) and can maximize the beneficial effects of exercise on physical function, muscular strength/endurance, and body composition, and is recommended for improving/preventing frailty and sarcopenia.
• The impacts of exercise have been vastly understudied in men with metastatic prostate cancer. Studies on frailty and sarcopenia and the mechanisms of how exercise could address such outcomes, are especially needed.
• Dieli-Conwright is an expert in exercise oncology and has led multiple clinical trials evaluating the impact of exercise in patients with prostate and other cancers.
• In this project, Dr. Dieli-Conwright and team will conduct a clinical trial, “FIERCE,” to assess the effects of a 16-week multicomponent exercise intervention, encompassing resistance, aerobic, and functional training, on frailty, sarcopenia, and disease progression, in men with metastatic prostate cancer receiving ADT.
• Eighty men with metastatic prostate cancer receiving ADT will be randomized to the exercise or attention control group. The 16-week exercise intervention will include 3x per week clinic-supervised resistance and functional exercise circuit training, and self-directed home-based aerobic exercise. The attention control group will receive a stretching program and will be offered the exercise program following the study period. The impacts on frailty and sarcopenia will be measured and compared.
• In addition, samples from patients will be used to identify biomarkers of exercise effects and potential mechanisms of how exercise may improve frailty and sarcopenia. For instance, inflammatory and muscle activity markers will be evaluated. These mechanisms will be further studied and validated in preclinical prostate cancer models.

What this means to patients:  ADT is the standard backbone treatment for patients with aggressive and advanced prostate cancer, but can cause significant side effects, including exacerbation of frailty and sarcopenia.  Dr. Dieli-Conwright and team will conduct a clinical trial to test the impact of a multicomponent exercise intervention on frailty and sarcopenia in men undergoing treatment with ADT.  The team will also identify biomarkers of response and mechanisms by which exercise improves these functions.  If successful, this study will establish an exercise treatment program to prevent degenerative effects of ADT and significantly improve quality of life and outcomes in men with prostate cancer.

2022 Patrice & Precious Motsepe-PCF VAlor Challenge Award

Principal Investigators: David Goodrich, PhD (Roswell Park Comprehensive Cancer Center), Gurkamal Chatta, MD (Roswell Park Comprehensive Cancer Center), Dean Tang, PhD (Roswell Park Comprehensive Cancer Center), Dominic Smiraglia, PhD (Roswell Park Comprehensive Cancer Center)

Co-Investigators: Mark Long, PhD (Roswell Park Comprehensive Cancer Center), Himisha Beltran, MD (Dana-Farber Cancer Institute)

Project Title: Developing and Translating Innovative Strategies to Therapeutically Target Prostate Cancer Lineage Plasticity

Description:

• Androgen receptor (AR)-targeted therapy is standard of care for advanced prostate cancer, yet virtually every patient eventually develops treatment resistance and progresses to castration resistant prostate cancer (CRPC).  CRPC can take on various forms in the same patient, including forms driven by AR pathway alterations and forms that no longer rely on AR (AR-independent), such as neuroendocrine prostate cancer (NEPC).
• Lineage plasticity, the ability of cancer cells to alter their phenotype and take on characteristics of alternate cell types, is known to be a key contributor to treatment resistance and progression to NEPC.
• While prior studies have focused on the role of lineage plasticity in NEPC and other forms of AR-independent CRPC, Dr. Goodrich and team hypothesize that lineage plasticity actually drives all forms of CRPC, and that a subset of cancer cells can develop this potential early and persist through therapy. Thus, therapeutic approaches that target lineage plasticity may prevent CRPC.
• In this project, the team will investigate three treatment strategies to target lineage plasticity in prostate cancer and prevent progression to CRPC: 1) targeting a gene that appears essential in AR-independent prostate cancer cells (BCL2), and 2) targeting epigenetic mechanisms that enable lineage plasticity (DNA methylation).  Both of these strategies will be tested in combination with a third strategy, which uses supraphysiologic androgens (bipolar androgen therapy) to suppress prostate cancer cell reprogramming from an AR-dependent to an AR-independent state.
• These studies will use a combined approach of experimental models and samples from clinical trials testing these treatments in patients, to determine the potential therapeutic utility and mechanisms of action of these treatment strategies for preventing CRPC and prolonging the efficacy of AR-targeted therapy.
• If successful, this project will identify new therapeutic strategies to prevent lineage plasticity and progression to CRPC.

What this means to patients:  Lineage plasticity is a biological process important in early organism development, that is hijacked by cancer cells to adapt to cancer therapies and progress. This project will test the ability of several therapeutic approaches to prevent lineage plasticity and the development of CRPC.  This may lead to innovative new combination approaches that improve patient outcomes by extending the clinical benefit of AR-targeted therapies.

2022 PCF Challenge Award

Principal Investigator: Massimo Loda, MD (Weill Cornell Medicine)

Co-Investigators: David Nanus, MD (Weill Cornell Medicine), Christopher Barbieri, MD, PhD (Weill Cornell Medicine), Caroline Ribeiro, PhD, MSc (Weill Cornell Medicine), Marcus DaSilva Goncalves, MD, PhD (Weill Cornell), Katie Hootman, PhD (Weill Cornell Medicine), James Kelly, PhD (Weill Cornell Medicine), Karla Ballman, PhD, MS (Weill Cornell Medicine), Pier Vitale Nuzzo, MD, PhD (Weill Cornell Medicine), Steve Plymate, MD (University of Washington) Johan Swinnen, PhD (International Food Policy Research Institute)

Project Title: Targeting Lipid Metabolism and Diet in Patients with Locally Advanced Prostate Cancer

Description:

• A hallmark of cancer cells is altered cellular metabolism, to support their constant and rapid growth. In contrast to normal cells, which take up nutrients from their environment according to their needs, prostate cancer cells fuel themselves by synthesizing large amounts of lipids.
• FASN is an enzyme critical for lipid generation in prostate cancer cells. Previous preclinical studies have demonstrated that targeting FASN suppresses prostate tumor growth. This suggests that FASN-inhibitors may be promising treatments for prostate cancer.
• Further, Dr. Loda and colleagues hypothesize that dietary modulation of the exogenous lipids used in lipid synthesis pathways can potentiate the efficacy of FASN-inhibitors.
• In this project, Dr. Loda and team are conducting a phase 2 clinical trial to evaluate the efficacy of a FASN inhibitor plus a custom and metabolically defined PUFA-rich, limited-fat diet in patients newly diagnosed with locally advanced prostate cancer who plan to undergo subsequent radical prostatectomy.
• Whether molecular imaging and metabolic/lipid profiling may function as biomarkers to monitor patient responses to the FASN-inhibition + a PUFA-rich diet intervention, will be investigated.
• In parallel, preclinical studies will be conducted to evaluate the mechanisms by which PUFAs enhance the efficacy of pharmacologic FASN inhibition.
• If successful, this project will result in a new therapeutic approach combining diet and pharmacologic intervention of a critical metabolic vulnerability in prostate cancer, and will determine the mechanisms of action of this treatment.

What this means to patients:  Altered metabolism is a hallmark of cancer but may also represent a vulnerability that can be therapeutically targeted.  Prostate cancer fuels itself through synthesizing its own lipids using the enzyme FASN.  Dr. Loda and team are conducting a clinical trial to test the effects of combining a treatment targeting FASN with a diet that modulates the levels of dietary lipids used in lipid synthesis pathways.  This may ultimately lead to a new treatment for prostate cancer patients, insights into the mechanisms of action, and biomarkers to guide management of patients considering or undergoing this treatment.

2022 John Black Charitable Foundation-PCF Challenge Award

Principal Investigator: Nigel Mongan, PhD (University of Nottingham)
Co-Investigators: Corinne Woodcock (University of Nottingham), Nathan Archer, PhD (University of Nottingham), Rupert Fray, PhD (University of Nottingham), Victoria James, PhD (University of Nottingham), Jennie Jeyapalan, PhD (University of Nottingham), Jennifer Lothion-Roy BVM BVS (University of Nottingham), Anna Harris BSc (University of Nottingham)

Project Title: Epitranscriptomic Determinants of Treatment Resistance in Prostate Cancer

Description:

• The androgen receptor (AR) is a primary driver of prostate cancer and is a key therapeutic target in patients with aggressive and advanced disease.  Unfortunately, resistance to AR-targeted therapy inevitably occurs.  Understanding the mechanisms of resistance and discovery of new ways to inhibit AR activity are urgently needed.
• Dr. Nigel Mongan and team have identified altered RNA methylation as a possible mechanism of resistance to the AR-targeted therapy enzalutamide.
• In this project, Dr. Mongan and team will investigate the roles of the RNA methylation in prostate cancer. The team previously found that RNA methylation plays a role in gene regulation in more aggressive prostate cancer.
• In this project, RNA methylation and its associations with clinical outcomes will be investigated in ethnically diverse prostate cancer cohorts from across the disease spectrum.
• Whether enzalutamide treatment alters the landscape of RNA methylation will be investigated in prostate cancer models.
• The team will also determine whether targeting RNA methylation may enhance the treatment efficacy of enzalutamide in preclinical prostate cancer models.
• If successful, this project will establish the role and potential of RNA methylation as a therapeutic target in prostate cancer.

What this means to patients:  Altered RNA methylation may contribute to treatment resistance in prostate cancer by changing the landscape of gene expression.  Dr. Mongan and team will determine whether aberrant regulation of RNA methylation is a driver of enzalutamide resistance, and whether therapies targeting RNA methylation may overcome enzalutamide resistance.  These data could lead to a new treatment strategy for patients with prostate cancer.

2022 Michael & Lori Milken Family Foundation-PCF Challenge Award

Principal Investigators: Akash Patnaik, MD, PhD (University of Chicago), Amy Moran, PhD (Oregon Health & Science University), David Sykes, MD, PhD (Massachusetts General Hospital)

Co-Investigators: Peter Sorger, PhD (Harvard Medical School), Jia-Ren Lin, PhD, MS (Harvard Medical School), Michael Haffner, MD, PhD (Fred Hutchinson Cancer Research Center), Colby Thaxton, MD, PhD (Northwestern University), Massimo Loda, MD (Weill Cornell Medicine), Theodore Karrison, PhD, MS (University of Chicago), Thomas Gajewski, MD, PhD (University of Chicago),

Young Investigators: Kiranj Chaudagar, PhD (University of Chicago), Mindy Graham, PhD (Johns Hopkins School of Medicine), Taghreed Hirz, PhD (Massachusetts General Hospital), Shenglin Mei, PhD (Harvard Medical School)

Project Title:  Activating the NLRP3 Inflammasome to Treat Advanced Prostate Cancer

Description:

• Immune checkpoint immunotherapies are cancer treatments that have been highly effective in several cancer types and can result in long term regressions and cures; however, these treatments have yet to be optimized in prostate cancer.
• A major reason for immunotherapy failure in prostate cancer is the “cold” tumor microenvironment which suppress anti-tumor immune cell activity. Strategies to improve immunotherapy in immunologically “cold” tumors such as prostate cancer are urgently needed.
• Prostate tumors are infiltrated with high levels of immunosuppressive myeloid cells, particularly tumor-associated macrophages (TAM).  Therapeutic strategies to reprogram TAMs may overcome immunosuppression within the metastatic prostate tumor microenvironment.
• Patnaik and colleagues have found that NLRP3, an immune-activating protein, is highly expressed in TAMs from patients with metastatic prostate cancer treated with ADT, and is a promising therapeutic target for reprogramming TAMs from immune-suppressive to immune-activating phenotypes.  In preclinical prostate cancer models, NLRP3 activation blocked tumor growth and was synergistic with androgen deprivation therapy (ADT).
• In this project, Dr. Patnaik and colleagues will investigate whether activation of NLRP3 will overcome TAM-mediated immunosuppression and sensitize advanced prostate cancer to immune checkpoint immunotherapy.
• The role of NLRP3 in tumor-infiltrating TAMs and other immune cells will be investigated in patient samples, before and after ADT treatment.
• The mechanisms by which ADT enhances NLRP3 expression and activity within TAMs will be investigated.
• The mechanisms and therapeutic efficacy of NLRP3 activating treatments, alone and in combination with ADT and immune checkpoint immunotherapies, will be investigated in preclinical prostate cancer mouse models.
• If successful, this project will determine the mechanisms and provide rationale for NLRP3-activation-based immuno-oncology combinations for advanced prostate cancer treatment.

What this means to patients:  Prostate cancers are typically immunologically “cold,” and thus immunotherapy rarely works.  Dr. Patnaik and team have identified NLRP3 as a promising target for reprogramming the prostate tumor microenvironment from immune-suppressive (“cold”) to immune-activating (“hot”). In this project, the team will demonstrate the mechanisms and potential for NLRP3-activation as a new treatment strategy, alone or in combination with immunotherapy and/or ADT. This will provide rationale for clinical trials testing NLRP3-activating agents in prostate cancer, which are already in clinical development.

2022 Igor Tulchinksy-Leerom Segal-PCF Challenge Award

Principal Investigators: Mark Rubin, MD (University of Bern), Gunnar Rätsch, PhD (ETH Zurich), Rahul Kanadia, PhD (University of Connecticut)

Co-Investigators: Anke Augspach, PhD (University of Bern), Andre Kahles, PhD (ETH Zurich), Takemoto Kazumasa, PhD (University of Connecticut)

Project Title: Leveraging Poison Introns for Therapeutics and Diagnostics of Lethal Prostate Cancer

Description:

• Genes are encoded in the genome in a non-contiguous fashion. During the RNA transcription process, various pieces of RNA code, called introns are removed, and other pieces called exons are spliced together to form the final messenger RNA code that is translated into proteins. Minor introns (often called “poison introns” because failure to remove them will result in significant protein alterations) are present in a small number of genes and a unique splicing complex called the minor spliceosome must splice them out.
• Dr. Mark Rubin and team are studying the biological processes by which altered RNA splicing contributes to prostate cancer pathogenesis.  They previously found that minor intron-containing genes enrich as direct interactors of prostate cancer-causing proteins. In addition, components of the minor spliceosome such as U6atac correlate with prostate cancer progression and represent a vulnerability of advanced prostate cancer. Importantly, prostate cancer cells were vulnerable to the inhibition of the minor spliceosome that was achieved through downregulation of U6atac.  These data suggest that the minor spliceosome and minor intron splicing may be a master regulator of prostate cancer.
• In this project, Dr. Rubin and the team will investigate the biology of minor RNA intron splicing in prostate cancer.
• The team will design novel strategies to downregulate U6atac to inhibit minor spliceosome and block minor intron splicing
• The molecular mechanisms by which the minor intron splicing complex, the minor spliceosome, contributes to splicing of minor and major intron during prostate cancer progression will be investigated.
• The team will also develop a prostate cancer risk assessment biomarker using differential minor spliceosome intron splicing complex component expression and activity.
• If successful, this project will define the biological role of minor splicing in prostate cancer, determine the therapeutic potential of targeting this process and develop a biomarker-based on this process to inform on prostate cancer progression and diagnosis.

What this means to patients: The role of minor intron splicing in prostate cancer is unclear but may be a crucial regulator of disease progression and therapy resistance. This project will provide a comprehensive insight into the impact of minor splicing on prostate cancer biology and therapy resistance and its potential as a risk assessment biomarker. This may ultimately lead to the development of new treatments targeting this pathway for patients with incurable, lethal prostate cancer.

2022 PCF Challenge Award

Principal Investigators: Howard Scher, MD (Memorial Sloan Kettering Cancer Center), Behfar Ehdaie, MD, MPH (Memorial Sloan Kettering Cancer Center), David Knorr, MD, PhD (Memorial Sloan Kettering Cancer Center), Matthew Dallos, MD (Memorial Sloan Kettering Cancer Center)

Co-Investigators: Andrea Are, PhD (Memorial Sloan Kettering Cancer Center), Anuradha Gopalan, MD (Memorial Sloan Kettering Cancer Center), Christopher Gaffney, MD (Memorial Sloan Kettering Cancer Center)

Project Title:  Enhancing Antigen Presentation and Antitumor Immunity for Prostate Cancers Through an Intratumorally Delivered, Fc-Enhanced Anti-CD40 Antibody Therapy

Description:

• Immunotherapy has revolutionized the treatment of many cancers, but unfortunately has helped only a minority of patients with prostate cancer. It is therefore critical that new immunotherapy approaches are developed that can eliminate prostate cancer cells early in the course of a patient’s illness, prevent progression and recurrence and increase the potential for cure.
• Needed is a more in-depth understanding of how the immune system responds to the disease itself, and how it is affected by the androgen deprivation approaches that are the backbone of treatment for prostate cancer.
• The immune system identifies cells using a process that begins with antigen presentation. Howard Scher and team have found that the lack of effective antigen presentation is a critical bottleneck to the immune system’s ability to identify and attack the disease.
• CD40 is a protein found on the surface of immune cells. The team has found that targeting CD40, using a novel antibody vaccine developed by the team, can enhance the ability of the immune cells to kill the cancer cells both at the site of injection and in other sites of spread in patients with metastatic disease.
• Building on the collective efforts of this multidisciplinary team, this project will test this novel drug, known as a CD40 agonist, within the context of a clinical trial that includes patients with intermediate risk disease who can safely in the view of their treating physician, postpone radical prostatectomy to receive the drug alone, and separately, patients with high-risk localized or metastatic disease in combination with standard androgen deprivation therapy.
• These studies will significantly impact our understanding of the how and why prostate cancers remain resistant to immune-based approaches, as well as test a novel approach to overcoming barriers to achieving an effective immune response.
• If this treatment is effective, it may result in the elimination of all disease and enable patients with prostate cancer to live longer with an improved quality of life.

What this means to patients:  Immunotherapy is a highly promising form of cancer treatment, yet barriers remain to realizing the full potential these treatments for prostate cancer.  Dr. Scher and team have developed a novel immunotherapy that targets a key immune activation pathway and will test and determine the mechanisms of action of this treatment in patients with prostate cancer.  This may lead to an effective new, and possibly even curative treatment for prostate cancer.

2022 PCF Challenge Award

Principal Investigators: Di Zhao, PhD (The University of Texas MD Anderson Cancer Center), Ana Aparicio, MD (The University of Texas MD Anderson Cancer Center), Sangeeta Goswami, MD, PhD (The University of Texas MD Anderson Cancer Center)

Co-Investigator: Wenyi Wang, PhD (The University of Texas MD Anderson Cancer Center)

Young Investigator: Wei Shi, PhD (The University of Texas MD Anderson Cancer Center)

Collaborators: Nora Navone, MD, PhD (The University of Texas MD Anderson Cancer Center), James Allison, PhD (The University of Texas MD Anderson Cancer Center)

Project Title:  Targeting B7-H3 in Aggressive Variant Prostate Cancer

Description:

• Aggressive variant prostate cancer (AVPC) is a rapidly lethal form of metastatic castration resistant prostate cancer (mCRPC) that can be identified by clinical and molecular features. AVPCs have dismal prognoses and effective therapies for this subset are urgently needed.
• Di Zhao and team have previously demonstrated that AVPCs commonly express high levels of B7-H3, an immune-regulatory protein that has emerged as a promising target for cancer immunotherapy. They also found that depletion of B7-H3 in AVPC models impaired tumor progression and reversed the immunosuppressive tumor microenvironment.
• These data suggest that B7-H3 may be a promising therapeutic target for patients with AVPC.
• In this project, Dr. Zhao and team will use cutting edge digital pathology to assess the expression patterns and role of B7-H3 in mCRPC and AVPC. The association between B7-H3 patterns with treatment responses and clinical outcomes will be investigated.
• The mechanisms that cause B7-H3 overexpression in AVPC will be determined.
• DS-7300 is a B7-H3-targeted antibody drug conjugate that is currently under pharmaceutical development for various types of cancer, that has shown promising activity in early clinical trials. The team will investigate the efficacy and mechanisms of action of DS-7300 treatment in preclinical AVPC models.
• If successful, this project will provide biological rationale for clinical trials testing B7-H3-targeting treatments in patients with AVPC.

What this means to patients:  AVPC is a highly aggressive and lethal form of advanced prostate cancer for which there are currently no effective treatments.  Dr. Zhao and team will determine the role of B7-H3 in AVPC and mCRPC and its potential as a therapeutic target, thus laying the foundation for clinical trials testing B7-H3-targeting treatments in patients with currently untreatable forms of aggressive prostate cancer.

2022 PCF – Janssen Special Challenge Award

Principal Investigators: Eric Small, MD (University of California, San Francisco), Rahul Aggarwal, MD (University of California, San Francisco), Julian Hong, MD, MS (University of California, San Francisco), David Quigley, PhD (University of California, San Francisco)

Co-Investigators: Meera Chappidi, MD, MPH (University of California, San Francisco), Adam Foye, BS (University of California, San Francisco), Li Zhang, PhD (University of California, San Francisco)

Project Title: Advancing the Drug Development Process in Metastatic Prostate Cancer through Machine Learning

Description:

• Clinical trials are necessary to test the efficacy and safety of new treatments and provide the data necessary for regulatory approval for patients. However, trials can often take a long time, due in part to the endpoints measured, such as overall survival (OS).  This endpoint takes many years to reach in men with metastatic prostate cancer.
• Attempts to identify intermediate biomarkers for overall survival have largely been unsuccessful, as traditional one-dimensional approaches have evaluated simple kinetics or just one or two clinical parameters at a time.
• Eric Small and team are using longitudinal machine learning approaches that can test billions of combinations of kinetic clinical variables, to identify novel patterns that may serve as intermediate endpoints that are highly predictive of overall survival.
• The team will apply machine learning models to comprehensive molecular, clinical, and outcomes data from nearly 6,000 patients with metastatic prostate cancer on clinical trials. Promising models will be validated in large real-world datasets.
• This project will develop and validate two types of models: 1) predicting survival at 72 months, using data from the first 18 months of treatment, and 2) predicting survival at 12 months with data from the first 2 months of therapy.
• If successful, this project will identify intermediate clinical endpoints are highly predictive of overall survival in patients with metastatic prostate cancer and may help to speed clinical trials in this setting.

What this means to patients:  The identification of intermediate clinical endpoints which can be used much earlier in clinical trials to determine the impact of a new treatment on patients’ overall survival will greatly speed the development of new treatments. Dr. Small and team will use a machine learning approach to identify novel kinetic, multi-dimensional biomarkers that can serve as accurate predictors of overall survival, which will accelerate the “readout” timeline for late phase studies in metastatic prostate cancer, and lead to faster patient access to effective new therapies.

2022 Count Me In-PCF Special Challenge Award for Metastatic Prostate Cancer

Principal Investigators: Eliezer Van Allen, MD (Harvard: Broad Institute of MIT & Harvard)

Co-Investigators: Ben Zola, BS (Harvard: Broad Institute of MIT & Harvard), Parker Chastain, MPH (Harvard: Broad Institute of MIT & Harvard), Elana Anastasio, BA (Harvard: Broad Institute of MIT & Harvard), and Matias Vergara, MS (Harvard: Broad Institute of MIT & Harvard)

Project Title: Metastatic Prostate Cancer (MPC) Project

Description:

• Count Me In is patient-partnered research program at the Harvard: Broad Institute of MIT & Harvard and Dana-Farber Cancer Institute that allows patients with cancer who live in the U.S and Canada to contribute their data and samples to research. Patients may join by registering online, which gives the program permission to contact their doctors and obtain their medical records, archival cancer samples and saliva or blood samples.
• The Metastatic Prostate Cancer Project, led by Dr. Eliezer Van Allen, is a project within Count Me In that specifically focuses on understanding the genomics and biology of metastatic prostate cancer. Over 1,000 patients with metastatic prostate cancer have already enrolled in this project.
• In this project, genomic sequencing and in-depth molecular profiling on prostate cancer samples is being performed and artificial intelligence and machine learning technologies are being used to understand relationships between biological features, clinical features and patient outcomes. Data from the project are de-identified and released on open access genomics discovery portals so that other researchers may study the data. Results from these studies are also shared with patients, to create a true patient-researcher partnership paradigm.
• The goals of this project are to comprehensively profile the genomics and molecular features of metastatic prostate cancer, identify biomarkers for precision oncology and discover new biology and treatment strategies.

What this means to patients:  Count Me In and The Metastatic Prostate Cancer Project are opportunities for patients with cancer to contribute to research breakthroughs by contributing their medical data and tissue samples.  Dr. Van Allen and team are using data from over 1,000 enrolled patients to comprehensively profile the genomic landscape of metastatic prostate cancer and to make new discoveries that can be used to guide treatment decisions and discover new treatment strategies.