The PCF Young Investigator Award-Class of 2017 recipients are:
Sarah Amend, PhD
Johns Hopkins University
Mentor: Kenneth Pienta, MD
Proposal Title: Identification and Characterization of Lethal Disseminated Tumor Cells in Men with High-Risk Prostate Cancer
- As tumors grow, they leave the environment around them bare of nutrients, low in oxygen, and high in acid levels.
- Sarah Amend hypothesizes that this harsh environment forces some tumor cells to evolve to withstand difficult conditions, and that these are the tumor cells that are able to spread and form metastases.
- In this study, Dr. Amend will identify the features of prostate cancer cells that initiate metastases and define the tumor environmental conditions that contribute to the evolution of these cells.
- To characterize tumor cells that initiate metastases, tumor cells from high-risk prostate cancer patients that have disseminated to the bone marrow will be compared with tumor cells in low-oxygen regions of primary prostate tumors. Tumor cell types that correlate with early metastasis will be identified. Whether these cells exhibit “epithelial-mesenchymal” features, which enable cells to detach and migrate, will be determined.
- A specially engineered microfluidic device will be used to study how tumor cells adapt to changes in nutrient levels, oxygen levels, and acid levels, and identify the environmental parameters that promote the evolution of metastatic cells. Animal models will be used to validate the effect of these conditions on the metastatic activity of tumor cells and to more fully characterize these pro-metastatic tumor cells.
- If successful, this project will identify the conditions and tumor cell types that drive the development of metastatic prostate cancer.
What this means for patients: Understanding how prostate tumor cells gain the ability to colonize other body sites and form metastases is critical for the development of new therapeutic strategies. Dr. Amend will identify and characterize the specific tumor cell populations that form metastases and define tumor environmental conditions that drive the evolution of these cells. This will lead to new strategies for preventing or targeting metastases.
2017 Don Marron – PCF Young Investigator Award
2018 Rebecca and Nathan Milikowsky – PCF Young Investigator Award
2019 Republic of Tea – PCF Young Investigator Award
Michael Augello, PhD
Weill Cornell Medicine
Mentor: Mark Rubin, MD, Christopher Barbieri, MD, PhD
Proposal Title: The Role of CHD1 Loss on Cistrome Reprogramming and Prostate Cancer Progression
- CHD1 is a protein that regulates certain features of prostate cells. Deletion of the CHD1 gene occurs in ~20% of primary prostate cancer, suggesting that CHD1-loss plays a significant role in the development of the disease.
- Michael Augello will determine how CHD1-loss drives the development and progression of prostate cancer.
- The consequence of CHD1-loss on prostate cancer “epigenetics” will be assessed. Epigenetics is a system of regulating the 3D structure of DNA to enable or disable different genes from being expressed.
- The androgen receptor (AR) is the primary driver of prostate cancer. Whether and how CHD1-loss alters the activity of AR will be investigated.
- The effect of CHD1-loss on gene expression and growth of prostate cancer cells will be determined. The genes that drive prostate cancer growth following CHD1-loss will also be determined.
- The clinical impact of CHD1-loss will be studied by examining the outcomes of patients with this defect in their tumors. Whether CHD1-loss predicts responses to different therapies will be investigated.
- Finally, a drug screen will be performed to identify novel therapies that are effective against prostate tumors that have deleted CHD1.
- If successful, this study will define the mechanisms by which CHD1-loss drives prostate cancer and identify therapeutic options for patients with these tumors.
What this means for patients: Determining the impact of prostate cancer-driving mutations is critical for improving treatment for patients. Dr. Augello will investigate how a mutation observed in 1/5 of prostate cancer patients, CHD1-deletions, drives their disease and identify promising treatment options for these patients.
2017 Lori Milken – PCF Young Investigator Award
Maria Carlo, MD
Memorial Sloan Kettering Cancer Center
Mentor: Howard Scher, MD, Mark Robson, MD
Proposal Title: A Novel Approach to Facilitating Germline Genetic Testing in Men with Advanced Prostate Cancer
- Approximately 12% of metastatic prostate cancer patients have inherited mutations in genes that repair damaged DNA (DDR), which likely contributed to development of their cancer. Identifying patients with hereditary DDR mutations is critical, as tumors with these mutations may respond to PARP-inhibitors and platinum chemotherapy.
- Current national guidelines are not optimal for identifying the majority of these patients, while current genetic counseling models cannot meet the projected demand for testing of prostate cancer patients, some of whom face time-sensitive treatment decisions.
- Maria Carlo will evaluate an alternative approach to achieve timely and effective routine genetic testing for men with advanced prostate cancer.
- Carlo will conduct a prospective, single-arm study to examine how an alternative genetic counseling model that incorporates genomic testing with telephone genetic counseling and email questionnaires, affects patient outcomes. Optional in-person counseling for patients and their families will be offered.
- A total of 600 advanced prostate cancer patients will be accrued to this study. Patients will be tested for hereditary mutations in 12 DDR genes which have been linked to increased risk of prostate cancer and have potential therapeutic implications.
- The impact of this model will be measured by changes immediate changes in therapy, future therapy implications or immediate genetic counseling implications that would not have occurred if not for testing.
- Email questionnaires will be used to study how this genetic counseling model affects patients’ understanding and acceptance of genetic counseling and psychological and behavioral outcomes.
- If successful, this project will develop an alternate clinical genetics delivery model that is acceptable to patients and will enable routine genetic screening of men with advanced prostate cancer and improve their outcomes.
What this means for patients: Hereditary mutations in cancer risk genes are common in advanced prostate cancer patients, but current genetic counseling models cannot meet the demand that will be required for testing this number of individuals. Dr. Carlo will develop a new telephone-based genetic counseling model and determine its clinical utility and acceptability to patients. This will enable screening of all advanced prostate cancer patients for hereditary cancer-risk mutations and improve treatment selection and outcomes.
2017 Stewart Rahr – PCF Young Investigator Award
Elena Castro, MD, PhD
Spanish National Cancer Research Centre
Mentor: Gerhardt Attard, MD, PhD, David Olmos, MD, PhD, Rosalind Eeles, MD, PhD
Proposal Title: Prospective Study of Lethal Prostate Cancer Clinical and Genomic Evolution in DNA Repair Deficient Tumours
- Mutations in DNA damage repair (DDR) genes contribute to the progression of up to a third of advanced prostate cancers. For about half of these patients, these mutations were inherited (germline).
- DDR gene mutations often confer sensitivity to PARP-inhibitors, a new class of targeted therapy. However, in order to optimize treatment for these patients, studies are needed to clarify which treatments are most effective against tumors with different DDR gene mutations
- Elena Castro will study how different DDR gene mutations affect responses to therapy, clinical outcomes, and how tumors evolve over time.
- Castro is conducting a clinical trial called PROREPAIR-B, which is assessing the impact of inherited mutations in DDR genes on the survival and treatment responses of patients with metastatic castration-resistant prostate cancer.
- Over 400 mCRPC patients were enrolled into this study and examined for hereditary DDR mutations. Approximately 6% were found to be hereditary DDR mutation carriers.
- Inherited mutations in DDR genes typically only affect one gene copy. However, cells that become cancerous typically mutate the other copy. Tumor tissues from the patients in this study will be examined for acquired mutations in DDR genes. The ability to detect these mutations from blood samples, which carry circulating tumor DNA, will also be evaluated.
- Tumor and blood samples collected from patients throughout their clinical course will be used to study tumor cell evolution and how mutations affects responses to different therapies.
- If successful, this project will provide data for developing the most appropriate therapeutic strategies for patients with DNA repair gene defects.
What this means for patients: Mutations in DNA repair genes identify a subset of prostate cancer patients that may respond better to some treatments than others. Dr. Castro will characterize the impact of inherited and acquired DDR mutations on the genomic evolution of tumors and on the response to treatments. This data will clarify which treatments are best for DDR-deficient prostate cancer, and accelerate the development of optimal treatment for these patients.
2017 Tony Minella – PCF Young Investigator Award
Michael Cheng, MD
Memorial Sloan Kettering Cancer Center
Mentor: Howard Scher, MD, David Solit, MD
Proposal Title: Mediators of Intrinsic Sensitivity and Acquired Resistance to PARP Inhibition for the Treatment of BRCA-Mutant Castrate Resistant Prostate Cancer
- Mutations in DNA damage repair (DDR) genes such as BRCA occur in up to a third of castrate resistant prostate cancer (CRPC) and often render tumors sensitive to treatment with PARP-inhibitors. However, these mutations are very diverse, and biomarkers that can identify which patients are most likely to respond to various treatments are needed.
- Michael Cheng hypothesizes that the sensitivity of BRCA-mutant prostate tumors to PARP-inhibitors will depend on the exact BRCA mutation and how much it impairs DNA repair in the tumor.
- Memorial Sloan Kettering Cancer Center is conducting a phase II trial of the PARP inhibitor rucaparib in CRPC with acquired or inherited mutations in BRCA or other DDR genes.
- Cheng will evaluate BRCA-mutant patients in this trial to determine if responses to rucaparib associate with specific BRCA mutations or with a DNA repair biomarker score composed of several measures of DNA repair capability and genomic stability.
- Mechanisms by which BRCA-mutant tumors gain resistance to PARP-inhibition will be studied by evaluating new tumor mutations in patients who are progressing on therapy.
- In these studies, both tumor and blood samples will be evaluated. This will be used to determine whether blood tests, which contain shed tumor DNA, can signal cancer progression earlier than imaging or other clinical indicators.
- If successful, these studies will result in the development of biomarkers that identify patients likely to respond to PARP inhibitors, and will define mechanisms of resistance to these therapies.
What this means for patients: Mutations in BRCA and other DNA damage repair genes often render prostate tumors sensitive to treatment with PARP-inhibitors, although more studies are needed to identify patients who are most likely to respond. Dr. Cheng will develop predictive biomarkers to best identify patients who will respond to PARP-inhibitors, and will define mechanisms by which these tumors gain therapeutic resistance. This will enable optimal patient selection for treatment with PARP inhibitors.
2017 David Blitzer – PCF Young Investigator Award
Robert Flavell, MD, PhD
University of California, San Francisco
Mentor: John Kurhanewicz, PhD, Michael Evans, PhD
Proposal Title: Detection of Aggressive Prostate Cancer through pH Imaging using Hyperpolarized 13C Magnetic Resonance Spectroscopy
- Prostate cancer is a highly variable disease, being highly aggressive in some men, while in others may never become a health concern and would be better left untreated. Advancements in molecular imaging technologies will help to distinguish aggressive from non-aggressive prostate cancer, and lead to improved patient outcomes and avoidance of unnecessary treatment for patients with non-aggressive tumors.
- Robert Flavell is developing a novel molecular imaging technology, hyperpolarized 13C MRI, that distinguishes prostate cancer aggressiveness based on pH levels in tumor tissues, in order to improve prostate cancer diagnosis and prognosis.
- Animal models will be used to test the efficacy and sensitivity of hyperpolarized 13C MRI in distinguishing indolent vs. aggressive prostate cancer. These models will also be used to validate the hypothesis that tumor pH levels correlate with tumor grade and patient outcome.
- Genetically engineered animal models will be used to study the relationship between tumor pH and mutations that commonly drive prostate cancer.
- Finally, the methodology for generating a clinical grade 13C MRI imaging agent will be developed to prepare for translation of this imaging technology into humans.
- If successful, this project will result in preclinical validation of a novel, improved prostate cancer imaging technology that can be easily incorporated into routine prostate multi-parametric-MRI, and will set the stage for clinical trials of this technology.
What this means for patients: New imaging techniques are needed to improve diagnosis and staging of prostate cancer patients, in order to improve outcomes and reduce unnecessary treatments. Dr. Flavell is developing a novel imaging technology, hyperpolarized 13C MRI, that distinguishes prostate cancer aggressiveness based on pH levels in tumor tissues. This will result in a new imaging method that will improve prostate cancer prognostication.
2017 National Cancer Institute – PCF Young Investigator Award
Stephanie Harmon, PhD
National Cancer Institute
Mentor: Peter Choyke, MD
Proposal Title: Data-Driven Modeling of Prostate Cancer Decision Making and Outcomes
- Prostate cancer represents a broad spectrum of disease, from slow-growing low-risk tumors to rapidly progressing lethal variants. There is an urgent need to develop precision medicine strategies that will provide the best possible outcome for every individual. Accelerating precision medicine for prostate cancer requires comprehensive use of patient data that is currently collected in a disparate way.
- Stephanie Harmon proposes to create a novel way to capture and curate data from patients treated at the NCI to provide an evidence-based approach to selecting optimal treatments for patients based on preexisting medical information.
- Patient care and treatment planning is improved by team-based multidisciplinary tumor boards (MTBs) consisting of urologists, radiation oncologists, surgeons, medical oncologists, pathologists, radiologists and allied health personnel. However, data on how MTBs make decisions and affect patient outcomes is inherently complicated, and is rarely captured in a way that can be used for research purposes.
- Harmon will identify the patient-specific factors that drive treatment-selection by MTBs at the NCI. Machine learning methods will be created to retrospectively and prospectively predict MTB-recommended treatment plans based on preexisting medical data.
- Finally, the value of the machine learning algorithm as a decision-support system will be determined by evaluating consensus between the model-based treatment decision and the MTB treatment decision.
- If successful, this project will result in a decision-support system that can aid in precision medicine treatment selection based on MTB experiences.
What this means for patients: Precision medicine involves identifying the best treatment for individual patients, and success requires extensive experience with similar cases. Dr. Harmon will create a decision-support system that learns from multidisciplinary tumor boards to generate treatment recommendations that optimize patient outcomes.
2017 Judy and Ronald Baron – PCF Young Investigator Award
Stefanie Hectors, PhD
Icahn School of Medicine at Mount Sinai Hospital
Mentor: Bachir Taouli, MD
Proposal Title: Characterization of Prostate Cancer Aggressiveness with Advanced Multiparametric Magnetic Resonance Imaging
- Biopsies are currently required for diagnosis and staging of prostate cancer, but suffer from poor accuracy (the site of tumor may be missed by the biopsy) and can result in complications such as infections. New methods to accurately but noninvasively detect and stage prostate tumors are needed.
- Multiparametric MRI (mpMRI) is an emerging molecular imaging technology that has the potential to noninvasively assess prostate cancer aggressiveness.
- Stefanie Hectors will determine whether mpMRI can be used to accurately indicate the stage and grade of prostate tumors.
- A cohort of patients who underwent mpMRI followed by a prostatectomy will be retrospectively analyzed to compare mpMRI predictions of prostate cancer aggressiveness with assessments based on tumor tissues.
- A prospective clinical trial will also be conducted in which patients will undergo an mpMRI scan followed by a prostatectomy, to validate the accuracy of mpMRI in predicting prostate cancer aggressiveness.
- Finally, mpMRI-based predictions of tumor aggressiveness will be compared with a commonly used prostate cancer risk classification test based on tumor gene expression.
- If successful, this project will validate a novel, noninvasive method to diagnose prostate cancer and predict disease aggressiveness.
What this means for patients: New approaches are needed to improve the diagnosis and prognosis of prostate cancer, so that patients can be better matched with optimal treatment plans. Dr. Hectors will validate the accuracy of an emerging imaging technology, multiparametric MRI, for the accurate assessment of prostate cancer aggressiveness. This will lead to improved outcomes for patients by avoiding under and over-treatment.
2017 Jonathan Kovler – PCF Young Investigator Award
Thomas Hope, MD
University of California, San Francisco
Mentor: Eric Small, MD, Felix Feng, MD, Charles Ryan, MD
Proposal Title: Redefining M0 CRPC Patients using PSMA PET
- Current standard imaging technologies are not sensitive enough to detect very small tumors, leading to delays in diagnosis and treatment of metastatic prostate cancer.
- PSMA-PET imaging is a new imaging technology that is significantly more sensitive than conventional bone scans and computed tomography (CT) imaging.
- Thomas Hope hypothesizes that the use of PSMA-PET imaging will enable earlier detection of metastatic lesions and improve treatment and outcomes.
- Hope will use PSMA-PET imaging to examine a cohort of patients who are experiencing a PSA rise while on treatment with androgen deprivation therapy (ADT), who do not have metastatic lesions detectable by conventional bone scans or CT.
- Patients found to have three or fewer metastatic lesions and are determined to be good candidates for radiation will be treated with targeted radiation therapy. All tumors detected by PSMA-PET will be targeted. Patients will then be followed to determine the outcome of this treatment on PSA levels.
- Finally, metastatic lesions detected by PSMA-PET in these patients will be biopsied and studied to determine if these tumors have unique genetic characteristics as compared to patients with overt metastatic disease.
- If successful, this study will validate a new, highly sensitive imaging technology for the detection of early metastatic prostate cancer, and test a treatment strategy for these patients.
What this means for patients: New technologies that enable earlier detection of metastatic disease will lead to more appropriate treatment plans that improve patient outcomes. Dr. Hope will demonstrate the utility of PSMA-PET imaging for detecting early metastatic lesions and guiding successful targeted radiation treatment of these tumors.
2017 PCF Young Investigator Award in Honor of Earle Mack
Wouter Karthaus, PhD
Memorial Sloan Kettering Cancer Center
Mentor: Charles Sawyers, MD
Proposal Title: Identifying Novel Regulators of Lineage Plasticity in an Organoid Model of Anti-Androgen Resistance
- Patients that are treated with anti-androgen therapy sometimes relapse with a highly aggressive “plastic” castrate-resistant prostate cancer (CRPC) subtype that has taken on characteristics of other cell types, including neuroendocrine and stem cells. Understanding the drivers of this mode of anti-androgen resistance will enable the development of new therapies for this lethal disease.
- Wouter Karthaus will use organoids, which are mini-tumors that can be grown in the laboratory, to study the mechanisms underlying the development of this aggressive form of CRPC.
- The development of aggressive plastic CRPC was found to be driven by loss of the tumor suppressor genes p53 and Rb1. Mouse prostate cancer organoids will studied to determine how loss of p53 and Rb1 promote this subtype. The effect that restoration of the androgen receptor (AR) pathway has on this subtype will also be explored.
- Mouse prostate cancer organoids will be used to identify possible druggable targets of aggressive plastic CRPC.
- Finally, human models of p53/RB1-deficient CRPC will be developed by deleting these genes in human prostate cancer cell lines.
- If successful, this project will uncover mechanisms that drive the development of aggressive plastic CRPC, identify promising therapeutic targets, and develop model systems for studying this lethal prostate cancer subtype.
What this means for patients: Understanding mechanisms of therapeutic resistance is critical for developing new treatments for aggressive prostate cancer. Dr. Karthaus is studying mechanisms driving the development of a highly aggressive form of CRPC and identifying potential therapeutic targets. This will lead to the development of new treatments for this disease.
2017 National Cancer Institute – PCF Young Investigator Award
Fatima Karzai, MD
National Cancer Institute
Mentor: William Dahut, MD
Proposal Title: Combination of PD-L1 and PARP Inhibition in Men with Metastatic Castrate-Resistant Prostate Cancer.
- Checkpoint immunotherapy has shown remarkable activity in some patients with melanoma, lung cancer, and other tumor types, but not prostate cancer.
- PARP-inhibitors are a class of targeted therapy that are effective against prostate tumors with DNA damage repair (DDR) gene mutations, present in 25-30% of advanced prostate cancer.
- Fatima Karzai hypothesized that increased DNA damage caused by the PARP-inhibitor olaparib may complement the anti-tumor activity of the checkpoint immunotherapy durvalumab.
- A clinical trial is being conducted at the NCI to test the combination of olaparib and durvalumab in patients with progressive metastatic castrate resistant prostate cancer (mCRPC) and has shown highly promising early results. This project will accrue an additional 45 patients to the original 25 patient cohort. Twenty of the additional patients will have a known DDR gene defect.
- Tumors will be assessed for mutations, including DDR gene mutations, that correspond with treatment responses. Tumor samples will also be used to generate laboratory models for studying tumor biology and treatment sensitivities.
- Additionally, patients will be assessed for immune cell parameters that may serve as predictive biomarkers for response to this therapeutic regimen.
- If successful, this study will result in a powerful new treatment regimen and uncover which patients should receive this treatment and the biology underlying treatment responses.
What this means for patients: Preliminary analysis of an ongoing clinical trial has indicated significant activity for combining the PARP-inhibitor olaparib with the checkpoint immunotherapy durvalumab. Dr. Karzai will expand the number of patients being treated in this clinical trial and uncover mechanisms and predictive biomarkers of therapeutic responses. This may result in a new therapy that will benefit unselected patients with advanced prostate cancer.
2017 Andy Astrachan and Marc Utay – PCF Young Investigator Award
Ping Mu, PhD
Memorial Sloan Kettering Cancer Center
Mentor: Charles Sawyers, MD, Philip Kantoff, MD
Proposal Title: Identifying the SYNCRIP Gene Deletion as a Novel Biomarker of Antiandrogen Resistance in Advanced Prostate Cancer
- The androgen receptor (AR) is the primary driver of prostate cancer and therefore a critical therapeutic target. However, resistance to AR-targeting therapy is common. Understanding the mechanisms of resistance is critical for developing new treatment strategies.
- Ping Mu has identified deletion of the tumor suppressor gene SYNCRIP as a novel mechanism of resistance to the anti-AR therapy enzalutamide.
- Prostate cancer cells can develop resistance to AR-targeting therapy by taking on characteristics of other cell lineages (such as neuroendocrine cells), and hijacking the pathways that support survival of those cells. Whether SYNCRIP-deletions confer enzalutamide resistance via cell lineage switching will be investigated using laboratory and animal models.
- SYNCRIP is a novel tumor suppressor gene with many functions including the ability to interact with other proteins and with RNA. Mu will determine the mechanisms by which the SYNCRIP protein regulates enzalutamide resistance by studying cells expressing different portions of SYNCRIP.
- SYNCRIP-deletions were found to occur in ~15% of prostate cancer patients. Whether the SYNCRIP gene status is a biomarker of enzalutamide resistance will be investigated by examining the association between SYNCRIP gene status and enzalutamide response in patients with advanced prostate cancer.
- Finally, potential therapeutic approaches to prevent or overcome SYNCRIP-mediated enzalutamide resistance will be identified.
- If successful, this project will lead to increased understanding of how prostate cancer cells resist therapy and a therapeutic strategy for overcoming resistance in a prevalent subset of patients.
What this means for patients: Overcoming or avoiding resistance to anti-androgen therapy is critical for extending the lives of patients with prostate cancer. Dr. Mu will identify the mechanisms underlying a novel mode of enzalutamide resistance that occurs in a subset of patients. This project will also directly lead to the development of novel therapies for overcoming this mode of enzalutamide resistance.
2017 Genomic Health – PCF Young Investigator Award
Nicholas Nickols, MD, PhD
University of California, Los Angeles
Mentor: Matthew Rettig, MD
Proposal Title: Molecular Drivers of Metastasis of Lethal Prostate Cancer: Correlative Analyses from a Prospective Phase II Trial in Oligometastatic Patients in Veterans Affairs
- Oligometastatic prostate cancer is a distinct clinical state in which patients have five or fewer metastases. These patients tend to have improved outcomes compared with patients with overt (>5) metastases and may be candidates for curative therapy. Understanding the biological differences between clinically different states of prostate cancer will enable the development of better treatments for patients.
- Nicholas Nickols is investigating the mechanisms that enable primary prostate tumors to become metastatic.
- To uncover mechanisms of prostate cancer metastasis, Dr. Nickols will study tumor samples from US Veterans with oligometastatic prostate cancer who are enrolled in a clinical trial in the Veteran’s Affairs (VA) Hospitals. These patients are being treated with a potentially curative regimen consisting of radical prostatectomy, stereotactic ablative radiotherapy (SBRT) to metastatic sites, and six months of complete androgen-blockade therapy.
- Several “primary” tumors can often develop in the prostate concurrently, but only some will progress to metastatic disease. Nickols will use genomic profiling of metastatic and primary tumors to identify the “true” primary tumor that gave rise to metastases in each patient. This will enable identification of the factors that enable primary tumors to become metastatic.
- Nickols will also determine whether specific biological programs thought to promote metastasis are activated in primary tumors that became metastatic as compared with those that did not. The programs to be investigated include the tumor-promoting MAPK signaling pathway and epithelial-mesenchymal transition (EMT), a program in which cells become unattached from one another and gain the ability to migrate to and invade other tissues.
- If successful, this project will identify key features of potentially lethal primary prostate tumors.
What this means for patients: Dr. Nickols will study samples from US Veterans with prostate cancer in order to identify mechanisms that drive prostate cancer metastasis. This will enable development of new prognostication and treatment approaches to prevent and treat metastasis in prostate and potentially other cancers.
2017 Ilan Shalit – PCF Young Investigator Award
Yashar Niknafs, PhD
University of Michigan
Mentor: Arul Chinnaiyan, MD, PhD
Proposal Title: A Comprehensive Transcriptomics Resource to Enable Understanding and Clinical Detection of Aggressive Prostate Cancer
- Numerous studies have analyzed genes that are expressed by prostate and other cancers. Within this myriad of cancer gene expression datasets, there remains a significant untapped potential for further understanding the biology of metastatic prostate cancer and identifying diagnostic and prognostic biomarkers of aggressive disease. Harnessing these large and disparate datasets requires curation of the data and development of powerful new bioinformatics tools.
- Yashar Niknafs is developing tools for aggregating, curating, and analyzing cancer gene expression datasets, and will use this knowledge to identify biomarkers that can aid physicians in selecting optimal treatments for patients.
- Data from over 20,000 cancer samples, including over 1,000 prostate cancers, will be curated and loaded into a recently developed, publicly-available cancer gene expression data portal, miPanda.
- A prostate cancer-specific data portal, to be named PCF-Panda, will be developed to specifically house and analyze data from the prostate cancer samples.
- The prostate cancer dataset will be extensively analyzed, to identify genes specifically expressed by advanced prostate cancer.
- The most promising genes will be investigated for their association with patient clinical outcomes and treatment responses.
- Finally, assays will be developed to assess the expression of the most clinically prognostic genes in tumor tissues and urine samples, with the ultimate goal of developing biomarker assays that can be used by clinicians to distinguish aggressive from indolent disease and make optimal treatment decisions.
- If successful, this project will develop a rich resource for analyzing prostate cancer gene expression and identify clinically relevant predictive and prognostic biomarkers.
What this means for patients: Developing methods to interrogate the vast amounts of cancer data will lead to identification of new cancer mechanisms, treatment targets, and prognostic and predictive biomarkers. Dr. Niknafs will aggregate a huge dataset of prostate cancer gene expression data into a novel web portal and use this information to identify biomarkers that can predict aggressive disease. These studies will both provide a valuable new resource for prostate cancer researchers and help clinicians to improve patient prognostication and treatment selection.
2017 Progenics Pharmaceuticals – PCF Young Investigator Award
Mark Preston, MD, MPH
Harvard: Brigham and Women’s Hospital
Mentor: Lorelei Mucci, ScD, MPH, Adam Kibel, MD
Proposal Title: Risk Prediction of Aggressive Prostate Cancer using Baseline PSA during Midlife and Inherited Genetic Variants in African-American and Caucasian Men
- Men of African descent have a significantly higher risk of being diagnosed with aggressive prostate cancer and dying of their disease compared with Caucasian men. Studies that will improve prostate cancer screening for men of African descent and enable diagnosis at an earlier, more curable state of disease, are of critical need.
- Studies have suggested that PSA testing at a younger age may be more accurate in predicting prostate cancer risk, as there are fewer confounding factors affecting PSA levels.
- Mark Preston aims to improve prostate cancer screening by using baseline PSA levels taken at midlife (age 40-55) combined with data on inherited genetic variants to predict future risk of aggressive prostate cancer, with focus on African-Americans.
- The extent to which midlife PSA levels predict future aggressive prostate cancer diagnosis in African-American men during 13 years of follow-up will be investigated.
- A large existing cohort that consists of primarily Caucasian patients will be examined for genetic variants that associate with PSA levels or are related to prostate cancer risk. Whether these variants improve midlife PSA level-based prediction of future risk of advanced prostate cancer will be determined.
- A screening model will be created in which PSA-related genetic variants will be used to adjust midlife baseline PSA levels, to remove the effects of inherited variation in PSA and improve the accuracy of predicting future risk of prostate cancer.
- Finally, this prostate cancer prediction model will be applied to a large cohort of ~23,000 African-American men to validate its predictive accuracy.
- If successful, this project will lead to the development of an improved prostate cancer screening strategy for all men, including men of African descent.
What this means for patients: Dr. Preston will provide urgently needed evidence to create a smarter PSA screening strategy for African-American and white men through baseline PSA and genetic testing in midlife.
2017 Brian Sheth – PCF Young Investigator Award
David Quigley, PhD
University of California, San Francisco
Mentor: Felix Feng, MD, Alan Ashworth, PhD
Proposal Title: Modeling and Overcoming PARP Inhibitor Resistance in Castration-Resistant Prostate Cancer.
- Approximately 12% of men with metastatic castration-resistant prostate cancer (mCRPC) have inherited mutations inactivating a single copy of BRCA2 or another DNA damage repair (DDR) gene, which likely contributed to their disease. Most prostate tumors in these men have mutated the second copy of the gene.
- Dual-copy mutations in DDR genes render tumors sensitive to treatment with PARP-inhibitors, while tumors that retain a normal copy are not sensitive.
- David Quigley will explore strategies to force tumor cells with one mutated and one normal copy of a DDR gene to become sensitive to treatment with PARP-inhibitors. He will test strategies to target tumors that have only one mutated copy of BRCA2, as well as “BRCA2-revertant” cells. BRCA2-revertant cells are dual-copy BRCA2-mutant prostate cancer cells that were treated with PARP-inhibitors but developed resistance by acquiring mutations that restored one copy of BRCA2.
- Quigley will test the efficacy of targeting DNAPK, an enzyme involved in another form of DNA repair, against prostate cancer cells with one inactivated copy of BRCA2. The activity of enzalutamide will also be tested, as well as the combination of DNAPK-inhibitors or enzalutamide with PARP-inhibitors.
- Liquid biopsies, which contain tumor DNA, will be used to track the status of BRCA2 mutations during the course of PARP-inhibitor treatment, to identify patients that acquire resistance through BRCA2-reversion mutations. Whether liquid biopsies can identify the development of resistance to PARP-inhibitors earlier than PSA measurements or imaging will be determined. The ultimate goal is to develop a method that detects resistance to PARP-inhibitors as early as possible, so patients can be switched to other therapies.
- If successful, this project will develop methods to monitor the development of PARP-inhibitor resistance in patients, and indicate new therapeutic strategies for these patients.
What this means for patients: PARP-inhibitors are active against tumors with mutations in both copies of a DNA repair gene such as BRCA2. Dr. Quigley will develop strategies to sensitize cells with only one mutated copy of BRCA2 to PARP-inhibitors, and will develop methods to monitor patients for the development of resistance to PARP-inhibitors. This will lead to an expanded therapeutic window for this class of therapy.
Ayesha Shafi, PhD
Thomas Jefferson University
Mentor: Karen Knudsen, PhD
Proposal Title: Leveraging Novel Patient-Derived Models to Predict Therapeutic Response in Prostate Cancer
• The androgen receptor (AR) is critical to the development and progression of prostate cancer and is the primary therapeutic target. However, resistance to AR-targeted therapy is common and these patients often go on to develop lethal disease.
• Understanding the mechanisms that underlie responsiveness versus resistance to AR-targeted therapies will enable the development of improved treatment strategies.
• Dr. Ayesha Shafi is studying the biology of tumors from patients who were exceptional responders and exceptional non-responders to AR-targeted therapy.
• Genes with a possible role in regulating responses to AR-therapy will be identified by studying animal models of prostate tumors from patients who were exceptional responders or non-responders to AR-targeted treatment.
• The role of the tumor microenvironment in mediating responses vs. resistance to AR-targeted therapy will be evaluated in these models.
• Dr. Shafi will also evaluate whether patient tumor samples grown in animal models can be used to predict therapeutic responses and could have a clinical role in selecting optimal treatments for patients and identifying precision medicine biomarkers.
• If successful, this project will identify mechanisms of treatment response versus resistance, identify strategies for overcoming treatment resistance, and validate the use of animal models as a “co-clinical” approach to aiding precision medicine treatment decisions.
What this means for patients: Dr. Shafi is creating animal models of human prostate cancer as surrogates for predicting and understanding individual patient responses to therapy. This will enable the identification of optimal precision medicine treatment strategies and lead to new therapeutic approaches.
2017 James Fordyce – PCF Young Investigator Award
2018 Stewart Rahr – PCF Young Investigator Award
2019 Leon Wagner – PCF Young Investigator Award
Konrad Stopsack, MD, MPH
Memorial Sloan Kettering Cancer Center
Mentor: Philip Kantoff, MD, Jennifer Rider, ScD, MPH, Lorelei Mucci, ScD, MPH
Proposal Title: Intratumoral Cholesterol Metabolism to Guide Prostate Cancer Therapy
- Studies have suggested that cholesterol-lowering medications, such as statins, may reduce mortality from prostate cancer. However, understanding which patients are most likely to benefit is critical. A subgroup of prostate tumors that exhibit increased cholesterol synthesis are strongly associated with development into lethal disease.
- Konrad Stopsack hypothesized that prostate tumors with high cholesterol synthesis, as evidenced by high expression of squalene monooxygenase (SQLE), are more likely to progress on standard therapy, but are more likely to respond to treatment with statins.
- Stopsack will use well-annotated cohorts of localized prostate cancer patients with long-term follow up data and a cohort of metastatic CRPC patients to study the relationship between SQLE levels, therapeutic responses, and long-term outcomes.
- Whether SQLE is a biomarker of ADT responses or patient outcomes will be tested.
- In addition, these cohorts will be used to assess whether SQLE levels predict response to statins in localized and metastatic prostate cancer.
- If successful, this project will result in the development of a biomarker that indicates which patients have highly aggressive disease and may benefit from treatment with statins.
What this means for patients: Higher levels of cholesterol synthesis may be a marker of prostate cancers that are more aggressive but may respond to treatment with statins. Dr. Stopsack will determine whether SQLE, an indicator of cholesterol levels, is an actionable biomarker that can identify prostate cancer patients who should receive more aggressive therapy and/or statins.
2017 National Cancer Institute – PCF Young Investigator Award
David VanderWeele, MD, PhD
National Cancer Institute
Mentor: Kathleen Kelly, PhD
Proposal Title: Organoid Culture Screen for Combination Therapies to Target Aggressive Variant Prostate Cancer
- Aggressive variant prostate cancer (AVPC) is a diverse subset of highly aggressive CRPC with abnormal clinical features, which often exhibit poor responses to standard therapies including AR-targeted therapy and docetaxel. To provide new therapeutic options for AVPC, it is critical to develop model systems for studying this aggressive tumor type.
- David VanderWeele will develop novel AVPC tumor “organoids,” which are mini-prostate tumors derived from patient samples, that can be grown in the laboratory and used to study tumor biology and test drug sensitivity.
- AVPC organoids will be used to screen a large panel of candidate drugs to identify any that have potential activity against AVPC as single agents or in combinations.
- Promising therapies and combinations will be validated in mouse models of AVPC.
- If successful, this project will identify and prioritize new agents that may have activity against this lethal subset of prostate cancer.
What this means for patients: Aggressive variant prostate cancer (AVPC) is a lethal form of prostate cancer which does not respond to treatment with standard therapies. Dr. VanderWeele will develop a system for identifying drugs and drug combinations that may have activity against clinically relevant AVPC and prioritize these candidates for further clinical studies. This may lead to new treatment options for this growing subset of lethal disease.
Srinivas Viswanathan, MD, PhD
Harvard: Dana-Farber Cancer Institute
Mentor: Matthew Meyerson, MD, PhD, Mary-Ellen Taplin, MD
Proposal Title: Genomic and Functional Genetic Approaches to Studying Androgen Receptor Splicing and Therapy Resistance in Castration-Resistant Prostate Cancer
• There is currently no curative therapy for castration-resistant prostate cancer (CRPC), the lethal disease state that develops when the cancer progresses on androgen receptor (AR)-targeted therapy. Understanding the mechanisms that contribute to the development of CRPC is critical to creating new and potentially curative therapeutic interventions.
• Dr. Srinivas Viswanathan is studying the role of AR-variants, which are constantly active variants of the AR protein, in the development of CRPC.
• The structural alterations in the AR gene that enable CRPC cells to produce AR variant proteins will be identified.
• In addition, a genome-wide screen will be performed to identify genes that are necessary for the production of AR-variants. Data from clinical CRPC samples will be used to validate whether any of these genes are associated with AR-variant expression in patients.
• Two genes that regulate RNA splicing and the production of protein variants, PRMT1 and PRMT5, were identified in preliminary genome-wide screen studies as potentially having a role in the expression of AR-variants. The mechanisms by which PRMT1 and PRMT5 regulate AR-variant expression and whether they may serve as therapeutic targets for the treatment of CRPC will be investigated.
• If successful, this project will elucidate the mechanisms by which AR-variants are regulated in CRPC and identify possible therapeutic interventions for CRPC driven by AR-variant expression.
What this means for patients: Dr. Viswanathan is investigating the mechanisms underlying the production of AR-variants, which are constantly active AR proteins that may drive resistance to AR-targeted therapy. This study may reveal new pathways that mediate drug resistance via regulation of AR-variants and uncover novel therapeutic targets for the treatment of CRPC.
2017 John Tyson – PCF Young Investigator Award
Di Zhao, PhD
The University of Texas MD Anderson Cancer Center
Mentor: Ronald DePinho, MD, Raghu Kalluri, MD, PhD
Proposal Title: Novel Therapeutic Approaches for Advanced Prostate Cancer Harboring Specific Tumor Suppressor Deficiencies
- Synthetic lethality is the concept that tumor cells which have mutated one molecular pathway become highly dependent on a second, related pathway to survive. Targeting the second pathway in these tumors is a highly promising therapeutic strategy.
- Di Zhao identified CHD1 as a candidate synthetic-lethal target in prostate cancers that have lost the PTEN gene.
- Zhao will create genetically engineered animal tumor models to validate whether targeting CHD1 disables the survival or progression of PTEN-deficient prostate cancer.
- The PTEN-CHD1 axis may regulate the recruitment and activity of immune cells into tumors. Zhao will investigate impact of PTEN and CHD1-loss on the numbers and functions of different types of immune cells in prostate tumors in these animal models. Preliminary studies found that tumors with CHD1/PTEN-loss have decreased numbers of immune cell types that suppress tumor-killing immune cells, which suggests that these tumors may be sensitive to treatment with certain types of immunotherapy.
- The combination of CHD1-inhibition and anti-PD1/PDL1 immunotherapy, which works by reactivating tumor-killing immune cells, will be tested in PTEN-deficient prostate cancer models.
- If successful, this project will result in novel and promising therapeutic strategies for targeting PTEN-deficient prostate cancer.
What this means for patients: Certain tumor mutations may drive tumor growth but may also represent weaknesses that can be therapeutically targeted. Dr. Zhao will test the activity of targeting CHD1 and immunotherapy in PTEN-deficient prostate cancer, which may lead to new therapies for these patients.