The PCF Young Investigator Award-Class of 2020 recipients are:
Columbia University Medical Center
Mentors: Cory Abate Shen, PhD; Andreas Califano, PhD; Mark Rubin, MD
Investigating Novel Epigenetic Drivers of Bone Metastasis and Treatment Response in Metastatic Castration-Resistant Prostate Cancer
- The most common site of prostate cancer metastasis is to bone, which is a major contributor to the morbidity and mortality of this disease. In order to develop novel and more effective therapies for metastatic prostate cancer, a better understanding of the biology of bone metastasis is needed.
- Dr. Juan Arriaga has discovered the protein ATAD2 as a major player in prostate cancer bone metastasis, using a unique mouse model of bone metastasis that is molecularly conserved with human prostate cancer.
- In this project, Dr. Arriaga will determine the molecular basis by which ATAD2 contributes to prostate cancer bone metastasis.
- In addition, the potential for ATAD2-targeting small molecule inhibitors as a new treatment for prostate cancer in combination with hormone therapy will be tested in preclinical models.
- If successful, this will project will determine how ATAD2 impacts the development of bone metastasis and resistance to hormonal therapies, and validate its potential as a novel therapeutic target in metastatic prostate cancer.
What this means to patients: Dr. Arriaga is studying the biology of prostate cancer bone metastasis, specifically the role of ATAD2, and a driver of bone metastasis and possible new treatment target. This may result in an effective new therapeutic strategy to prevent or treat metastatic prostate cancer
University of California, Los Angeles
Mentor: Leonard Marks, MD
Micro-Ultrasound and MRI Investigation of Human Prostate Cancer
- Micro-ultrasound is a new imaging technology that has a 300% improvement in resolution compared to traditional ultrasound, and thus is highly promising for enabling visualization of prostate cancer.
- Dr. Wayne Brisbane is studying the potential for micro-ultrasound in prostate cancer imaging.
- In this project, Dr. Brisbane will conduct a clinical trial to compare micro-ultrasound to MRI and to the final pathology following prostate removal. In this trial, patients scheduled for radical prostatectomy will obtain pre-operative micro-ultrasound and MRI evaluations.
- A machine-learning algorithm will be developed to aid clinicians with diagnosing prostate cancer in real-time, possibly enabling micro-ultrasound use as a type of male mammogram.
- The potential for integrating micro-ultrasound-based treatment monitoring into technologies like HIFU for prostate cancer will be investigated.
- If successful, this study will be foundational in evaluating if micro-ultrasound is equivalent to MRI.
What this means to patients: Dr. Brisbane is studying the potential for a novel imaging technology, micro-ultrasound, for detection and prognosis of prostate cancer. This may lead to better optimization of treatment selection and improved outcomes for patients.
University of California, Los Angeles
Mentors: Johannes Czernin, MD; Matt Rettig, MD; Robert Reiter, MD
Validating a PET Imaging Biomarker for Targeting Fibroblast Activation Protein in Prostate Cancer Stroma
- Tumors are composed of cancer cells and surrounded by the “stroma”. The stroma essentially consists of cancer supportive structures. Stromal cells are not cancer cells but are primarily fibroblasts, immune cells, and blood vessels. Cancer associated fibroblasts are an essential component of the tumor stroma as they support tumor growth and invasiveness, can help cancer cells evade immune responses, and aid in therapy resistance by acting as a physical barrier to prevent drug access.
- Dr. Jeremie Calais is studying the potential for the cancer associated fibroblast protein FAP as a new target for treatments and cancer imaging agents in prostate cancer.
- In this project, Dr. Calais will study a new FAP-targeting tracer, 68Ga-FAPi-46, as a PET imaging agent for prostate cancer.
- To validate FAP as a biomarker in prostate cancer, the incidence, extent and degree of FAP protein levels will be evaluated in early vs. advanced stage prostate cancer samples.
- A clinical trial will be conducted to determine the potential for 68Ga-FAPi-46 as a FAP-targeted PET imaging agent. Patients scheduled for a surgical excision or biopsy of a primary or metastatic lesion will first undergo FAPi PET imaging and PSMA-PET imaging. Results from FAPi-PET will be compared with PSMA-PET to determine the performance of FAPi-PET for detecting prostate cancer.
- FAPi-PET results will also be compared with direct FAP protein level measurements in biopsy and surgical samples from the same patients, to determine how well FAPi-PET corresponds with FAP protein levels in tumors.
- Whether FAPi-PET imaging correlates with prostate cancer clinical indicators such as PSA levels and Gleason grade will also be determined.
- If successful, this project will validate the potential for FAPi-PET as a new prostate cancer imaging agent and be used to identify patients who may benefit from FAP-targeted treatments.
What this means to patients: Dr. Calais is developing a novel prostate cancer imaging agent, FAPi-PET, which looks at tumor stroma instead of the tumor cells themselves. This project will determine the performance of FAPi-PET for prostate cancer detection and prognosis, and will be used to launch the development of new FAP-targeting precision medicines.
University of California, San Francisco
Mentors: Felix Feng, MD; Lawrence Fong, MD; Matthew Cooperberg, MD, MPH
Understanding the Role of Androgen Signaling in Facilitating Immune Evasion in Advanced Prostate Cancer
- There is an urgent need to improve treatments for patients with advanced prostate cancer. Immunotherapy is one treatment option that has been highly successful in many cancer types but has had limited success in prostate cancer patients. Strategies to improve immunotherapy for prostate cancer are greatly needed.
- The major histocompatibility complex (MHC) are surface molecules that present antigens to immune cells and are required for T-cell activation. Theoretically, presentation of antigens from mutated proteins by MHC on cancer cells could induce immune responses against the cancer. However, prostate cancer and other cancer types typically downregulate MHC expression in order to evade anti-tumor immune responses.
- Dr. Lisa Chesner is studying the mechanisms of MHC downregulation in prostate cancer and methods for increasing expression. She hypothesizes that the androgen receptor (AR), the primary driver of prostate cancer, plays a role in MHC downregulation.
- In this project, Dr. Chesner will determine the biological relationship between AR and MHC levels in prostate cancer cells, including investigating whether AR directly suppresses MHC gene expression.
- Whether AR-targeted therapies used to treat prostate cancer can increase MHC levels will be investigated.
- In addition, whether AR-targeted therapy can synergize with checkpoint immunotherapy in the activation of anti-tumor immune responses, will be investigated.
- If successful, this project will yield insights into how AR regulates MHC and help identify new combination treatments that improve the efficacy of immunotherapy in patients with advanced prostate cancer.
What this means to patients: Dr. Chesner is investigating whether levels of MHC, which are proteins required for anti-tumor immune responses, are suppressed in prostate cancer via AR. This project will also reveal whether AR-targeted therapy may synergize with immunotherapy and could lead to new therapeutic strategies for patients with prostate cancer.
University of California, San Francisco
Mentors: Alan Ashworth, PhD; Felix Feng, MD
Discovering Precision Oncology Approaches for CDK12-Deficient Prostate Cancer
- Metastatic castration-resistant prostate cancer (mCRPC) is an incurable and invariably fatal disease, and new precision medicines are urgently needed.
- Studies have found that mCRPC is comprised of distinct molecular subtypes with differing biology, treatment responses, and clinical outcomes. One of the most recent subtypes identified is characterized by mutations in both copies of the CDK12 gene.
- CDK12-mutated prostate cancers have features of more aggressive disease, including higher Gleason score, and shorter time to developing resistance to hormonal therapies, compared to other subtypes.
- Dr. Jonathan Chou is studying the biology of CDK12-mutated prostate cancers, in order to identify new therapeutic strategies for this molecular subtype of prostate cancer.
- Dr. Chou will evaluate whether CDK12-loss alters the activity of the androgen receptor (AR), which is the primary driver of prostate cancer and the target of hormonal therapy.
- Whether targeting other related CDK genes can specifically kill tumor cells with CDK12 mutations will be tested.
- In addition whole genome CRISPR (gene knockout) screens will be conducted to identify any other proteins in the human genome that may be promising therapeutic targets in CDK12-mutated prostate cancer.
What this means to patients: Dr. Chou is studying the biology of CDK12-mutated prostate cancers, a distinct molecular subtype of prostate cancer, which is seen in ~7% of mCRPC patients. This project will identify the impact of CDK12 mutations on the AR pathway, and identify new treatment targets for patients with this more aggressive subtype of prostate cancer.
Mentors: Shahneen Sandhu, MBBS; Nicholas Huntington, PhD; Joseph Cursons, PhD
Defining the Role of Natural Killer Cells in the Radiotherapy Treatment Response of Metastatic Prostate Cancer
- 177Lutetium-PSMA (LuPSMA) is a highly promising new type of “radionuclide therapy” treatments that consists of a prostate cancer targeting molecule combined with a radioactive isotope. This treatment thus enables radiation to be delivered systemically, but specifically target and kill prostate cancer cells.
- Radiation therapy is known to have the potential to activate anti-tumor immune responses, and thus may have synergy with immunotherapies. Clinical trials are underway to evaluate the efficacy of combining LuPSMA with checkpoint immunotherapy in prostate cancer patients. However, the biological impact of these treatment combinations remains to be studied.
- Dr. Momeneh Foroutan is studying the role of natural killer (NK) immune cells in the efficacy of LuPSMA in patients with metastatic prostate cancer.
- In this project, Dr. Foroutan will use samples from patients on clinical trials testing LuPSMA combined with checkpoint immunotherapy or PARP-inhibitors to study the biology of NK cells.
- Whether there are any tumor cell molecular features that correlate with numbers and activity of NK cells in tumors will be investigated.
- The physical locations, numbers, and activities of NK cells within and surrounding tumors will be investigated in samples from these patients to determine NK cell profiles that correlate with treatment responses.
- The gene expression profiles of individual NK cells in tumor tissues and in blood will be studied over the course of treatment, to identify NK-based biomarkers that can predict patient outcomes.
- If successful, this project will reveal the biological role of NK cells and their potential as biomarkers in treatment responses to LuPSMA combined with checkpoint immunotherapy or PARP-inhibitors, and will identify potential targets for NK cell immune therapies.
What this means to patients: Dr. Foroutan is studying NK immune cell biology in patients treated with LuPSMA combined with checkpoint immunotherapy or PARP-inhibitors. This project may help to identify NK cell biomarkers that are predictive of response to therapy and potential targets that could be used for NK cell immunotherapy to increase the efficacy of therapy outcome in patients with poor clinical outcome.
University College London
Mentors: Caroline M. Moore, MD; Monique Roobol-Bouts, PhD
A Multi-Center Study to Assess the Impact of MRI for Detection of Aggressive Prostate Cancer in Men on Active Surveillance
- Multiparametric magnetic resonance imaging (mpMRI) has recently emerged as a promising imaging technology for prostate cancer detection and prognosis. MpMRI also appears promising for identifying patients who are optimal candidates for active surveillance, and may have little benefit from immediate therapy, but should still be monitored to allow prompt curative treatment if the disease shows signs of becoming more aggressive and potentially lethal.
- Dr. Francesco Giganti is developing and validating an mpMRI scoring system (“PRECISE score”) to create a risk stratified active surveillance program that can identify those men at highest risk of progression and metastatic spread.
- In this project, Dr. Giganti will apply the PRECISE scoring system to identify radiological progression (e.g. growth of tumors on serial scans) using international clinical cohorts of prostate cancer patients on active surveillance. Consensus guidelines for using the PRECISE score for this clinical purpose will be developed.
- If successful, this project will produce a new standardized method for using serial mpMRI to detect aggressive prostate cancer in patients on active surveillance, and allow closer and more accurate monitoring.
What this means to patients: Dr. Giganti is developing a new standardized mpMRI method (“PRECISE score”) for more accurate risk assessment and monitoring of disease progression in prostate cancer patients undergoing active surveillance. This will lead to reduced global incidence of advanced and potentially lethal prostate cancer.
University of California, San Francisco
Mentors: June Chan, ScD; Peter Carroll, MD, MPH; John Witte, PhD
Exploration of Metabolomics for the Prevention of Lethal Prostate Cancer
- Metabolic alterations are known to play a role in the development and progression of prostate cancer. It is unknown whether metabolic alterations may be used as biomarkers to predict patient outcomes or inform clinical treatment selection.
- Dr. Rebecca Graff is studying the potential for metabolic alterations as biomarkers to identify patients with localized prostate cancer who are at risk for developing lethal disease.
- In this project, Dr. Graff will comprehensively characterize the metabolites found in plasma from lethal vs. indolent prostate cancer cases, and identify the metabolic features that predict the development of lethal disease.
- Whether any of the prognostic metabolites differ according to obesity status will be determined.
- A prognostic metabolite signature will be validated using pre- and post-diagnostic blood samples from large, independent prostate cancer patient cohorts.
- If successful, this project will result in a new blood-based biomarker that can identify patients who will develop lethal prostate cancer, enabling more informed treatment decisions to be made.
What this means to patients: Dr. Graff is profiling metabolite alterations in prostate cancer patients in order to develop a biomarker that can be used to identify which patients are at highest risk for developing lethal disease. This will enable more informed treatment decisions for patients and may be leveraged for efforts to develop new targeted treatments.
Baylor College of Medicine
Mentor: Laising Yen, PhD
Investigating the Pathological Role of AZI1 RNA in TMPRSS2-ERG Gene Fusion Formation
- Certain genomic alterations are known to initiate the development of prostate cancer. One of the most frequent is gene fusion of the TMPRSS2 and ERG genes, which occurs in ~50% of cases. This alteration leads to overexpression of the ERG oncogene, which increases cell invasion and proliferation.
- Prior studies have suggested that genomic rearrangements could be driven by RNA molecules that bind to regions of both chromosomes due to sequence homology.
- Dr. Sachin Kumar Gupta is investigating whether RNAs may be responsible for directing the TMPRSS2-ERG gene fusion event that causes prostate cancer.
- Dr. Gupta has identified a cellular RNA (“AZI1”) with a sequence partially resembling that of the TMPRSS2-ERG fusion RNA found in prostate cancer. Overexpression of this RNA could induces gene fusion between the TMPRSS2 and ERG genes in prostate cancer cells that did not previously have the TMPRSS2-ERG fusion.
- In this project, Dr. Gupta will investigate the link between AZI1 RNA expression and TMPRSS2-ERG fusion formation. Whether AZI1 RNA expression correlates with TMPRSS2-ERG genomic fusions in prostate cancer clinical samples, and whether this relationship differs across racial/ethnic minority subpopulations, will be determined.
- The molecular mechanisms by which AZI1 RNA drives formation of the TMPRSS2-ERG fusion will be determined.
- If successful, this project will identify new mechanisms that drive prostate cancer-initiating genomic alterations, and potentially guide strategies to inhibit the development of future tumors.
What this means to patients: Dr. Gupta has discovered an RNA that may induce the gene fusions that drive the development of 50% of prostate cancer cases. This project will validate this phenomenon and describe its mechanisms, which may lead to new strategies to prevent the initiation of prostate cancer.
Clinical Research Division, Fred Hutch
Mentor: Charles Drake, MD, PhD
Association of Circulating Markers of Pro-Tumorigenic Inflammation with Clinical Progression and Race-Ethnicity in Men with Prostate Cancer
- The development of blood-based biomarkers that can monitor or predict responses to therapy in men with prostate cancer is of great clinical importance.
- Cytokines are proteins that are released from cells and regulate the functions of many cell types. Cytokines are best known for their functions in regulating immune responses, but can also regulate tumor growth.
- Dr. Jessica Hawley is studying whether serum cytokine levels and antibodies have potential as biomarkers in prostate cancer patients undergoing various treatments.
- In this project, Dr. Hawley will determine whether serum levels of certain tumor-promoting cytokines change during treatment with androgen deprivation therapy (ADT) or the immunotherapy sipuleucel-T, and correlate with patient outcomes.
- Whether serum cytokine levels are predictive for improved outcomes in African American men being treated with sipuleucel-T will be investigated.
- The antibody profiles of patients undergoing treatment with sipuleucel-T will be comprehensively profiled. Whether anti-tumor antibodies are induced by the treatment and correlate with clinical outcomes and as a function of race and ethnicity, will be investigated.
- If successful, this project will validate serum cytokines and antibodies as predictive biomarkers in prostate cancer patients undergoing certain treatments, and determine if these differ by race and ethnicity. This has implications for reducing health disparities as well as for identifying promising new immunotherapy treatment targets.
What this means to patients: Dr. Hawley is studying whether serum cytokines and anti-tumor antibodies have potential as biomarkers for treatment selection in men with prostate cancer. This project also aims to reduce health disparities by specifically studying African American patients. This will ultimately improve precision medicine for patients and may identify possible new immunotherapy treatment targets.
Mentors: Rakesh Heer, PhD; Robert Bristow, MD
Improving Outcomes for PARP Inhibition Treatment in Men with Lethal BRCA2 Mutant Prostate Cancer by Targeting the Tumor Microenvironment
- PARP-inhibitors are new precision medicines that have recently received FDA-approval for the treatment of advanced prostate cancer with certain DNA damage repair (DDR) gene alterations.
- BRCA2 is the most commonly mutated DDR gene in prostate cancer. BRCA2-mutated prostate cancer are particularly aggressive, but are also highly responsive to PARP inhibitors. Unfortunately, ~ 20% of patients with BRCA2 alterations do not respond to treatment with PARP inhibitors. Alternative therapeutic strategies are urgently needed for these patients.
- Dr. Anastasia Hepburn is studying the biology of treatment resistance to PARP-inhibitors in patients with BRCA2 alterations.
- In this project, Dr. Hepburn will develop new BRCA2-mutated prostate cancer models to study the biology by which low tumor oxygen levels (hypoxia) contribute to PARP inhibitor sensitivity.
- Candidate targets for new therapies to be used in combination with PARP inhibitors in BRCA2-mutated prostate cancer will be identified and tested in these models.
- If successful, this project could identify new therapeutic approaches for testing in clinical trials, potentially informing new prostate cancer precision medicine strategies for this subclass of patients.
What this means to patients: Dr. Hepburn is studying mechanisms of PARP inhibitor resistance in BRCA2-mutated prostate cancer and identifying new combination treatment strategies that will lead to improved outcomes for these patients.
BC Cancer Agency
Mentors: Kim Chi, MD; Alexander Wyatt, PhD
Developing a Novel ctDNA-Based Approach to Patient Risk Stratification and Treatment Selection in mCRPC: A Large Population-Based Cohort Study
- Precision medicine is an emerging treatment strategy for patients with prostate cancer, in which treatments for individual patients are selected based on their unique tumor biology, such as tumor mutations. Determination of tumor mutations has required invasive tumor biopsies, which are often difficult or not possible in patients with metastatic disease.
- Dr. Daniel Khalaf is studying tumor DNA released into the circulation as a non-invasive biomarker (aka, liquid biopsy) in prostate cancer patients to inform outcomes and optimize treatment selection.
- In previous studies, circulating tumor DNA fraction (%) showed the highest correlation with treatment outcomes, and undetectable levels identified a subgroup of patients with a very favorable prognosis.
- Dr. Khalaf will prospectively validate whether an undetectable level of circulating tumor DNA is a strong and independent biomarker of favorable outcomes in patients with metastatic castration resistant prostate cancer (mCRPC) undergoing standard of care treatments.
- In patients who have detectable levels of circulating tumor DNA, tumor mutations will be determined and used in combination with circulating tumor DNA fraction and clinical disease characteristics to develop a refined biomarker for optimal treatment selection.
- Dr. Khalaf will also investigate primary tumor mutations in patients with localized prostate cancer who have undetectable levels of circulating tumor DNA, in order to understand the biology of this favorable prognostic subgroup and potentially identify patients at risk of poor outcomes.
- If successful, this project will result in the development of non-invasive biomarkers to predict outcomes and inform treatment selection for prostate cancer patients.
What this means to patients: Dr. Khalaf is developing non-invasive, blood-based biomarker tests that evaluate circulating tumor DNA levels and tumor mutations to predict outcomes and identify optimal treatment strategies for patients. This project will greatly accelerate precision medicine and improve outcomes for patients with prostate cancer.
University of California, San Francisco
Mentors: Eric Small, MD; Thomas Hope, MD; Luke Gilbert, PhD
Using CDK4/6 Inhibition to Augment PSMA Expression in Advanced Prostate Cancer and Enhance Clinical Responses to PSMA-Targeted Radioligand Therapy
- Prostate-specific membrane antigen (PSMA) is a protein that is commonly present at high levels on prostate cancer cells but is low or absent on normal tissue, and is a promising new target for anti-cancer treatments.
- The PSMA-targeted radioligand therapy, 177Lu-PSMA-617, is a new PSMA-targeting therapy that delivers cancer-killing radiation to prostate cancer cells. 177Lu-PSMA-617 is currently being tested in phase III clinical trials in metastatic castration resistant prostate cancer (mCRPC).
- Dr. Vadim Koshkin had found that downregulation of CDK4 can increase PSMA levels on prostate cancer cells, and is investigating whether CDK4/6-targeting treatments can improve the efficacy of 177Lu-PSMA-617.
- In this project, Dr. Koshkin will test the effects of CDK4/6-inhibitors on PSMA levels in pre-clinical prostate cancer models, and use this information to design clinical trials testing CDK4/6-inhibitors + 177Lu-PSMA-617.
- Dr. Koshkin will then conduct a clinical trial to assess the impact of treatment with a CDK4/6-inhibitor on PSMA expression on prostate tumors, and the safety and efficacy of treatment with the CDK4/6-inhibitor followed by 177Lu-PSMA-617.
- If successful, this project will result in a highly promising new treatment strategy for patients with advanced prostate cancer.
What this means to patients: Dr. Koshkin will test the efficacy of a novel treatment strategy that uses a CDK4/6-inhibitor followed by PSMA-targeted radioligand therapy in patients with mCRPC, which may improve outcomes and treatment options in patients with advanced prostate cancer.
Weill Cornell Medicine
Mentors: Chris Barbieri, MD, PhD; Sandra Demaria, MD; Charles Drake, MD, PhD
Targeting Fc Gamma Receptors with Stereotactic Radiation to Reprogram Myeloid-Derived Immune Cells in the Prostate Tumor Microenvironment
- Immunotherapies have been highly effective in certain cancer types but have had limited activity in prostate cancer. New strategies to improve immunotherapy in prostate cancer are greatly needed.
- Stereotactic body radiation therapy (SBRT) is a form of highly focused radiation therapy that delivers extremely precise and intense doses of radiation to tumors. SBRT may also activate the immune system and synergize with immunotherapy.
- Dr. Ariel Marciscano is studying the impact of SBRT on myeloid cells in prostate cancer. Myeloid cells are a family of immune cells that are common in prostate cancer and can suppress the immune system’s ability to eradicate tumors.
- Myeloid cells express an important immune-signaling protein called Fc gamma receptor (FcɣR). The amount and type of FcɣRs expressed by myeloid cells can determine if a myeloid cell has immune-suppressive or immune-activating functions.
- In this project, Dr. Marciscano will determine if SBRT alters Fc gamma receptors (FcɣR) on myeloid cells in prostate tumors. He will also explore if radiation-induced FcɣRs can be therapeutically targeted to boost immune responses and improve immunotherapy in prostate cancer – particularly when combined with SBRT.
What this means to patients: Radiation therapy can sometimes activate anti-tumor immune responses, and strategies that boost this effect will improve treatment efficacy and outcomes for patients. Dr. Marciscano will explore whether targeting FcɣRs on myeloid cell is an effective strategy to enhance the immune response to SBRT in men with prostate cancer.
Corporal Michael J. Crescenz VA Medical Center; University of Pennsylvania
Mentors: Naomi Haas, MD; Kyle Robinson, MD
Towards Targeting African American Prostate Cancer with PARP Inhibitors and Immunotherapy
- African American men have a significantly higher chance of developing prostate cancer and dying from prostate cancer compared to men of European descent. The cause of this disparity is likely multi-factorial and may be due to biological, environmental or social factors, or a complex interaction of all three.
- Dr. Kara Maxwell is investigating the genetic mechanisms underlying the efficacy of PARP inhibitors and checkpoint immunotherapy treatments for African American prostate cancer. These treatments are approved for the treatment of prostate cancer patients who have certain tumor alterations.
- In this project, Dr. Maxwell will study the genomic and gene expression biology of prostate tumors from African American vs. European American Veterans to identify the genetic mechanisms underlying homologous recombination DNA repair deficiency. This type of DNA repair alterations may render tumors sensitive to treatment with PARP inhibitors.
- In addition, Dr. Maxwell will study the genomic and gene expression of tumors to identify the genetic mechanisms underlying mismatch DNA repair deficiency in African American vs European American prostate tumors. This type of DNA repair alterations may render tumors sensitive to checkpoint immunotherapy.
- Finally, Dr. Maxwell will establish organoid models of homologous recombination and mismatch DNA repair deficient prostate cancer from African American patients to directly study PARP inhibitor and checkpoint immunotherapy responses.
- If successful, this project will provide data on the mechanisms of DNA repair deficient phenotypes in African American prostate cancer, including from a veteran population. The study will identify the appropriate genetic biomarkers to understand DNA repair based drug response and resistance.
What this means to patients: Dr. Maxwell will provide a comprehensive analysis of the genomic and other molecular alterations that render prostate tumors sensitive to treatment with the recently FDA-approved prostate cancer precision medicines, PARP inhibitors and checkpoint immunotherapy, in the African American Veteran population. These studies will inform new clinical trials and the way African American patients, including the vulnerable Veteran population, with aggressive and lethal prostate cancer are treated clinically.
University of British Columbia (UBC)
Mentors: Martin Gleave, MD; Amina Zoubeidi, PhD
Uncovering Lineage Plasticity in the Context of Specific Genomic Alterations in High Risk Prostate Cancer
- The mechanisms of resistance to androgen receptor (AR)-targeted therapies in prostate cancer are not fully understood. One mechanism of AR-targeted therapy resistance, is lineage plasticity, in which prostate cancer cells lose prostate cell features and gain features of other cell types such as neuroendocrine cells. Understanding the mechanisms that enable lineage plasticity is critical, and will enable the development of new treatments for these lethal forms of prostate cancer.
- Dr. Lucia Nappi is studying molecular mechanisms of prostate cancer lineage plasticity.
- Dr. Nappi is conducting a neoadjuvant (pre-surgery) precision medicine clinical trial, in which patients with high-risk localized prostate cancer are treated with AR-targeted therapy for 8 weeks followed by one of four therapy protocols based on their tumor genomic profile, for additional 16 weeks. Patients will then undergo radical prostatectomy and assessment for the degree of remaining tumor.
- Pre-treatment biopsy and post-treatment surgical samples will be evaluated for gene expression and epigenetic profiles. Gene expression signatures and epigenetic patterns associated with treatment response or resistance in any of the four precision medicine treatment groups will be investigated. Those indicative of lineage plasticity will be specifically evaluated.
- The PAM50 classifier is used to identify major molecular subtypes of breast cancer based on gene expression profiles, and may be useful in prostate cancer. Whether PAM50 classification is associated with epigenetic patterns, lineage plasticity, and with treatment response or resistance in patients on this trial will be investigated.
- If successful, this project will result in validation of a precision medicine treatment paradigm, as well as biological insights into early molecular events associated with development of treatment resistance and lineage plasticity.
What this means to patients: Dr. Nappi is investigating mechanisms of treatment resistance and response in patients with high-risk localized prostate cancer in a neoadjuvant precision medicine clinical trial. This study will uncover mechanisms associated with lineage plasticity and early signatures of treatment resistance, enabling refinement of future precision medicine approaches.
Corporal Michael J. Crescenz VA Medical Center; University of Pennsylvania
Mentors: Alicia Morgans, MD, MPH; Ravishankar Jayadevappa, PhD
Biomarker-Based Approaches to Predict Fracture Risk among Men with Metastatic Hormone-Sensitive Prostate Cancer
- Long-term androgen deprivation therapy (ADT), alone or with other agents, is a standard of care, life-extending therapy for metastatic hormone-sensitive prostate cancer (mHSPC). Despite these benefits, ADT accelerates bone loss and is associated with 10-20% risk of significant bone fractures, which result in decreased quality of life, independence, and functional status, and may also increase mortality rates. There is an urgent need to identify men with mHSPC undergoing ADT who are at increased risk of fracture and should be prescribed bone maintenance therapies, as these therapies are not routinely prescribed in this patient population.
- Dr. Ravi Parikh is developing novel biomarkers to improve fracture risk assessment and facilitate targeted management strategies for men with mHSPC beginning ADT.
- In this project, Dr. Parikh will validate several potential biomarkers of fracture risk that can be easily integrated into routine labs and staging in mHSPC.
- The biomarkers to be studied include a technique that assesses bone density and bone strength from routine CT scans, and a blood test to look at a marker of bone damage (Type I collagen C-telopeptide (CTX)).
- Dr. Parikh will study the performance of these biomarkers for predicting future fracture risk in cohorts of Veterans with mHSPC who are undergoing ADT.
- If successful, this project will improve care and quality-of-life outcomes for patients with mHSPC, starting with the Veteran population, by developing new biomarker tests to identify patients who are at risk of future fractures and may benefit from early anti-resorptive therapy.
What this means to patients: Dr. Parikh is developing new clinical biomarker tests that can identify which patients undergoing hormonal therapy are at risk for developing bone fractures, and should be prescribed early bone maintenance therapies. This will significantly improve quality-of-life for patients with advanced prostate cancer, starting with the Veteran population.
Mentors: Jiaoti Huang, MD, PhD; Andrew Armstrong, MD
Interrupting Neuroendocrine Prostate Cancer Phenotypes by a Suppressor of Cytokine Signaling 2
- Most prostate cancers are “adenocarcinomas,” meaning they originated in the mucus-producing cells of the prostate gland, and still retain many prostate cell features. However, highly aggressive, treatment-resistant variants such as neuroendocrine prostate cancer (NEPC) can arise in some patients.
- NEPC has lost prostate adenocarcinoma features and has developed features of neuroendocrine cells. New treatments are urgently needed for NEPC, which is a currently untreatable form of prostate cancer.
- Dr. Jung Wook Park is investigating the mechanisms that control the transition of adenocarcinoma into NEPC.
- In this project, Dr. Park will identify the proteins that act as master controllers of this transition, their specific roles, and the timing by which they act during prostate cancer progression.
- Whether any of the identified factors are promising therapeutic targets will also be investigated in preclinical models.
- If successful, this project will identify the master control factors that drive progression of prostate adenocarcinoma into NEPC and identify possible new therapeutic targets.
What this means to patients: Dr. Park will identify the essential genetic/molecular switches that control progression of prostate cancer into NEPC and enable NEPC to grow rapidly, which may represent new therapeutic targets for preventing or reversing NEPC development.
Institute of Cancer Research (ICR)
Mentors: Johann de Bono, MD, PhD; Stephen Plymate, MD; Ganesh Raj, MD, PhD
Metabolic Adaptations to Androgen Receptor Blockade and the Prostate Cancer Transcriptome.
- Despite recent advances in the treatment of metastatic castration resistant prostate cancer (mCRPC), acquired resistant disease remains invariably fatal.
- Androgen receptor (AR) variants such as AR-V7, which are constantly activated and lack the domains of AR that are targeted by existing AR-directed therapies, have been proposed to be key contributors to the development of treatment resistance in CRPC.
- Efforts to target AR-V7 directly have, however, proven challenging. Thus there remains an urgent clinical need for novel therapeutic strategies to target AR-V7 to improve the outcomes of patients with advanced prostate cancer.
- Alec Paschalis is studying the mechanisms that control the expression of AR-V7 in CRPC. In prior studies, Dr. Paschalis has identified that the 2-oxoglutarate (2OG)-dependent oxygenase JMJD6 is potentially a key regulator of AR-V7, and may be a promising new therapeutic target in prostate cancer.
- In this project, Dr. Paschalis will explore the relationship between metabolism and transcription, and determine the mechanisms by which JMJD6 senses environmental changes and consequently regulates AR-V7 expression and drives prostate cancer growth.
- Additionally, the potential for targeting JMJD6 as a novel therapeutic strategy in CRPC will be validated in preclinical models.
- If successful, this project will elucidate major mechanisms of AR-V7 regulation and begin to identify new ways of treating prostate cancer.
What this means to patients: Dr. Paschalis is studying a novel environmental metabolic sensing pathway that may drive CRPC by altering expression levels of AR-V7. This project will determine the mechanisms of this pathway and validate the potential for targeting this pathway as a new treatment strategy in CRPC.
University of Bern
Mentors: Mark Rubin, MD; Savatore Piscuoglio, PhD
Molecular Pathology-Artificial Intelligence Approach to Therapy Response Prediction for Castration Resistant Prostate Cancer
- In the past few years, a multitude of new therapies have become approved for patients with advanced prostate cancer. However, how to choose between therapies at the time of each new treatment decision for individual patients, remains unclear. Predictive biomarkers are urgently needed to guide appropriate selection of the next best therapy for each patient.
- Dr. Antonio Rodriguez-Calero is developing a new classification system for metastatic castration resistant prostate cancer (mCRPC), which will improve precision medicine treatment decisions for patients.
- In this project, Dr. Rodriguez-Calero will integrate comprehensive tumor genomic and gene expression data, pathology, and clinical data from patients on a recently completed precision medicine clinical trial, and use this in combination with machine learning, to develop a new classifier for mCRPC that predicts patient treatment responses and outcomes.
- This classifier will be validated in other patient cohorts and simplified to include only the most critical data elements.
- If successful, this project will ultimately result in a molecular testing kit that can be used in clinics to select optimal standard treatments and improve clinical trial design for patients with advanced prostate cancer.
What this means to patients: Dr. Antonio Rodriguez-Calero is developing a new artificial intelligence-based classification system for mCRPC based on molecular, pathology, and clinical data that will improve precision medicine treatment selection for patients with advanced prostate cancer.
University of California San Diego
Mentors: Anders Dale, PhD; Michael Hahn, MD, PhD; Loren Mell, MD
Phase II Biomarker Study of Advanced Diffusion MRI in High-Risk, Localized Prostate Cancer Treated with Radiotherapy and Androgen Deprivation Therapy
- Patients with high-risk prostate cancer benefit from androgen deprivation therapy (ADT) and radiotherapy, with each conferring a survival benefit. However, while this treatment combination may cure some patients, others are not cured, and would benefit from additional treatment. New tests are needed to predict early-on, which patients will eventually recur and to guide treatment decisions after initial therapy.
- Dr. Tyler Seibert is developing a new MRI scan technique, “Restriction Spectrum Imaging” (RSI), that can be used as an early biomarker for treatment effectiveness in prostate cancer treated with ADT and radiotherapy.
- In this project, Dr. Seibert will conduct a phase 2 clinical trial to evaluate RSI imaging as a biomarker to identify patients who will experience biochemical recurrence within 3 years post-radiotherapy, and patients who will fail to have PSA levels drop below <0.5 ng/mL within 18 months post-radiotherapy. Participants will undergo three RSI MRI scans: prior to ADT, prior to radiotherapy, and after radiotherapy.
- The performance of the RSI imaging technique will be compared with other standard and experimental MRI scan techniques.
- If successful, this project will result in a new biomarker for treatment response that could guide earlier treatment decisions and ultimately improve cure rates for men with high-risk prostate cancer.
What this means to patients: Dr. Seibert is developing a new MRI scan technique that will help to identify patients with high-risk localized prostate cancer who will vs. will not be cured by ADT + radiation therapy. This will enable clinicians to identify which patients should have additional therapy before waiting for recurrence to become apparent, and will lead to improved outcomes for patients with high-risk prostate cancer.
Harvard University/Dana-Farber Cancer Institute
Mentors: Eliezer Van Allen, MD; Myles Brown, MD; Mary-Ellen Taplin, MD
Integrated Single-Cell Analysis of Mechanisms of Therapeutic Resistance in Prostate Cancer Patients
- High-risk localized prostate cancer is associated with a significant risk of disease progression and prostate-cancer specific mortality. Efforts are underway to develop new treatment strategies to improve outcomes in these patients.
- Recent phase 2 trials of neoadjuvant (prior to surgery) anti-androgen therapies including enzalutamide, apalutamide and/or abiraterone with standard androgen deprivation therapy (ADT) for six months, followed by prostatectomy, have had highly promising results. These studies have led to an ongoing phase 3 trial testing combination anti-androgen neoadjuvant therapy before prostatectomy for high-risk localized prostate cancer.
- Dr. Alok Tewari is studying the biological impact of intense anti-androgen neoadjuvant therapy in patients with high-risk localized prostate cancer.
- In this project, Dr. Tewari will perform comprehensive molecular analyses of samples from patients treated with intense anti-androgen neoadjuvant therapy as well as from rapid autopsy samples from advanced disease to identify common and divergent mechanisms and biomarkers of treatment response vs. resistance.
- Dr. Tewari will also leverage multi-platform analysis of rapid autopsy samples to study mechanisms of resistance to other therapies including radiopharmaceuticals in advanced prostate cancer.
- If successful, this project will determine why neoadjuvant hormonal therapy works for some patients but not in others, identify predictive biomarkers for appropriate treatment selection in high-risk patients and uncover tumor and microenvironmental mediators of resistance and response to therapies such as radiopharmaceuticals in advanced disease.
What this means to patients: Dr. Tewari is investigating molecular mechanisms and biomarkers of response vs. resistance to intense anti-androgen neoadjuvant therapy, radiopharmaceuticals, and other treatments. This will result in improved selection of patients who will benefit from these treatments and potentially inform drug development efforts to improve the chance of cure for patients with prostate cancer.
University of Michigan
Mentors: Arul Chinnaiyan, MD, PhD; Todd Morgan, MD; Bruce Trock, PhD
Refinement, Validation and Clinical Application of a Novel Panel of High-Grade-Cancer-Specific Biomarkers in the Overall and African American Populations
- Early detection and treatment of aggressive prostate cancer is critical to reducing its harms and improving the chance of cure for patients. Current diagnostic tests are unable to reliably differentiate between patients with aggressive, potentially-lethal prostate cancer and those with indolent cancer or no cancer at all.
- Dr. Jeffrey Tosoian is combining recently-identified urinary markers of aggressive prostate cancer with existing cancer markers to define a biomarker panel capable of accurately identifying clinically-relevant prostate cancer.
- In this project, Dr. Tosoian will develop and validate a novel multigene urine test to identify high grade prostate cancers (Grade Group ≥2) that stand to benefit from early detection and treatment.
- Based on known prostate cancer disparities in the African-American population, this effort includes a specific focus on identifying markers that are highly accurate in African-American men – which could differ from the Caucasian population.
- If successful, this project will result in novel, non-invasive tests to accurately diagnose aggressive prostate cancer at an early stage, at which patients stand to benefit most from treatment.
What this means to patients: Dr. Tosoian and a collaborative team are developing more accurate tests to diagnose prostate cancer and distinguish aggressive cancers requiring definitive treatment from indolent cancers that can safely be monitored on active surveillance.
Memorial Sloan Kettering Cancer Center
Mentors: Charles Sawyers, MD; Sebastian Klinge, PhD
Biochemical, Structural and Molecular Dissection of Androgen Receptor Transcriptional Activity
- The androgen receptor (AR) is the central driver of prostate cancer, and androgen deprivation therapy (ADT) has served as backbone for prostate cancer treatment for decades. Unfortunately, resistance to ADT and to newer and more potent AR-targeting therapies occurs in nearly all patients, even in cancers that continue to be driven by AR.
- A better understanding of how AR is regulated is critical for developing more effective new treatments for prostate cancer.
- Dr. Elizabeth Wasmuth is employing various methods to obtain molecular snapshots of AR, in order to better understand how AR activity is regulated, and to design better AR-targeting agents.
- The elements of AR that interact with other molecules important in prostate cancer and regulate its activity and functions will be identified.
- The AR-regulating mechanisms identified in these fundamental studies will be applied to preclinical models to validate how these mechanisms affect prostate cancer growth and AR activities.
- If successful, these studies will identify how AR is regulated on an atomic level and provide a platform for the design of novel AR-targeting therapies.
What this means to patients: Dr. Wasmuth will identify the precise regions of the AR that regulate its oncogenic activities and reveal novel strategies for developing new drugs to target this critical prostate cancer driver.
City of Hope
Mentors: Rick Kittles, PhD; Tanya Dorff, MD
HER2 and AR Signaling in Prostate Cancer
- African American men suffer from significantly increased prostate cancer incidence and mortality compared with European American men. African American men are often underrepresented in prostate cancer studies and clinical trials, and thus there is a significant lack in knowledge regarding the biology and treatment responses of African American men with prostate cancer. There is an urgent need to better understand the biology of African American prostate cancer that can be used to predict which patients are more likely to suffer from an aggressive form of the disease, and develop better patient-specific treatments.
- Dr. Leanne Woods-Burnham is studying the biology contributing to the worse prognosis observed in African American prostate cancer patients.
- The androgen receptor (AR) is the major driver of prostate cancer. African American prostate cancer patients have been found to have a higher frequency of inherited and tumor mutations in AR, as well as increased AR activity.
- HER2 is a breast cancer associated protein that has also been associated with more aggressive prostate cancer. In preliminary studies, Dr. Woods-Burnham has found a correlation between HER2 gene expression and West African ancestry in African American prostate cancer patients.
- In this project, Dr. Woods-Burnham will study AR and HER2 levels and mutations in African American prostate cancer, in order to indicate the therapeutic potential for combining anti-HER2 and anti-AR treatments in HER2+ African American prostate cancer patients.
- The circulating levels of HER2 and AR will be determined in African American and European American prostate cancer patients.
- Genomic sequencing will be performed on tumor samples from African American and European American prostate cancer patients in order to identify HER2 and AR mutations, and determine their association with other genomic features.
- If successful, this project will validate whether HER2 and AR are amplified in African American prostate cancer patients. This information will be used to design a Phase II race-stratified clinical trial with a focused African American target accrual to treat HER2+ prostate cancer patients with newer, more efficient anti-HER2 drugs.
What this means to patients: Dr. Woods-Burnham will determine whether HER2 is a biomarker of aggressive prostate cancer and possible treatment target in African American prostate cancer patients. This information will be used to design African American-focused precision medicine clinical trials testing new HER2-targeting therapies, which could significantly reduce prostate cancer disparities in African American men.
Memorial Sloan Kettering Cancer Center
Mentors: Charles Sawyers, MD; Michael Morris, MD
Studying the Mechanisms of Lineage Plasticity in Prostate Cancer
- The androgen receptor (AR) is the primary driver of prostate cancer and also the main therapeutic target in patients with advanced disease. Unfortunately, resistance to androgen deprivation therapy (ADT) and more potent AR-targeted therapies such as abiraterone and enzalutamide invariably occurs and patients progress to castration resistant prostate cancer (CRPC), for which there are currently no curative treatments.
- Multiple mechanisms can drive AR-targeted therapy resistance, and understanding these will enable the development of more effective treatment strategies for patients.
- Dr. Samir Zaidi is studying “lineage plasticity,” a mechanism of treatment resistance that occurs in ~20% of patients with CRPC. Lineage plasticity is a phenomenon in which prostate cancer cells lose typical prostate cell features and take on the features of alternative cell types which do not depend on AR for growth and survival.
- In this project, Dr. Zaidi will develop new human and mouse prostate cancer models to study how different genomic alterations drive lineage plasticity. These models will include deletion of the tumor suppressor genes RB1 and p53, which are common genomic alterations associated with lineage plasticity.
- The mechanisms by which different gene expression programs and their master regulators may drive lineage plasticity, and how these alterations are enabled by deletion of RB1 and p53, will be studied.
- If successful, this project will greatly improve understandings of lineage plasticity in CRPC and may identify key dependencies that can be targeted pharmacologically.
What this means to patients: Dr. Zaidi is studying the biology of lineage plasticity, a mechanism that drives development of an aggressive form of CRPC. These findings will uncover new therapeutic targets for drug development for this currently lethal prostate cancer subtype.
Memorial Sloan Kettering Cancer Center
Mentor: Charles Sawyers, MD
Investigating Cell of Origin and Molecular Mechanisms of Lineage Plasticity in Neuroendocrine Prostate Cancer
- Next-generation androgen receptor (AR) targeted therapies such as abiraterone and enzalutamide have improved the quality of life and extended survival of patients with metastatic castration resistant prostate cancer (mCRPC). Unfortunately, acquired resistance to AR-targeted therapies inevitably develops.
- One mechanism of resistance that occurs in ~20-25% of mCRPC is “lineage plasticity,” in which tumors undergo a transformation from a prostate cell identity into a neuroendocrine-like or other cell type in order to lose dependence on the AR pathway for growth and survival. Understanding the mechanisms that drive neuroendocrine transformation and identifying novel therapeutic strategies to treat neuroendocrine prostate cancer (NEPC) remains a significant unmet challenge.
- Dr. Jimmy Zhao is investigating the cell of origin and the molecular drivers of neuroendocrine transformation in patients with NEPC.
- In this project, Dr. Zhao will perform single-cell analyses on different prostate cell populations in genetically engineered prostate cancer mouse models, to identify the cells of origin in NEPC.
- Genes that promote lineage plasticity will be identified by deleting or overexpressing different genes in prostate cancer models.
- Whether neutrophils, a type of inflammatory immune cell, may contribute to drug resistance and lineage plasticity in will be investigated in prostate cancer models. Whether tumor-associated neutrophils may be promising therapeutic targets will be determined.
- If successful, this project will identify the critical molecular and cellular drivers of drug resistance and lineage plasticity in patients who develop NEPC. This may reveal promising new targets and therapeutic strategies for patients with one of the most aggressive forms of prostate cancer.
What this means to patients: Dr. Zhao is investigating the molecular drivers and role of neutrophils in lineage plasticity, a major form of treatment resistance in patients with mCRPC. This will lead to new understandings and identify promising new therapeutic strategies for patients with this highly aggressive form of prostate cancer.