The PCF Young Investigator Award-Class of 2018 recipients are:
2018 Paz Littman & Morris Kahn–PCF Young Investigator Award
Harvard: Dana-Farber Cancer Institute
Mentor: Eliezer Van Allen, MD
Proposal Title: Novel Epidemiological and Computational Genomic Approaches to Explore the Missing Heritability of Primary and Metastatic Prostate Cancer
- Prostate cancer is one of the most highly heritable forms of cancer, with up to 60% of prostate cancer risk attributable to inherited genetic defects. However, studies have only identified the heritable genes responsible for ~5% of primary prostate cancer and ~10% of metastatic prostate cancer.
- Saud AlDubayan is working to identify previously undiscovered inherited genetic factors that increase the risk of developing prostate cancer, particularly in underrepresented populations of non-European ancestry.
- To identify novel mechanisms for inherited cancer risk, cancer progression and treatment resistance, the germline genomic profiles of Arab prostate cancer patients and ancestry-matched controls will be examined. This will be achieved through using large prostate cancer biobanks and centers in Saudi Arabia.
- In addition, novel genetic factors that contribute to prostate cancer heritability will be identified using computational analyses of paired germline whole exome and transcriptome sequencing data of prostate cancer patients using the TCGA database. This approach will identify non-canonical splice site, non-coding genetic and epigenetic events.
- If successful, this study will identify novel inherited prostate cancer risk genes, and will improve the ability of patients to determine if their cancer was inherited and whether other family members may be at increased risk.
What this means for patients: Dr. AlDubayan will identify new inherited genetic alterations that increase risk for prostate cancer, including in Arab populations. This will improve screening and prevention measures as well as improve our understanding of the biology of inherited prostate cancer.
2018 Clovis Oncology – PCF Young Investigator Award
University of Surrey, UK
Mentor: Hardev Pandha, MB CHb, David Spring, MBBS, David Neal, DPhil
Proposal Title: Characterization and Pre-Clinical Development of a Novel Dual Activity Anti-Androgen for Castration Resistant Prostate Cancer
- The androgen receptor (AR) is the major driver of prostate cancer and a key therapeutic target. However, the development of resistance to AR-targeted therapy and progression to castrate-resistant prostate cancer (CRPC) is common, and no curative treatments yet exist for this lethal form of prostate cancer.
- Resistance to AR-targeted therapy is often associated with expression of constantly active variants of the AR protein (AR-Vs) that cannot be inhibited by current treatments.
- Mohammad Asim is developing a novel AR-targeting treatment for prostate cancer, which is able to block the activity of full-length AR as well as AR-Vs.
- Preclinical studies will be performed to validate the efficacy and mechanisms of action of a novel anti-AR compound (CAM-09) in prostate cancer cells.
- New derivatives of CAM-09 will be developed to identify compounds with improved activity and therapeutic properties.
- The most promising of these new compounds will be tested for efficacy in prostate cancer animal models including CRPC models, in preparation for clinical trials.
- If successful, this project will result in the development and preclinical validation of a novel AR-targeted therapy that can prevent the development of CRPC or effectively treat CRPC.
What this means for patients: Dr. Asim will develop novel AR-targeting therapies with promising preclinical activity for the treatment or prevention of CRPC, and ready these drugs for testing in clinical trials.
2018 Lenny Sands–PCF VAlor Young Investigator Award
University of California, San Francisco
Mentors: Eric Small, MD, Celia Kaplan, PhD
Proposal Title: Leveraging health information technology to understand and address disparities in prostate cancer clinical trial participation
- Only a fraction of patients who participate in cancer clinical trials are non-Caucasian or non-English speaking. As prostate cancer treatment is becoming increasingly individualized, if racial/ethnic minority participation in treatment clinical trials remains unacceptably low, disparities in treatment outcomes are likely to increase.
- Hala Borno is developing a multilingual digital clinical trial tool to increase the diversity of patients enrolled in prostate cancer trials.
- A prospective study will be conducted at two diverse hospitals, including a VA hospital, to develop and test a disease specific clinical trial matching tool, “Trial Library,” in men with advanced prostate cancer. English or Spanish-reading patients recruited to the study will participate in interviews and surveys to identify domains of interest that will be used to refine the Trial Library tool.
- A pilot study will be conducted to determine if an online version of the Trial Library tool increases enrollment of minorities into clinical trials in the UCSF area. Methods to increase enrollment, including emailing all UCSF patients through the UCSF patient portal, optimizing the tool for Google search algorithms or geographically targeting the UCSF catchment region will be explored.
- Finally, a multi-site study will be conducted in geographically diverse regions, using the refined online tool to measure racial/ethnic minority and veteran recruitment into prostate cancer clinical trials.
- If successful, this study will result in a digital clinical trial tool that can increase recruitment of minorities and non-English speaking patients into advanced prostate cancer clinical trials.
What this means for patients: Dr. Borno is developing a novel multi-lingual digital tool that can match patients to clinical trials for advanced prostate cancer, and will improve recruitment of minorities and non-English speaking patients into clinical trials in order to reduce prostate cancer disparities.
2018 Jay Jordan – PCF Young Investigator Award
University of Michigan
Mentors: Russell Taichman, DMD; Laura Buttitta, PhD; Arul Chinnaiyan, MD, PhD
Proposal Title: Targeting the Hippo Pathway in Advanced Prostate Cancer
- Approximately 20-30% of men with advanced prostate cancer have tumors with mutations in DNA damage repair (DDR) genes, which render them less able to repair damaged DNA. These tumors have been found to be sensitive to treatments that damage DNA, such as platinum chemotherapy, and treatments that inhibit other pathways that repair damaged DNA, such as PARP-inhibitors.
- Frank Cackowski is studying a relatively unexplored pathway that functions in DNA repair, the Hippo pathway, and whether it may be a therapeutic target for DDR gene-deficient prostate cancer.
- YAP1 and TAZ are proteins in the Hippo pathway that have been shown to protect other cancers from cell death induced by radiation and platinum chemotherapy. Whether and how YAP1 and TAZ protect prostate cancer cells from death when treated with PARP inhibitors or platinum chemotherapy will be determined. Whether YAP1 and TAZ activity is associated with patient outcomes and treatment responses in metastatic castrate resistant prostate cancer (mCRPC) samples will be determined.
- The Hippo pathway can be regulated by signals from the cell environment. Whether interaction with bone cells regulates YAP1/TAZ activity in prostate cancer cells will be determined. The role for these interactions in the pathogenesis and treatment responses in prostate cancer bone metastases will be explored.
- Finally, a pre-clinical strategy for targeting the Hippo pathway in prostate cancer will be determined.
- If successful, this project will illuminate the role of the Hippo pathway effectors YAP1 and TAZ in treatment induced cell death and lay the groundwork for future prostate cancer clinical trials of drugs targeting the Hippo pathway.
What this means for patients: Dr. Cackowski will determine the role of the Hippo/YAP1/TAZ pathway in prostate cancer progression and treatment resistance, and credential this pathway as novel therapeutic targets for treatment alone or in combination with other therapies for metastatic prostate cancer.
2018 Tony D. Minella–PCF VAlor Young Investigator Award
University of Michigan; Ann Arbor Veterans Affairs Hospital
Mentors: Ted Skolarus, MD, Ajjai Alva, MD
Proposal Title: Variation and Comparative Effectiveness of Systemic Therapy in Advanced Prostate Cancer among Veterans
- A number of life-extending treatment options for metastatic castration-resistant prostate cancer (CRPC) have been approved in recent years. However, widespread variation in treatment and uncertainty about optimal treatment patterns remain. The treatments for advanced prostate cancer are widely available, expensive, and likely to be influenced by non-clinical factors such as race, region of the country, distance to a treating facility, and physician-level variables.
- Megan Caram is studying contemporary treatment patterns and their effectiveness in U.S. Veterans with advanced prostate cancer.
- Contemporary treatment patterns for patients with advanced prostate cancer will be identified and the influence of non-clinical factors, such as race, income, geographic region, and provider, on specific treatment patterns will be determined.
- Studies will be conducted to determine the effects that specific treatment patterns have on patient outcomes.
- If successful, this project will identify treatment patterns that lead to best outcomes and the key determinants of variation, which will enable implementation of strategies to help providers overcome barriers, and deliver best care for men with advanced prostate cancer.
What this means for patients: Dr. Caram will identify the factors that determine treatment patterns for Veterans with advanced prostate cancer, and identify treatment patterns that result in best outcomes. This will enable the implementation of strategies to improve the care and outcomes of Veterans.
2018 Todd Boehly–PCF Young Investigator Award
University of Bern, Switzerland
Mentor: Mark Rubin, MD
Proposal Title: Role of m6A methylation in post-transcriptional regulation and prostate cancer disease progression.
- Epigenetics, a system of adding or removing chemicals to DNA to enable or disable different genes from being expressed, plays an important role in prostate cancer development and progression. RNA can also be regulated by similar chemical modifications (“epitranscriptomics”). However, the role of epitranscriptomic modification of RNAs in prostate cancer progression has not yet been studied.
- Kellie Cotter is investigating the role of modification of RNAs by m6A methylation in prostate cancer. m6A methylation of mRNAs can alter RNA stability, protein translation efficiency, and patterns of alternative splicing (a phenomenon in which different segments of a gene are used to make RNA, so that different forms of the protein can be made).
- The role of the m6A methylation will be explored in prostate cancer progression and metastasis by turning off or overexpressing the m6A methylation enzyme, METTL3 in prostate cancer models.
- Whether the androgen receptor (AR) or AR-regulated genes are affected by m6A methylation will be examined by identifying RNA sites where m6A methylation occurs and determining the activity of AR when METTL3 levels are altered.
- Finally, the role of m6A methylation in regulation of protein levels will be studied in clinical samples from prostate cancer patients.
- If successful, this project will reveal the role of epitranscriptomics in prostate cancer and open up an entirely new field of study which may lead to new understandings and therapeutic opportunities.
What this means for patients: Dr. Cotter will investigate the role of epitranscriptomics, the chemical modification of RNA, in the development and progression of prostate cancer. This is an entirely new field of study that may lead to new strategies to treat prostate cancer.
2018 Jeremy Coller–PCF Young Investigator Award
University of Melbourne
Mentors: Christopher Sweeney, MBBS, Eliezer Van Allen, MD, Niall Corcoran, MB BCh, PhD
Proposal Title: Somatic Genomic Alterations as Predictors of Clinical Outcomes and Benefit from Chemohormonal Therapy in Metastatic Hormone Sensitive Prostate Cancer (mHSPC): A Correlative Study of E3805 CHAARTED
- The randomized phase III CHAARTED clinical trial previously demonstrated a significant survival benefit with the addition of docetaxel to standard androgen deprivation therapy (ADT) for men with mHSPC, thereby establishing a new treatment standard. Long term follow-up analyses found that the benefit of docetaxel was confined to men with high volume metastatic disease.
- Genomic determinants of the natural history of mHSPC and therapeutic benefit of ADT versus ADT plus docetaxel remain to be defined.
- Anis Hamid will examine genomic alterations in tumors from patients in the CHAARTED trial to identify mutations associated with clinical outcomes and treatment responses.
- Biopsy specimens from 200 patients will be obtained and genomically sequenced to characterize the genomic landscape of alterations in this cohort.
- Mutations in the tumor suppressor genes TP53, PTEN, and RB1 are associated with poor outcomes in advanced prostate cancer patients. The frequencies of mutations in these genes will be determined and correlated with clinical outcomes and responses to ADT or ADT + docetaxel to determine if these genes may act as biomarkers for treatment responses or clinical outcomes in patients with mHSPC.
- Clinical factors of mHSPC (volume of metastases, presentation with metastatic disease versus relapse after local therapy, presence of visceral metastasis, Gleason score ≥8) will be correlated with tumor mutations and this data will be used to and develop a prognostic risk model of overall survival for mHSPC.
- Finally, gene expression and mutations present in mHSPC will be compared with more advanced and aggressive prostate cancer disease states, including neuroendocrine prostate cancer (NEPC) and aggressive variant prostate cancer.
What this means for patients: Dr. Hamid will characterize the genomic landscape of patients with metastatic hormone sensitive prostate cancer (mHSPC) in order to determine genomic biomarkers that predict response to ADT versus ADT + docetaxel and clinical outcomes. This will lead to improved understanding of the biology of mHSPC and matching of patients to treatments that will provide the most benefit.
2018 National Cancer Institute–PCF Young Investigator Award
National Cancer Institute (NCI)
Mentor: James Gulley, MD, PhD
Proposal Title: Evaluation of Extracellular Vesicles (EVs) as Predictive and Early Response Biomarkers for the Treatment Metastatic Castrate Resistant Prostate Cancer
- Extracellular vesicles (EVs) are small cellular bits continually released by all types of cells, which carry surface receptors and cargo (RNA, DNA, and other biomolecules) characteristic of their cells of origin. EVs have tremendous potential as non-invasive biomarkers for diagnosis, risk stratification, treatment selection, and treatment monitoring.
- Jennifer Jones is has developed a novel technology to study tumor EVs harvested from patient blood samples, and is studying the use of EVs to perform real-time monitoring of patient treatment responses, tumor biology, and immune responses.
- Prostate cancer cell-derived EV surface receptors and RNA cargo signatures for EVs from prostate cancer cells will be identified, using well prostate cancer cell lines and plasma samples from patients with prostate cancer. The sensitivity and specificity of these EV analyses will be compared with other promising liquid biomarkers including cell-free tumor DNA (ctDNA) and circulating tumor cell (CTC) assays.
- EVs from prostate cancer patient immune cells will be identified and used to develop immune signatures that predict responses to treatment or detect early responses to treatment with immune-based therapies.
- If successful, this project will result in the development of EV-based technologies for studying prostate cancer and biomarkers for use in personalized and adaptive treatment strategies.
What this means for patients: Dr. Jones is studying the use of extracellular vesicles (EVs) secreted by tumor and other cells into the circulation as prostate cancer and immune biomarkers that can indicate tumor biology and treatment responses. The application of this technology may enable clinicians to make more efficient patient-specific adjustments to treatment and improve patient outcomes.
2018 John & Daria Barry Foundation–PCF VAlor Young Investigator Award
Baylor College of Medicine
Mentors: Nicholas Mitsiades, MD, PhD, Bert O’Malley, MD, Michael Ittmann, MD, PhD
Proposal Title: Defining the Epigenetic Landscape of African American Prostate Cancer
- Prostate cancer mortality is ~2.5-fold higher in African American (AA) than in Caucasian American (CA) men, yet little is known about the underlying molecular basis for this highly aggressive behavior of AA prostate cancer. Consequently, there is an unmet need to identify actionable targets in AA prostate cancer in order to develop more effective therapeutics and, ultimately, improve clinical outcomes for AA patients.
- Beyond mutations, cancer can be driven by epigenetic changes, which are chemical modifications on DNA that affect which genes can and cannot be expressed.
- Salma Kaochar has discovered that AA prostate cancer exhibits increased activity of cancer-driving transcription factors MNX1 and SREBP1, which result in altered expression of metabolic genes. The increase in the MNX1/SREBP1 pathway was found to be initiated by the androgen receptor (AR), the primary driver of prostate cancer.
- The role of AR, MNX1, and SREBP1 as drivers of AA prostate cancer will be defined. How AR, MNX1, and SREBP1 affect gene expression and the epigenetic state of AA prostate cancer will be determined.
- The target genes that are affected by AR, MNX1, and SREB1 reprogramming in AA prostate cancer will be identified.
- If successful, this project will map the epigenetic landscape of AA prostate cancer which is more aggressive and fatal. The genes and DNA regions found to regulate more aggressive features in AA prostate cancer may be new targets for therapeutic intervention.
What this means for patients: Dr. Kaochar will investigate the role of oncogenic transcription factors — AR, MNX1, and SREBP1 — in African American prostate cancer, and will provide a path to identifying new targets for therapeutic intervention that will benefit all prostate cancer patients and, additionally, address the health disparities that burden African American patients.
2018 Michael & Lori Milken Family Foundation–PCF Young Investigator Award
Weill Cornell Medicine
Mentor: Himisha Beltran, MD
Proposal Title: Notch Regulation of Lineage Plasticity in Advanced Prostate Cancer
- Prostate cancer is highly reliant on the androgen receptor (AR) as the major source of growth and survival signals. Treatments that target AR have delivered promising benefits for patients with advanced prostate cancer, but in many patients treatment resistance ultimately ensues and patients progress to castration-resistant prostate cancer (CRPC).
- Neuroendocrine prostate cancer (NEPC) is an aggressive form of CRPC, in which prostate cancer cells have lost prostate cell features and taken on features of neuroendocrine cells.
- Sheng-Yu Ku is studying mechanisms that cause development of NEPC, and has found that loss of the Notch protein may play a major role.
- Experimental prostate cancer models will be studied to determine the effect of the presence or absence of Notch in the development of NEPC, and how Notch expression is regulated in prostate cancer. The effect of targeting proteins that repress Notch will also be studied.
- The effect of compounds that activate Notch expression or block activity of Notch repressors as a treatment for NEPC will be investigated in prostate cancer models. Drug libraries will also be screened to identify novel compounds that can activate Notch and are effective in prostate cancer models.
- Clinical primary and metastatic CRPC/NEPC samples will be evaluated to determine the timing of suppressed Notch signaling and co-occurring alterations during prostate cancer disease progression.
- If successful, this project will determine the role of Notch inactivation in the development of NEPC and identify novel treatment strategies to reactivate Notch and prevent progression to this aggressive and lethal form of prostate cancer.
What this means for patients: Dr. Ku will determine the role of the Notch protein in regulating the development of neuroendocrine prostate cancer (NEPC), an aggressive form of CRPC, and develop new treatments that prevent NEPC by reactivating Notch.
2018 John & Daria Barry Foundation–PCF VAlor Young Investigator Award
University of California, San Francisco
Mentor: Felix Feng, MD, Peixuan Guo, PhD
Proposal Title: Interrogating the Role of SChLAP1-AS in Prostate Cancer Progression
- Long non-coding RNAs (lncRNA) are a newly discovered class of ~60,000 genes which perform functions as RNA molecules instead of being used to make proteins. LncRNAs have been found to play a role in many cellular processes and many have been implicated in diseases, including prostate cancer.
- SChLAP1-AS is a lncRNA that was previously found to be highly expressed in prostate cancer and is highly prognostic for metastatic progression.
- Hui Li is studying the role of SChLAP1-AS in prostate cancer progression and metastasis, and whether SChLAP1-AS may serve as a therapeutic target.
- Studies will be conducted to determine the mechanisms by which SChLAP1-AS promotes prostate cancer. The RNA and proteins that SChLAP1-AS interacts with and whether they drive growth and metastasis of prostate cancer cells will be determined.
- Whether SChLAP1-AS expression in prostate cells promotes the development of prostate cancer will be investigated in genetically engineered mouse models.
- Whether SChLAP1-AS may be an effective therapeutic target will be tested in preclinical models. In addition, targeted therapeutics to inhibit SChLAP1-AS will be developed and tested.
- If successful, this project will identify the role of SChLAP1-AS in prostate cancer development and progression, credential SChLAP1-AS as a therapeutic target, and develop new drugs to target SChLAP1-AS.
What this means for patients: Dr. Li will determine the mechanisms by which SChLAP1-AS, a long non-coding RNA, drives prostate cancer. In addition, this project will establish whether SChLAP1-AS may be a therapeutic target for prostate cancer and develop new SChLAP1-AS-targeting treatments.
ASTRO-PCF Career Development Award to End Prostate Cancer
Harvard: Dana-Farber Cancer Institute
Mentors: Timothy Rebbeck, PhD, Paul Nguyen, MD
Proposal Title: Integrative Genomics of Prostate Cancer Disparities
- African American (AA) men are at significantly increased risk for developing aggressive and lethal prostate cancer compared with Caucasian men. The prognostic tools and treatment guidelines that are standardly used likely contribute to this disparity, as they were developed based on studies primarily in Caucasian men and may not adequately identify aggressive from non-aggressive prostate cancer in AA men.
- Brandon Mahal is developing a novel precision medicine framework to identify AA men most likely to be at risk of an adverse prostate cancer outcome.
- Data from several large prostate cancer studies and registries will be used to identify and validate clinical and demographic factors that are most predictive of prostate cancer outcomes in men of African descent. These datasets include several large national and international registries and collectively represent over 15,000 men of African descent from around the world, including where racial disparities in lethal prostate cancer are the greatest.
- Various molecular biomarkers (mutated genes and aberrant protein levels) that have been found to predict for aggressive or lethal forms of prostate cancer in previous studies will be studied for their predictive value in men of African descent.
- The clinical factors, demographic factors and molecular biomarkers that are found to be predictive of aggressive prostate cancer in AA men will be used to create a novel risk stratification method to identify AA men most likely to be at risk of an adverse prostate cancer outcome.
- If successful, this project result in the development of a novel risk-stratification method that is more accurate at identifying African-American men most likely to be at risk of an adverse prostate cancer outcome, and lead to improved patient management and clinical outcomes.
What this means for patients: Dr. Mahal will identify the clinical, demographic, and molecular factors that are associated with increased risk for poor-prognosis prostate cancer in men of African descent. This information will be used to develop more accurate patient prognostication tools, and will improve treatment selection and outcomes for African American men with prostate cancer.
2018 Thomas H. Lee–PCF VAlor Young Investigator Award
New York University; VA New York Harbor Healthcare System
Mentor: Herbert Lepor, MD
Proposal Title: Exploring contextual factors associated with effectiveness of a physician-centered behavioral intervention to de-implement guideline-discordant prostate cancer imaging
- Inappropriate (guideline-discordant) imaging use for staging of low-risk prostate cancer is a large contributor to the misallocation of medical resources and unnecessarily burdens the medical financial system. Despite the development of guidelines for imaging and prostate cancer staging, physicians, not patients, have been found to be the drivers of inappropriate imaging.
- Danil Makarov is developing a theory-based physician-focused behavioral intervention to be applied in the Veterans Administration (VA) health system to reduce inappropriate use of imaging.
- Makarov has developed Prostate Cancer Imaging Stewardship Intervention (PCIS), a behavioral intervention combining three intervention strategies: audit and feedback, academic detailing, and an Electronic Health Record order check.
- Physicians at multiple VA sites who care for men with prostate cancer will be given a survey that assesses demographic variables including years since graduation from residency, race/ethnicity, sex, age, sub-specialty, case load, and schedules.
- Physicians will then be given the intervention, followed by surveys and interviews to assess attitudes toward the intervention, how they were influenced by physician practice style, and perceptions of context on prostate cancer imaging.
- Multi-modal analysis of this data will be performed to determine of how multiple factors may affect physician decision making and attitudes toward the intervention.
- If successful, this project will reveal the factors affecting how clinicians in the VA make patient management decisions and inform the development of programs to improve the use of best practices for managing and treating patients with prostate cancer.
What this means for patients: Dr. Makarov has designed a physician behavioral intervention to be applied in the VA health system to reduce the inappropriate use of imaging. This study will uncover the intervention’s effectiveness, identify barriers to implementation, and inform on how to educate physicians on best practices for the management of prostate cancer patients.
2018 Thomas Finke–PCF VAlor Young Investigator Award
Rhonda Bitting, MD
Mentors: Daniel George, MD, Andrew Armstrong, MD, ScM, Michael Kelley, MD
Proposal Title: Race-Related Germline and Somatic Variations Associated with Response to Second Generation Androgen-Directed Therapies in Men with Metastatic Castrate Resistant Prostate Cancer
- African American (AA) men have higher incidence, aggressiveness, and mortality from prostate cancer than men of other racial groups, even after accounting for differences in social and behavioral determinants of health. Genetic factors may contribute to the observed racial disparities in susceptibility to prostate cancer and response to androgen-directed treatment.
- Rhonda Bitting is studying the role of inherited genetic variants in response to prostate cancer treatments, and how they relate to race and patient outcomes.
- The frequencies of 5 germline single nucleotide polymorphisms (SNPs) in androgen metabolism genes which have been shown to influence response to androgen deprivation therapy (ADT), will be evaluated in two clinical trials (Abi:Race and PANTHER) testing abiraterone in AA vs. Caucasian advanced prostate cancer patients. This will reveal whether these SNPs vary in AA vs. Caucasian patients, and whether they influence responses to abiraterone.
- New SNPs that associate with response to abiraterone and vary in frequency by ancestry will be identified.
- The TMPRSS2:ERG gene fusion is present in ~50% of prostate cancer and is thought to be a driver of prostate cancer development. This fusion is less prevalent in men of African descent. Whether the prevalence of the TMPRSS2:ERG fusion in black and white patients and whether or not the fusion associates with response to abiraterone, will be investigated using the VA Precision Oncology Program Database and the Abi:Race and PANTHER
- If successful, this project will identify genetic differences between AA and Caucasian prostate cancer, and will identify genomic biomarkers that help to predict responses to abiraterone and may help in treatment selection for patients.
What this means for patients: Dr. Bitting will investigate genetic differences between African American and Caucasian prostate cancer in order to better understand biologic contributors to poorer outcomes in African American patients. In addition, this project will determine whether genetic variants can predict responses to abiraterone and be used to improve treatment selection for patients.
2018 Rebecca and Nathan Milikowsky–PCF Young Investigator Award
Harvard: Dana-Farber Cancer Institute
Mentors: Alan D’Andrea, MD, Mary-Ellen Taplin, MD
Proposal Title: Developing Preclinical Tools to Study DNA Repair Deficiency in Prostate Cancer
- Alterations in DNA damage repair (DDR) genes are common in advanced prostate cancer and are associated with an aggressive clinical phenotype. DDR-deficient prostate tumors may be less responsive to conventional treatment, but may have particular therapeutic vulnerabilities such as sensitivity to PARP inhibitors, platinum chemotherapy or immune checkpoint blockade. However, the role and effects of most clinically observed DDR gene mutations in prostate tumor formation, evolution, and therapy response is unknown.
- Kent Mouw is studying the impact of DDR gene alterations in prostate cancer.
- The functional impact of different DDR gene mutations will be determined by expressing normal versus various clinically observed mutant forms of DDR genes in cell lines that lack that gene. Whether the mutations affect the ability to repair damaged DNA, or sensitivity to PARP inhibitors or platinum chemotherapy, will be determined.
- The impact of DDR gene mutations on the functions of normal prostate cells will be investigated, including effects on genomic stability, ability to repair damaged DNA, growth rates, metastatic properties, and sensitivity to established and emerging prostate cancer therapies.
- Finally, tests to rapidly determine the functional status of DNA repair pathways in prostate cancer tissues will be developed.
- If successful, this study will elucidate the impact of various DDR mutations on prostate biology and treatment responses, and develop a test for pathologists to determine DDR gene status at point-of-care for improving precision medicine treatment selections.
What this means for patients: Dr. Mouw will determine the biologic impact and therapeutic sensitivities conferred by various clinically observed mutations in DNA damage repair (DDR) genes in prostate cancer. Tests to determine characterize DDR gene status in prostate cancer tissues will be developed and used to improve precision medicine treatment selection for patients.
2018 James Maguire–PCF Young Investigator Award
University of Pennsylvania; Abramson Cancer Center
Mentor: Carl June, MD
Proposal Title: Evaluating Resistance Mechanisms and Enhancing Efficacy of PSMA-directed/TGFβ-insensitive CAR-T Cells in Advanced Prostate Cancer
- CAR (Chimeric Antigen Receptor) T cells are a promising type of cancer immunotherapy, in which a patient’s own immune cells are genetically modified to identify and kill tumor cells.
- A phase I trial has recently been opened to test a CAR T cell product for prostate cancer. These CAR T cells, PSMA-TGFβRdn, target the prostate specific molecule PSMA and carry a gene that confers resistance to suppressive signals from tumor cells, in order to maintain activity for a longer period of time.
- Vivek Narayan is seeking to identify mechanisms and biomarkers of resistance to PSMA-TGFβRdn CAR T cells.
- Tumor biopsy samples from patients in the clinical trial obtained before and after treatment with PSMA-TGFβRdn CAR T cells will be analyzed for the types and activities of T cells that have infiltrated the tumor. These characterizations will include normal T cells, CAR T cells, and negative regulatory T cells. The levels of immune regulatory proteins in the tumor will also be evaluated.
- Blood samples obtained from patients in the clinical trial before and periodically after treatment with PSMA-TGFβRdn CAR T cells will be assessed to identify biomarkers of treatment resistance. Circulating tumor cell (CTC) levels, tumor phenotypes, expression of negative regulatory immune checkpoint molecules, and various immune cell properties will be comprehensively investigated.
- If successful, this project will identify tumor and/or immune based biomarkers that predict response and resistance to prostate cancer –targeting CAR T cell immunotherapy
What this means for patients: Dr. Narayan will investigate tumor and immune biomarkers of resistance to prostate cancer –targeting CAR T cells using biopsy and blood samples from patients being treated with PSMA-TGFβRdn CAR T cells. This study will lead to improved CAR T cell design, treatment strategies and patient selection for treatment.
2018 John & Daria Barry Foundation–PCF VAlor Young Investigator Award
University of California, San Francisco
Mentor: Lawrence Fong, MD
Proposal Title: Single Cell Discrimination of Immunotherapy-Induced Changes in the Prostate Tumor Microenvironment
- Checkpoint immunotherapy is a type of cancer immunotherapy that activates a person’s own immune system to target and kill their cancer. In some types of cancers such as melanoma and lung cancer, checkpoint immunotherapy has been highly effective and can even result in apparent cures for some patients. However, responses to checkpoint immunotherapy are only rarely seen in prostate cancer.
- David Oh is studying prostate cancer patients who have exhibited exceptional responses to checkpoint inhibitors in order to understand the mechanisms of response.
- To determine if T cell responses in the prostate tumor environment are shared or distinct from T cells in the circulation, single cell analyses will be conducted using tumor and blood samples from prostate cancer patients being treated on a clinical trial with a combination of hormone therapy, radiation, and checkpoint immunotherapy.
- Whether checkpoint immunotherapy enhances pre-existing populations of T cells or induces novel populations with treatment will be investigated using samples from the patients on this trial.
- If successful, this project will help to uncover the mechanisms by which checkpoint immunotherapy exerts its effects in prostate cancer.
What this means for patients: Dr. Oh will characterize immune cells from patients being treated with a combination regimen of hormone therapy, radiation, and checkpoint immunotherapy, to identify if and how checkpoint immunotherapy is able to activate anti-tumor T cells in prostate cancer. This knowledge will help to improve determination of when immunotherapies are working in patients and improve immunotherapy strategies in prostate cancer.
2018 Darius Bikoff–PCF Young Investigator Award
University of Oxford
Mentors: Ian Mills, PhD, Richard Kennedy, MD, PhD
Proposal Title: The Role of the cGAS-STING Immune Pathway in Metastasis and Response to Immune Checkpoint Therapy in High-Risk Immune-Active Early Prostate Cancer
- The cGAS-STING pathway is a molecular pathway that plays a major role in activating immune responses to pathogens, may drive the development of immune responses to cancer, and may also influence the efficacy of immunotherapy.
- Eileen Parkes has discovered that a subset of high-risk primary prostate cancer exhibit DNA damage and chromosomal instability, as well as cGAS-STING pathway activation (“Met-Hot” subtype). In this project, the role of the cGAS-STING pathway in prostate cancer biology and responses to immunotherapy will be investigated.
- A DNA damage repair-deficient mouse model of metastatic prostate cancer will be developed (which is hypothesized to recapitulate human “Met-Hot” tumor biology) to determine whether the inability of tumor cells to repair damaged DNA leads to activation of the cGAS-STING pathway and the development of anti-tumor immune responses.
- A STING-deficient mouse model of metastatic prostate cancer will be generated to investigate the role of STING in prostate cancer metastasis and anti-tumor immune responses.
- Whether DNA damage repair-deficient prostate cancer is more sensitive to treatment with various types of immunotherapy or to a novel cGAS-STING-inhibitor will be investigated in mouse models.
- Approximately 10% of primary prostate cancer carry mutations in the cGAS-STING pathway, suggesting that loss of this pathway is important for evasion of anti-tumor immune responses. The relationship between expression of the cGAS and STING proteins and immune cell activity will be investigated in clinical prostate cancer samples.
- Prostate cancer cell lines with low cGAS-STING pathway activity will be studied to determine whether the pathway is turned off by epigenetics (chemical modification of DNA). Whether epigenetic treatments can reactivate the cGAS-STING pathway will be investigated.
- If successful, this project will elucidate the role of the cGAS-STING pathway in regulating prostate cancer biology and response to immunotherapy, and identify strategies to exploit this pathway to improve the efficacy of immunotherapy in prostate cancer.
What this means for patients: Dr. Parkes will study the role of the immune-activating cGAS-STING pathway in prostate cancer and identify strategies to target this pathway to improve the effects of immunotherapy. This research will be used to inform the design of rational, biomarker-based immunotherapy clinical trials for prostate cancer.
2018 Gina Rinehart–PCF Young Investigator Award
Vall d’Hebron Institute of Oncology (VHIO), Spain
Mentors: Johann de Bono, MB ChB, PhD, Anwar Padhani, MBBS
Proposal Title: A Two-Stage study to Clinically Qualify Whole-Body Diffusion-Weighted MRI in Patients with Metastatic Castration Resistant Prostate Carcinoma with Bone Metastases
- Current standard imaging techniques (bone scans and CT) are not sufficient for imaging the true extent of bone metastases and are suboptimal in capturing biological changes in response to treatment. Improved methods for imaging bone metastases are needed for more precise prostate cancer care.
- Raquel Perez-Lopez is developing the use of diffusion-weighted imaging (DWI), a functional magnetic resonance imaging (MRI) technique that uses the movement of water molecules within a tissue to produce images, for improved detection of prostate cancer.
- Perez-Lopez has previously shown that whole-body DWI in prostate cancer patients with bone metastases informs on tumor burden and is prognostic, and can be used to indicate response to treatments.
- In this project, a multicenter study will be performed to test and validate whole-body DWI as a response biomarker in patients with mCRPC and bone metastases treated with abiraterone/enzalutamide.
- Whether early changes in DWI measurements or other algorithms using MRI measurements are biomarkers of response and resistance to abiraterone/enzalutamide will be explored.
- The use of DWI for identifying different anatomic regions that are responding or resistant to abiraterone/enzalutamide will be investigated. When patterns of differential response or focal resistance are identified, the regions will be biopsied and studied to determine if the evolution of unique tumor clones is driving disease progression.
- If successful, this project will optimize and validate a powerful new imaging method with improved sensitivity for measuring changes in tumor burden during treatment with abiraterone/enzalutamide.
What this means for patients: Dr. Raquel Perez-Lopez is developing the use of a new magnetic resonance imaging (MRI)-based technique with improved sensitivity for measuring sites and burden of metastatic prostate cancer during treatment with abiraterone and enzalutamide.
2018 Keith Frankel, Michael DeAddio, & Thomas H. Lee–PCF VAlor Young Investigator Award
Sethuramasundaram Pitchiaya, PhD
University of Michigan
Mentor: Arul Chinnaiyan, MD, PhD
Proposal Title: Unraveling Molecular Heterogeneities in Advanced Prostate Cancer at Single Cell Resolution
- A major challenge in prostate cancer is to distinguish low-risk indolent cancers from aggressive ones that need immediate therapeutic intervention and to identify factors that mediate therapeutic resistance. However, prostate cancer can be highly heterogeneous in a patient, with tumor cells in different locations having different mutations and gene expression patterns, which markedly complicates clinical risk stratification of patients.
- Unraveling the extent and causalities of heterogeneity will improve understanding of prostate tumor biology and enable development of more accurate prognostic and/or predictive biomarkers for guiding treatment decisions in the clinic.
- Sethuramasundaram Pitchiaya will use novel single cell analysis technologies to characterize tumor heterogeneity during prostate cancer progression and in response to treatment. These technologies, when applied to tissues samples, enable spatial mapping of tumor cell biology.
- Genetic alterations that mediate resistance to prostate cancer treatments will be identified in prostate cancer cell lines. The evolutionary path of cells that develop resistance to various treatments will also be identified using a novel lineage-tracing technology.
- The evolution of tumor heterogeneity will be studied in animal models, in which prostate tumors will be molecularly characterized at a single cell level over time. The impact of treatment with chemotherapy or immunotherapy on tumor heterogeneity will also be assessed in these models.
- Single cell analysis technologies will be used to characterize variations in cell type composition, gene expression, and genomic alterations in normal prostates and in clinical prostate cancer samples, including from a cohort of Veterans Administration (VA) patients. This information will be used to develop biomarker panels for prostate cancer risk-stratification.
- If successful, this project will improve understanding of tumor cell heterogeneity during tumor progression and the development of treatment resistance on a spatial and temporal level, and lead to improved methods for clinical risk stratification.
What this means for patients: Dr. Pitchiaya will study how the biology of tumor cells change over time and differ in different areas of the tumor during disease progression and during the development of treatment resistance. This information will be used to create biomarkers that will improve the identification of patients with indolent versus aggressive prostate cancer.
2018 Seth Bernstein–PCF Young Investigator Award
University of Washington
Mentors: Jonathan Liu, PhD, Lawrence True, MD, Colin Pritchard, MD, PhD
Proposal Title: 3D Light-Sheet Microscopy for Next Generation Prostate Cancer Diagnostics
- The technology used to diagnose prostate cancer in biopsies has barely changed over the past century, i.e. glass slides viewed under a light microscope. This method samples only a small fraction (1-5%) of the available tissue and damages DNA and RNA, thereby impairing robust molecular analyses. A new approach to microscopy is needed to better detect small amounts of high risk cancer missed with traditional microscopy and to better preserve nucleic acids for emerging molecular tests.
- Nicholas Reder is studying whether a new microscopy method, 3D Light-Sheet Microscopy, can be used to improve prostate cancer diagnosis and molecular analyses.
- Light-Sheet Microscopy is a method that enables visualization of a deep section of intact tissues, in 3D. Reder and team have developed a novel Light-Sheet Microscopy imaging system that is tailored to the needs of clinical specimens.
- The ability of 3D Light-Sheet Microscopy to detect high grade cancer missed by traditional microscopy will be investigated by comparing Gleason scoring using Light-Sheet Microscopy versus traditional microscopy on tissues from the same patient.
- Optimal methodologies to enable both improved images as well as collection of high quality DNA and RNA from prostate cancer samples will be developed.
- Genomic analyses will be conducted using DNA isolated from tissues processed for 3D Light-Sheet Microscopy versus conventional microscopy to validate the ability to properly measure genomic alterations in tumor samples using this method.
- If successful, this project will result in the development of a novel imaging method that has improved accuracy for diagnosis and prognosis of prostate cancer, and also allows tissues to be used for high integrity molecular analyses.
What this means for patients: Dr. Reder will develop 3D Light-Sheet Microscopy, a novel prostate cancer imaging technology that renders 3D images with improved diagnostic accuracy. Unlike conventional microscopy, tissues processed by this method retain the ability to be used for more accurate molecular tests.
2018 Igor Tulchinsky–PCF VAlor Young Investigator Award
University of Michigan
Mentors: Daniel Spratt, MD, Scott Tomlins, MD, PhD
Proposal Title: Non-Invasive Interrogation of Oligometastatic Castration-Resistant Prostate Cancer and the Benefit of Metastasis Directed Therapy in the Phase II FORCE Randomized Clinical Trial
- Oligometastatic prostate cancer, a state in which less than five sites of metastases are detectable, is hypothesized to represent an early and potentially curable form of metastatic prostate cancer. Metastasis-directed therapy (MDT) using ablative doses of radiotherapy to focally treat metastatic foci is being studied in multiple clinical trials in prostate cancer.
- Zachery Reichert is conducting the FORCE trial, a randomized phase II clinical trial assessing the benefit of MDT in oligometastatic castration resistant prostate cancer (CRPC) in combination with first line CRPC therapy.
- The safety of this treatment strategy will be determined in the FORCE trial.
- Whether metastases seen exclusively by more sensitive new molecular imaging methods (PSMA-PET) but not by conventional imaging (CT and bone scan) are clinically relevant and represent future sites of disease progression, will be determined.
- Whether circulating tumor cell (CTC) numbers and levels of circulating tumor DNA (ctDNA) are prognostic biomarkers and can be used to study response or resistance during treatment with MDT in patients with oligometastatic prostate cancer will be determined.
- If successful, this project will determine the safety and efficacy of metastasis-directed therapy (MDT) as a treatment for oligometastatic prostate cancer and identify optimal imaging methods and biomarkers for measuring responses in this group of patients.
What this means for patients: Dr. Reichert will study the safety and efficacy of metastasis-directed therapy (MDT) using ablative doses of radiotherapy to treat all sites of disease in patients with oligometastatic prostate cancer, and determine optimal imaging and blood-based biomarkers for measuring sites of disease and response to treatment.
2018 Clay Hamlin-PCF Young Investigator Award in Honor of H. Ward Hamlin Jr.
Thomas Jefferson University; Sidney Kimmel Cancer Center
Mentors: Karen Knudsen, PhD, William Kevin Kelly , DO
Proposal Title: Identification of Novel Targetable NPC-Mitotic Regulated Mechanisms in Lethal Prostate Cancer
- Nuclear Pores are protein complexes embedded within the nuclear envelope (NE) of cells that regulate a wide range of critical cellular functions including genome integrity, gene expression and cell division. Alterations in the NE, the Nuclear Pore Complex (NPC), and in nucleoporins, which are the components of NPCs, are often observed in cancer cells. However, the specific nucleoporins and nucleoporin-based mechanisms contributing to cancer remain ill-defined, while their role in prostate cancer is completely unknown.
- Veronica Rodriguez-Bravo is studying the role of nucleoporins and NPCs in prostate cancer progression.
- Rodriguez-Bravo has observed NPC alterations in prostate cancer and identified POM121 as being the most upregulated nucleoporin in aggressive prostate cancer.
- The effects of POM121 upregulation on genome stability and cell division rates will be investigated in prostate cancer cell lines. Pathways involved in genomic stability and cell division that are affected by changes in POM121 will be identified.
- Whether POM121-based effects are associated with responses to conventional and experimental prostate cancer treatments will be investigated in preclinical prostate cancer models.
- If successful, this project will identify the contribution of nuclear pores to prostate cancer aggressiveness, identify novel targetable pathways, and determine whether NPCs may act as biomarkers to improve the clinical management of prostate cancer patients.
What this means for patients: Dr. Rodriguez-Bravo will identify whether and how nuclear pore complexes function to drive prostate cancer progression and determine whether nuclear pore complex components may function as biomarkers of response to various treatments.
2018 Michael & Lori Milken Family Foundation–PCF Young Investigator Award
Harvard: Beth Israel Deaconess Medical Center (BIDMC)
Mentors: Steven Balk, MD, PhD, Huihui Ye, MD
Proposal Title: HER2-mediated Mechanisms of Abiraterone and Enzalutamide Resistance in Advanced Metastatic Prostate Cancer
- Abiraterone and enzalutamide are potent hormone therapies for advanced prostate cancer which target the androgen receptor (AR). Unfortunately, these treatments are only effective for a few months to years, before tumors are able to develop resistance and progress. The spectrum of mechanisms driving resistance to abiraterone and enzalutamide, and corresponding therapeutic targets, remain to be established.
- Joshua Russo is studying the role of upregulation of the breast cancer-associated protein, HER2, as a resistance mechanism to AR-targeted therapies.
- HER2 was found to be activated in prostate cancer following hormone therapy. In addition, a constantly activated form of HER2 was found to be upregulated in advanced castration resistant prostate cancer (CRPC) compared to primary tumors and in abiraterone/enzalutamide-resistant prostate cancer models.
- Whether expression of the constitutively active form of HER2 (d16HER2) drives resistance to AR-targeted therapy will be investigated in prostate cancer models.
- Expression levels of d16HER2 and activity of HER2-pathways will be examined in tumor tissues from patients with CRPC.
- Whether HER2-inhibitors may be effective treatments for CRPC will be investigated in prostate cancer animal models. Mechanisms of resistance to HER2-directed therapies will be identified.
- If successful, this project will determine the role of the HER2 pathway in driving resistance to AR-targeted therapies, and validate the efficacy of HER2-inhibitors as an effective treatment for HER2-driven CRPC.
What this means for patients: Dr. Russo will determine the role of the breast cancer-associated HER2 pathway in driving the development of resistance to AR-targeted therapies, and credential HER2-inhibitors as an effective treatment for some patients with CRPC. These studies will be used to facilitate clinical trials testing HER2-targeted therapies in advanced CRPC.
2018 Larry Ruvo–PCF Young Investigator Award
Institute of Cancer Research (ICR), UK
Mentors: Johann de Bono, MD, PhD, Stephen Plymate, MD, PhD
Proposal Title: Specific Targeting of mRNA Splicing as a Therapeutic Strategy for Lethal Prostate Cancer
- Despite initial robust responses to androgen deprivation therapy (ADT), nearly all patients with advanced prostate cancer relapse with lethal castration resistant prostate cancer (CRPC). Progression to CRPC can be associated with persistent androgen receptor (AR) signaling, which at least in part, is due to the expression of constantly active AR variants (AR-Vs) such as AR-V7. The development of therapies that can inhibit AR-Vs is a critical unmet medical need.
- Adam Sharp is developing a novel strategy to inhibit AR-Vs by specifically inhibiting key regulators of AR-V mRNA splicing. mRNA splicing is the process which produces AR-Vs by using alternate regions of the AR gene to create the RNA instructions for the protein.
- Cell stresses that induce AR-V generation will be evaluated in order to identify the stress-associated genes critical to AR-V production in prostate cancer.
- Whether genes that are critical for AR-V expression may serve as novel therapeutic targets to overcome AR-V signaling in lethal prostate cancer will be evaluated.
- Whether the expression of these novel identified therapeutic targets are associated with clinical outcomes and response to treatments in patients with metastatic CRPC (mCRPC) will be investigated.
- Drug screening studies will be performed to identify pharmacological inhibitors that specifically inhibit AR-V generation and are effective in models of CRPC. Validated compounds will be optimized to select a clinical candidate for further pre-clinical studies and consideration of early phase clinical trials.
- If successful, this project will identify novel therapeutic targets and potential new treatments for the treatment of CRPC.
What this means for patients: Dr. Sharp will describe the mechanisms that regulate the expression of constitutively active AR variants (AR-Vs), and identify novel treatments for CRPC that prevent AR-V expression which will be considered for testing in clinical trials. This may lead to a new treatment strategy to prevent or overcome CRPC.
2018 PCF Young Investigator Award in Honor of Selma Rabin
Memorial Sloan Kettering Cancer Center
Mentors: Howard Scher, MD, David Solit, MD
Proposal Title: METACURE: Combined PARP and PD-1 Checkpoint Inhibition Plus Androgen Deprivation Plus Locoregional Therapies in Incurable Non-Castrate Prostate Cancer and their Impact on Tumor Immune Microenvironment
- Checkpoint immunotherapy is a cancer treatment that activates a patient’s own immune cells to fight cancer. This type of treatment has been highly effective, even curative, in some patients with melanoma and several other cancers, but has not yet been optimized in prostate cancer. Combining checkpoint immunotherapy other treatments may be necessary to elicit effective responses in prostate cancer.
- Min Yuen Teo is conducting a clinical trial testing a checkpoint inhibitor (anti-PD1; JNJ-63723283) in combination with the PARP-inhibitor niraparib, and androgen deprivation therapy (ADT), in patients with very high-risk localized or low volume metastatic hormone sensitive prostate cancer, who are not otherwise curable with single treatment modality.
- The clinical activity of niraparib plus JNJ-63723283 and ADT as part of combination treatment strategy with the goal of curing localized high-risk and metastatic hormone sensitive prostate cancer will be evaluated.
- Mechanisms of response and resistance to niraparib plus JNJ-63723283 and ADT will be evaluated by performing molecular characterizations on samples from extreme responders and residual disease.
- The immune profile of the tumor microenvironment and its response to therapy will be evaluated using tumor biopsy samples obtained from patients prior to and following therapy.
- If successful, this project will determine whether combining checkpoint immunotherapy with PARP inhibitors and ADT may be effective in patients with patients with very high-risk localized or low volume metastatic hormone sensitive prostate cancer, and identify biomarkers and mechanisms of response and resistance to treatment.
What this means for patients: Dr. Teo will test the efficacy of combining checkpoint immunotherapy with PARP inhibitors and ADT in patients with patients with very high-risk localized or low volume metastatic hormone sensitive prostate cancer in a clinical trial and identify biomarkers and mechanisms of response and resistance to treatment. This proposed drug combination may serve as a first-step towards active immunotherapy in prostate cancer.
2018 Seth Bernstein–PCF Young Investigator Award
Harvard: Broad Institute of MIT & Harvard
Mentor: Stuart Schreiber, PhD
Proposal Title: Targeting the Androgen-Indifferent State of Prostate Cancer Cells through Induction of Ferroptotic Cell Death
- Emerging evidence suggests that castration resistant prostate cancer (CRPC) cells are vulnerable to an unusual lipid-mediated form of cell death known as ferroptosis. In these cells, inhibition of the ferroptosis regulator GPX4 leads to accumulation of toxic lipid peroxides and results in rapid ferroptotic death.
- Vasanthi Viswanathan is studying whether GPX4 inhibition may be an efficacious strategy to treat CRPC.
- Patient-derived cell lines and animal models of CRPC that are resistant versus sensitive to ferroptotic cell death will be identified by exposing them to small molecule inhibitors of GPX4 and genetic reagents that induce GPX4 loss.
- Ferroptosis-sensitive CRPC models will be used to validate the anti-cancer activity of targeting GPX4.
- The mechanisms underlying GPX4 dependency in CRPC will be investigated. Gene expression and metabolic changes in castration-sensitive versus castration-resistant prostate cancer cells will be compared. Genes that are essential for the sensitivity of CRPC to GPX4 inhibition will be identified.
- If successful, this project will credential GPX4 as a novel therapeutic target for CRPC and identify biomarkers to enable selection of patients most likely to respond to GPX4-inhibiting drugs.
What this means for patients: Dr. Viswanathan will determine whether GPX4, a protein that prevents buildup of toxic lipid metabolites, is a promising therapeutic target for the treatment of CRPC. Biomarkers to enable selection of patients most likely to respond to GPX4-inhibiting drugs will also be identified. This project will encourage investment in this area by pharmaceutical companies, several of which already have GPX4-inhibitor discovery and development efforts underway.
2018 National Cancer Institute–PCF Young Investigator Award
National Cancer Institute (NCI)
Mentor: Adam Sowalsky, PhD, William Dahut, MD
Proposal Title: Investigating the Spatial Genomic and Imaging Heterogeneity of Response and Resistance to Intense Neoadjuvant Androgen Deprivation Therapy
- Therapies targeting the androgen receptor (AR) are highly effective treatments for prostate cancer. Unfortunately, in many patients, resistance eventually develops and disease progression to castration resistant prostate cancer (CRPC) occurs. Clinical trials are testing the efficacy of neoadjuvant anti-androgen therapy, followed by radical prostatectomy, in patients with intermediate-high risk localized disease, as an opportunity to improve patient outcomes.
- Scott Wilkinson is studying the mechanisms underlying exceptional response or resistance to neoadjuvant anti-androgen therapy in order to better identify patients who may benefit from this treatment strategy.
- Specific genomic alterations that distinguish exceptional versus poor responders to neoadjuvant anti-androgen therapies will be identified, using tissues from patients with intermediate-high risk localized prostate cancer on a clinical trial testing enzalutamide plus androgen deprivation therapy (ADT) for 6 months prior to radical prostatectomy.
- Patients on the trial will be periodically imaged using multiparametric magnetic resonance imaging (mpMRI), to guide initial biopsy and to identify sites of tumor that do or do not respond to neoadjuvant AR-targeted therapy, in order to evaluate the biology of these sites in surgical specimens following radical prostatectomy.
- The ability of mpMRI to optimally target diagnostic biopsies and to predict efficacy of neoadjuvant ADT will be evaluated by comparing mpMRI images with results from biopsy and post-treatment assessments of tumor specimens.
- If successful, this project will uncover the mechanisms underlying exceptional response or resistance to neoadjuvant anti-androgen therapy, and assess the utility of mpMRI to guide biopsy for prostate cancer diagnosis and as an imaging biomarker for treatment responses.
What this means for patients: Dr. Wilkinson is studying the efficacy of neoadjuvant AR-targeted therapy in patients with intermediate-high risk localized prostate cancer, and will identify mechanisms of response and biomarkers to identify patients most likely to benefit from this possibly more effective, but also more toxic treatment strategy.
2018 John & Daria Barry Foundation–PCF VAlor Young Investigator Award
New York University
Mentors: Kwok-Kin Wong, MD, PhD, Michael Garabedian, PhD
Proposal Title: Overcoming Immune Evasion in Androgen Receptor-Independent Prostate Cancer through Targeting Dickkopf-1 (DKK1)
- Androgen receptor (AR)-targeted therapy can be highly effective for the treatment of prostate cancer. Unfortunately, most patients will eventually develop resistance and progress to castration resistant prostate cancer (CRPC), an incurable form of the disease. Identifying the mechanisms of treatment resistance will reveal new strategies to prevent or overcome AR-therapy resistance.
- David Wise is studying the role of DKK1 as a driver of some forms of CRPC.
- Wise previously found that DKK1 is upregulated in a subset of metastatic CRPC with low or no expression of AR and that do not have features of neuroendocrine or small cell prostate cancer. DKK1 is a secreted protein that is known to inhibit the WNT signaling pathway and can also inhibit the development of anti-tumor immune responses.
- To determine if DKK1 drives the progression of AR-independent CRPC through promotion of an immunosuppressive microenvironment, immune cell subsets in DKK1-expressing versus DKK1-negative prostate cancer will be characterized.
- Whether DKK1 is a required for creating a tumor microenvironment that suppresses immune cell activity will be determined using patient-derived 3D culture models.
- The effects of DKK1 blockade on the types and number of immune cells infiltrating tumors will be evaluated in samples from advanced prostate cancer patients on a phase 1/2 clinical trial testing the DKK1-inhibitor DKN01 plus docetaxel.
- If successful, this project will determine whether DKK1 drives the development of CRPC by preventing anti-tumor immune responses, and will determine the efficacy of targeting DKK1 for the treatment of advanced prostate cancer.
What this means for patients: Dr. Wise will determine the role of the secreted protein DKK1 in driving the development of CRPC and in preventing anti-tumor immune responses, and will determine the clinical efficacy of targeting DKK1 in advanced prostate cancer patients. This may lead to a new treatment for a subset of patients with CRPC and improve our understanding of immune tolerance in prostate cancer.