The PCF Young Investigator Award-Class of 2019 recipients are:
Remi Adelaiye-Ogala, PhD
National Cancer Institute (NCI)
Mentors: Kathleen Kelly, David VanderWeele
Investigating alteration in AR regulome following response to kinase inhibitors
- The androgen receptor (AR) is the primary driver of prostate cancer growth and survival and AR-targeted therapy is a standard treatment for advanced disease.
- Unfortunately, many patients will eventually develop resistance to AR-targeted therapy and progress to castration-resistant prostate cancer (CRPC).
- In CRPC, treatment with AR-targeted therapy prevents normal activities of the AR protein, but may still allow alternate activities that drive disease progression.
- Remi Adelaiye-Ogala hypothesizes that prevention of alternate AR activities can restore sensitivity to AR-targeted therapy.
- In this study, Dr. Adelaiye-Ogala will investigate molecular mechanisms and biomarkers of normal and alternate AR activities in CRPC, and will determine the impact of treatment with kinase inhibitors and extremely high doses of testosterone on normal and alternate AR activities.
- If successful, this project will identify mechanisms that drive prostate cancer resistance to AR-targeted therapy and determine whether treatment with kinase inhibitors is able to overcome drug resistance.
What this means to patients: Dr. Adelaiye-Ogala’s project aims to understand the biology of treatment-resistant prostate cancer and identify treatment strategies to overcome resistance and prevent disease progression.
Mike Beshiri, PhD
National Cancer Institute (NCI)
Mentor: Kathleen Kelly
Investigation of the subpopulation dynamics of treatment-emergent neuroendocrine prostate cancer using patient-derived organoids.
- Neuroendocrine prostate cancer (NEPC) is a highly aggressive and lethal form of prostate cancer that has acquired resistance to androgen receptor (AR)-targeted therapies such as enzalutamide and abiraterone. NEPC is characterized by loss of prostate adenocarcinoma features and gain of neuroendocrine cell features.
- A better understanding of the biology of NEPC is necessary to develop new treatment strategies for this currently untreatable form of prostate cancer.
- Mike Beshiri has established new patient-derived experimental models of NEPC to study this form of prostate cancer.
- In this project, Dr. Beshiri will use these models to determine the biological steps and processes underlying the transformation of prostate adenocarcinoma into NEPC, and determine drug sensitivities for prostate cancer cells at different states of transition between prostate adenocarcinoma and NEPC.
- If successful, this project will provide insight into the biology of NEPC and identify promising new therapeutic strategies.
What this means to patients: Dr. Beshiri’s project will uncover the biological mechanisms that enable prostate adenocarcinoma to transform into the highly aggressive NEPC form, and will identify new therapeutic strategies that may be effective against NEPC.
Mehmet Bilen, MD
Mentors: Haydn Kissick, Martin Sanda, Omer Kucuk
Priming the metastatic prostate tumor microenvironment with TLR activation and IL2 to respond to checkpoint blockade
- The immune system has the potential to recognize and kill cancer cells, and immunotherapy seeks to elicit effective anti-tumor immune responses. However, immunotherapy has thus far had limited efficacy in patients with prostate cancer.
- Mehmet Bilen and team have discovered a population of T cells that when present in tumors, limits tumor growth and is responsible for the effectiveness of immunotherapy. However, these T cells, as well as the “antigen presenting” immune cell populations that are necessary to support them, are very rare in prostate cancer.
- In this project, Dr. Bilen will conduct a clinical trial in patients with advanced prostate cancer, testing the efficacy and safety of a novel triple-immunotherapy combination designed to activate both T cells and antigen presenting cells.
- This project will also determine the impact of this treatment on immune cell numbers and activities in primary and metastatic tumor samples from patients.
- If successful, this project will determine the efficacy, safety, and biological effects of a new immunotherapy treatment regimen in patients with advanced prostate cancer.
What this means to patients: Dr. Bilen will conduct a clinical trial testing a novel triple immunotherapy regimen designed to turn on critical immune cell activities that are missing in prostate cancer patients, and will determine the clinical and biological impact of this treatment.
James Byrne, MD, PhD
Harvard: Dana-Farber Cancer Institute (DFCI)
Mentors: Anthony D’Amico, Robert Langer
Extremophile RNA delivery for Radioprotection in Prostate Cancer Patients
- Radiation therapy is a standard of care treatment for localized prostate cancer and can be curative. However, patients may experience severe debilitating short and long-term toxicities caused by radiation damage to the nearby urinary and intestinal systems.
- Certain organisms in nature have the ability to withstand extremely large doses of radiation as a result of radiation protection proteins that prevent DNA damage.
- James Byrne will perform preclinical studies to determine whether these proteins can be safe and effective as treatments to protect normal tissues adjacent to the prostate during radiation therapy.
- If successful, Dr. Byrne’s project will result in a new treatment to mitigate the side effects from radiation therapy, and may allow patients to receive higher doses of radiation that could improve outcomes.
What this means to patients: Dr. Byrne’s project aims to establish whether proteins that protect certain organisms in nature from large doses of radiation may be effective for protecting against urinary and intestinal side effects from radiation therapy. If shown successfully in preclinical studies, this therapy will be tested in clinical trials.
Arianna Calcinotto, PhD
Institute of Oncology Research (IOR)
Mentor: Andrea Alimonti
The role of the microbiota in driving castration-resistant prostate cancer
- The microbiota is the diverse population of microorganisms that live in symbiosis with the host and are involved in many normal functions including digestion and immunity. Alterations in the microbiota, termed microbial dysbiosis, may play a role in cancer progression and treatment responses. Little is known about how intestinal microbiota alterations affect prostate cancer.
- Arianna Calcinotto’s project will address the role of the intestinal microbiota in the development of castration-resistant prostate cancer (CRPC).
- Calcinotto has previously found that treatment with antibiotics that eliminate intestinal microbiota reduces prostate tumor growth and improves survival in mouse CRPC models, and identified two microbial species associated with castration-resistance in these models.
- In this study, the impact of these and other microbial species on castration-resistance and anti-tumor immune responses will be determined.
- This project will also catalog the intestinal microbiota of human prostate cancer patients, and identify species that are associated with progression to CRPC.
- Whether manipulating the intestinal microbiota may prevent progression to CRPC will be investigated in preclinical models.
- If successful, this project will determine the impact of intestinal microbiota on the development of CRPC and may inform the development of new treatment strategies.
What this means to patients: Dr. Calcinotto’s project will determine whether intestinal microbiota species can impact CRPC progression and will provide insights into how the microbiota can be manipulated to improve outcomes in men with prostate cancer.
Goutam Chakraborty, PhD, MSc
Memorial Sloan Kettering Cancer Center (MSKCC)
Mentors: Philip Kantoff
Investigating the underlying biology and molecular mechanisms of BRCA2-RB1 co-deletion and its relationship to aggressive prostate cancer and the consequent identification of a druggable target
- The tumor suppressor genes BRCA2 and RB1 are located near one another in the genome, on chromosome 13q. The genomic region that contains these genes is commonly deleted in prostate cancer and is associated with worse prognosis.
- Goutam Chakraborty has created a model of prostate cancer in which BRCA2 and RB1 have been deleted, in order to study the impact of these gene losses on prostate cancer progression. This model has a highly aggressive and invasive phenotype.
- In this project, the mechanisms by which BRCA2/RB1-loss drive highly aggressive prostate cancer will be determined.
- Chakraborty and colleagues have previously found that the enzyme WNK1 becomes activated following BRCA2/RB1 loss, and will determine whether WNK1 plays a role in prostate cancer progression. The team will also test whether targeting WNK1 may be a promising treatment strategy alone or in combination with PARP-inhibitors. PARP-inhibitors have recently been demonstrated to be effective in prostate cancers with mutations in BRCA2.
- If successful, this project will determine biological mechanisms and identify promising new treatments for a highly aggressive form of prostate cancer.
What this means to patients: Dr. Chakraborty’s project will determine the biology and identify promising new treatment options for a highly aggressive form of prostate cancer that has lost the tumor suppressor genes BRCA2 and RB1.
Catherine Coombs, MD
University of North Carolina, Chapel Hill
Mentors: Himisha Beltran, Matthew Milowsky
Examining the interaction between clonal hematopoiesis and clinical outcomes among patients with metastatic castration-resistant prostate cancer treated on A031201
- Clonal hematopoiesis (CH) is an age-related condition characterized by the accumulation of mutations in subpopulations (clones) of blood cells. Individuals with CH are at increased risk for hematologic malignancies and cardiovascular disease.
- CH is associated with worse outcomes in individuals with cancer, including prostate cancer, though the reasons for this are not yet clear.
- Catherine Coombs will investigate the relationship between the presence of CH and prostate cancer outcomes and responsiveness to therapy.
- Coombs will also investigate whether CH is associated with worse side effects, including cardiovascular toxicities, in prostate cancer patients undergoing treatment with anti-androgen therapy.
- If successful, this project will determine whether and how the presence of CH may lead to worse outcomes in men with prostate cancer, and determine if these patients may benefit from interventions targeting CH or more aggressive management of modifiable risk factors such as hyperlipidemia, hypertension, and smoking.
What this means to patients: Clonal hematopoiesis (CH) is an age-related condition that is associated with worse prostate cancer outcomes. Dr. Coombs’ study will determine whether CH interferes with treatment responses or worsens side effects from therapy, and will help to identify whether prostate cancer patients with CH may benefit from additional therapeutic strategies.
Matthew Dallos, MD
Columbia University Medical Center
Mentors: Charles Drake, Andrea Califano
Combining Treg Depletion with Androgen Deprivation in the Neo-Adjuvant Setting
- Immunotherapy is a highly effective treatment for many cancers, but has yet to be optimized for prostate cancer. This is thought to be due in large part, to a lack of anti-cancer immune cells entering the tumors.
- In prostate cancer, treatment with androgen deprivation therapy (ADT) has been shown to increase the number of immune cells in prostate tumors. However, both anti-tumor T cells and immune-suppressive T cells (called Tregs) increase in number after ADT.
- Matthew Dallos hypothesizes that this increase in Tregs may profoundly limit anti-tumor immunity, and proposes targeting Tregs as a promising clinical strategy.
- In this project, Dr. Dallos will initiate a randomized phase 2 clinical trial to test whether adding a Treg-targeting drug (CTLA-4-nf) to ADT can improve anti-tumor immune responses, compared with ADT alone, in men with high-risk localized prostate cancer. Patients will then undergo radical prostatectomy to remove the primary tumor.
- The impact of these treatments on immune cell types and activities in will be determined in tumor samples from patients on the trial.
- If successful, this project will result in an effective new immunotherapy and hormone therapy combination for men with prostate cancer.
What this means to patients: Developing new treatment strategies that can effectively activate anti-tumor immune responses will greatly benefit prostate cancer patients. Dr. Dallos’ study will test the efficacy and biological impact of a new immunotherapy and hormone therapy combination in men with high-risk localized prostate cancer.
Navonil De Sarkar, PhD
Fred Hutchinson Cancer Research Center
Mentors: Peter Nelson, Robert Bruce Montgomery
Accurate and Predictive Classification of Prostate Cancers for Therapeutics Targeting DNA Repair
- PARP-inhibitors and platinum chemotherapy are effective in a subset of prostate cancer patients, particularly those who have defects in certain DNA damage repair (DDR) genes involved in a type of DNA repair called homologous recombination (HR). Still, there are individuals without DNA repair function damaging mutation who respond, and patients with demonstrated HR defects who do not.
- Navonil De Sarkar’s project aims to improve the accuracy of identifying metastatic castration resistant prostate cancer (mCRPC) patients with DNA repair defects who will respond to PARP-inhibitors and/or platinum chemotherapy.
- De Sarkar developed a machine learning based classification framework, termed “integrated homologous recombination defect” (iHRD), to identify tumors with HR defects based on multiple genomic features and determinants associated with HR deficiency in tumor genomic sequencing data.
- Whether the iHRD classification system can better identify patients who have HR defects and will respond to PARP-inhibitors and/or platinum chemotherapy will be tested.
- Whether an iHRD status can also be inferred from genomic sequencing performed on liquid biopsies will be determined.
- Finally, other mechanisms that lead to defective HR activity in tumors without mutations in HR genes will be determined.
- If successful, this project will result in a tool to improve the identification of prostate cancer patients who are likely to respond from PARP-inhibitors and platinum chemotherapy.
What this means to patients: Dr. De Sarkar’s project will improve identification of patients with defective DNA damage repair (DDR) who are more likely to respond to PARP-inhibitors and platinum chemotherapy and will identify new mechanisms that render tumors sensitive to these treatments.
Arianna Giacobbe, PhD
Columbia University Medical Center
Mentors: Cory Abate-Shen, Charles Drake
Investigating the heterogeneity of circulating tumor cells in metastatic prostate cancer
- A hallmark of cancer is genomic instability and the acquisition of many new mutations when tumor cells divide. This results in a population of cancer cells that are highly variable (aka, heterogeneous). Tumor heterogeneity is poorly understood but a highly important feature that enables cancer to quickly evolve and develop resistance to treatments and metastasize to new body sites.
- Arianna Giacobbe is developing methodologies and models to study single circulating tumor cells (CTCs) from animal models and prostate cancer patients, in order to better understand the landscape of tumor heterogeneity.
- These models will be used to determine how tumor heterogeneity impacts metastatic propensity and treatment responses and to elucidate mechanisms of tumor metastasis and progression.
- If successful, this project will lead to the identification of mechanisms that drive tumor metastasis and guide improved therapeutic approaches in advanced prostate cancer.
What this means to patients: Dr. Giacobbe’s project will use animal models and patient-derived models of prostate cancer to study the role of tumor heterogeneity in disease progression and will identify mechanisms that drive metastasis and treatment resistance.
Gavin Ha, PhD
Fred Hutchinson Cancer Research Center
Mentors: Peter Nelson, Colin Pritchard
Developing novel computational approaches to study therapeutic resistance in castration-resistant prostate cancer using circulating tumor DNA.
- Metastatic castration-resistant prostate cancer (CRPC) is a lethal disease with no curative treatment. It is critical to study the full spectrum of genomic alterations that drive CRPC in order to better understand disease biology and uncover new treatment opportunities.
- Circulating tumor DNA (ctDNA) from liquid biopsies (blood-draws) provides a non-invasive route to profile tumor genomes and to study genomic changes during therapy, but has not yet been widely used to study whole genome structural alterations.
- Gavin Ha will develop a computational algorithm to characterize the landscape of CRPC genomic structural alterations using patient ctDNA, and identify genomic alterations that predict treatment responses.
- If successful, this project will provide a new non-invasive method to evaluate tumor genomes and identify precision therapies for patients with advanced prostate cancer.
What this means to patients: Dr. Ha’s project aims to provide a new non-invasive method to evaluate tumor mutations and identify precision therapies for patients with advanced prostate cancer.
Junjie Tony Hua, PhD
University of California, San Francisco (UCSF)
Mentors: Felix Feng, Housheng He
Investigating Biological Drivers and Clinical Consequences of DNA Methylation in Metastatic Castration-Resistant Prostate Cancer
- DNA methylation is an important mechanism by which gene expression is regulated, and occurs by the addition of chemical groups to DNA, which control its 3-dimensional structure and the ability of other proteins to interact with that region of DNA. Aberrant DNA methylation is involved in many diseases, including cancer.
- Junjie Tony Hua is studying the role and clinical consequences of aberrant DNA methylation in metastatic castration-resistant prostate cancer (mCRPC).
- Dr. Hua has previously identified several genomic mutations in DNA methylation pathways that are associated with abnormally high levels of DNA methylation in mCRPC.
- In this project, Dr. Hua will validate and characterize these associations in preclinical prostate cancer models.
- Whether abnormal DNA methylation is associated with worse clinical outcomes in patients will be investigated.
- In addition, potential treatment approaches for mCRPC with abnormal DNA methylation levels will be identified in preclinical models.
- If successful, this project will determine the mechanisms and clinical impact of aberrant DNA methylation in mCRPC, and will determine optimal treatment strategies for this subset of patients.
What this means to patients: Dr. Hua’s project will determine the biology, clinical consequences, and optimal treatment options for mCRPC with abnormally high DNA methylation levels, and will inform new precision medicine approaches for patients.
Anuradha Jayaram, MBBS
University College London (UCL) Cancer Institute
Mentors: Gerhardt Attard
Characterisation of Peripheral Blood Immune Cell Dynamics Before and After Start of Hormone Therapy And Evaluation of Their Role as Predictive Biomarkers in Hormone-Sensitive Prostate Cancer
- Checkpoint immunotherapy has been highly successful and even curative in many types of cancer, but has yet to be optimized for prostate cancer.
- Anuradha Jayaram hypothesizes that standard therapies used to treat prostate cancer may alter a patient’s immune system and impact responses to subsequent treatment with immunotherapy.
- In this project, Dr. Jayaram will evaluate how the immune system changes in prostate cancer patients throughout the course of treatment with different standard therapies.
- Whether there are genomic alterations in tumors that impact the immune system, and whether these changes associate with patient outcomes will be investigated.
- If successful, this project will determine how prostate cancer treatments impact the immune system in patients, and determine the interplay between tumor genomics and host immunity. This will support the development of non-invasive immune-genomic biomarkers that can predict outcomes and may identify patients who may benefit from new immunotherapeutic strategies.
What this means to patients: Dr. Jayaram’s project will determine if and how standard prostate cancer treatments alter a patient’s immune system, and the clinical relevance of these changes. This knowledge will help to illuminate how to optimize immunotherapy treatments for patients with prostate cancer.
Janggun Jo, PhD
University of Michigan
Mentors: Xueding Wang, Raoul Kopelman, Evan Keller
Evaluating Prostate Cancer by Functional Photoacoustic Imaging with Nanoprobe
- The standard diagnostic procedure for aggressive prostate cancer is transrectal ultrasound (TRUS)-guided needle biopsy. However, due to the low sensitivity of TRUS to cancerous tissues in the prostate, small yet clinically important tumors are often missed. Improved imaging technologies that can better detect the most clinically relevant sites of prostate cancer during diagnostic biopsy procedures are needed.
- Janggun Jo will develop a new imaging technology that can be used with TRUS to improve imaging-guided needle biopsies. This new technology, photoacoustic (PA) imaging, will use nanoparticles that are loaded with a pH-sensing optical agent that is optimized to become activated in tumors.
- Jo will optimize and test the safety, sensitivity and specificity of this new imaging technology in animal models of prostate cancer. Whether this new imaging technique can accurately indicate tumor aggressiveness will be determined.
- Additionally, Dr. Jo will determine if the nanoparticles can be simultaneously loaded with chemotherapy and used to deliver drug to tumors during imaging.
- If successful, project will lead to a prototype imaging platform for targeted prostate biopsy that can also be used to deliver chemotherapy to prostate tumors.
What this means to patients: Dr. Jo’s project aims to establish a new imaging technology that will improve prostate cancer diagnosis and treatment by ensuring that the most clinically important sites are imaged and biopsied. This technology will also be tested as delivery vehicle for chemotherapy, which will result in an image-guided personalized treatment for prostate cancer.
Amar Kishan, MD
University of California, Los Angeles (UCLA)
Mentors: Joanne Weidhaas, Matthew Rettig, Paul Boutros
Transcriptomic and Germline Landscape of High Grade Localized Prostate Cancer: Implications for Prognostication and Treatment Decisions
- Treatments for localized high-grade prostate cancer can vary in approach and intensity, and may include combinations of surgery, external beam radiation therapy (EBRT), brachytherapy (BT), and androgen deprivation therapy (ADT). Improved stratification of patients with high-grade localized prostate cancer who will benefit from different treatment regimen intensities is critical, in order to improve survival rates while reducing side effects and long-term toxicities.
- Amar Kishan aims to develop biomarkers that can better select the most appropriate treatment regimens for patients with localized high-grade prostate cancer.
- Kishan hypothesizes that patients who have inherent radiation-resistance or deficient anti-tumor immunity will have worse outcomes if treated with less intense treatment regimens, and would do better with more intense regimens. In this project, Dr. Kishan will determine whether tumor expression levels of genes involved in radiation-resistance or immune-responses can be used to identify patients who will benefit from treatment intensification.
- Kishan will also determine whether the presence of any germline (inherited) mutations can predict patient outcomes and treatment responses.
- If successful, this project will identify molecular biomarkers that can be used to determine optimal treatment regimens for patients with localized high-grade prostate cancer.
What this means to patients: Dr. Kishan will develop biomarkers that can be used to identify which patients with localized high-grade prostate cancer will benefit from more intense treatment regimens, while preventing overtreatment and unnecessary side-effects in patients who do not need more intense treatment.
Steven Kregel, PhD, MSc
University of Michigan
Mentors: Weiping Zou, Arul Chinnaiyan, Ajjai Alva
Employing murine models with humanized immune systems to study therapeutic approaches for advanced prostate cancer
- The promise of immunotherapy as an effective and potentially curative treatment option for prostate cancer has yet to be realized. Currently, there are no animal models that can properly model interactions between the immune system and human cancer. The development of such models would greatly accelerate cancer immunotherapy research.
- Steven Kregel will develop a murine model of human metastatic castration-resistant prostate cancer (mCRPC) that can be used to study patient responses to immunotherapy as well as anti-androgen therapies.
- In this project, Dr. Kregel will develop and characterize a series of patient-derived prostate tumor models representing different disease subtypes in huNOG mice, a new mouse model with intact human immune systems.
- The impact of androgens and anti-androgen therapies on the immune system and on prostate cancer growth and progression will be evaluated using these models and validated using patient samples.
- Kregel will also identify mechanisms of response and resistance to immunotherapies using these models and patient samples, including the impact that anti-androgen therapies have on responses.
- If successful, this project will develop the first immune-competent model of metastatic human prostate cancer and determine how hormonal therapies impact responses to immunotherapy.
What this means to patients: Dr. Kregel will develop an animal model that can be used to accurately study interactions between human prostate cancer and the intact immune system, and will enable researchers to evaluate strategies to optimize treatment with immunotherapy.
Damien Leach, PhD
Imperial College London
Mentors: Charlotte Bevan, Ian Mills, Gail Risbridger
The Ability of the Primary and Metastatic Niche to Promote Disease progression and Influence the Response of Prostate Cancer to Anti-Androgen Therapy
- Androgen deprivation therapy (ADT) and stronger forms of anti-androgen therapy such as enzalutamide and abiraterone are standard treatments for advanced prostate cancer. These treatments work by blocking the activity of the androgen receptor (AR), which is the primary driver of prostate cancer growth and survival.
- However, a number of other cell types, both in the prostate and in other organs, express AR and are responsive to androgens, but how these cell types respond to systemic anti-androgen therapy and the consequence of these responses is not known.
- Damien Leach will investigate how the non-cancer cells in the microenvironment of primary and metastatic prostate tumor niches are impacted by treatment with enzalutamide.
- Whether the responses of cells in the primary tumor to anti-androgen therapy affect the metastatic potential of prostate cancer will be investigated.
- Leach will also investigate if the efficacy of anti-androgen therapy is impacted by responses of non-cancer cells in the microenvironment of primary prostate tumors and/or liver metastases.
- If successful, this project will determine if and how the responses of non-cancer cells within tumors impact the efficacy of anti-androgen therapies such as enzalutamide.
What this means to patients: Dr. Leach will investigate the mechanisms by which non-cancer cells impact the efficacy of anti-androgen therapies in patients with advanced prostate cancer. These studies will enable the identification of new ways to monitor and target advanced prostate cancer.
Deli Liu, PhD
Weill Cornell Medicine
Mentors: Chris Barbieri, Andrea Sboner
The impacts of RNA-based classifiers on prostate cancer prognosis
- Prostate cancer is a highly variable disease that can be sub-classified into several molecular subclasses based on certain genomic alterations, such as ERG-fusions, DNA repair gene alterations, PTEN-deletions, SPOP-mutations, and CHD1-deletions.
- However, the long-term clinical impacts of these genomic alterations are unknown, as patient cohorts with genomic sequencing have limited follow up. In contrast, gene expression (RNA) data are widely available among prostate cancer cohorts that often have long follow-up.
- Deli Liu will develop an RNA-based classifier that can identify certain prostate cancer molecular subtypes and assess their clinical impact in cohorts with long-term follow-up collectively comprising over 10,000 patients.
- These analyses will also enable the identification of molecular features and biological mechanisms of African American vs. Caucasian prostate cancer and nominate signaling pathways and targeted therapies specific for each population.
- If successful, this project will provide a new framework for precision risk stratification, and will identify new potential therapeutic targets for different subclasses of prostate cancer, to advance precision medicine for prostate cancer.
What this means to patients: Dr. Liu’s project aims to provide a new framework to improve precision medicine treatment selection for prostate cancer patients.
Francesca Lorenzin, PhD
Universita’ degli Studi di Trento
Mentors: Francesca Demichelis
ERG-mediated biphasic cell response unlocks vulnerabilities for novel therapeutic opportunities in CRPC
- Approximately 40-50% of prostate cancer cases are driven by ERG gene fusions. Thus, ERG may represent an attractive therapeutic target.
- Francesca Lorenzin has discovered that ERG-fusions can result in two divergent phenotypes in prostate cancer cells: lower ERG levels appear to drive cancerous activities, while very high levels reduce cellular fitness.
- In this project, Dr. Lorenzin will investigate the biology of ERG-fusions in prostate cancer and identify new therapeutic strategies that target vulnerabilities caused by ERG-fusions.
- The mechanisms by which ERG can generate these two dose-dependent divergent phenotypes will be investigated.
- A system to exploit and induce very high ERG levels that drive death of prostate cancer cells will be developed and investigated as a potential new therapeutic strategy.
- In addition, genes that prostate cancer cells become dependent on for survival in the presence of very high ERG levels will be identified and investigated for their potential as therapeutic targets.
- If successful, Dr. Lorenzin’s project will result in new therapeutic strategies for the ~50% of prostate cancer patients whose disease is driven by ERG-fusions.
What this means to patients: Dr. Lorenzin will determine how the ERG-fusion mutation, which drives 40-50% of prostate cancer cases, can be therapeutically exploited, which will lead to novel treatment strategies for many patients.
Patrick Pilié, MD
The University of Texas MD Anderson Cancer Center
Mentors: Timothy Thompson, Ana Aparicio, Christopher Logothetis
Rational Combinations to Target the Replication Stress Response in Prostate Cancer
- DNA damage repair (DDR) pathways are responsible for ensuring that any broken DNA is detected and mended, in order to prevent mutations from being acquired and passed on when cells divide.
- Prostate cancers with certain DDR pathway defects are sensitive to treatment with PARP-inhibitors and platinum chemotherapy. Other precision medicine opportunities may be identified by further study of DDR pathways.
- Replication stress response (RSR) pathways are a type of DDR pathway that are involved in preventing cells with damaged DNA from dividing until the DNA is repaired.
- Patrick Pilié is investigating whether RSR pathway defects render tumors sensitive to certain treatments and whether RSR genes such as ATR may be promising therapeutic targets.
- Whether defects in RSR genes predict responses to PARP-inhibitors or olaparib will be determined by evaluating tumor mutations from advanced prostate cancer patients on a clinical trial testing the PARP-inhibitor olaparib following treatment with cabazitaxel + carboplatin chemotherapy. Tissues from these patients will also be evaluated to determine how these treatments impact RSR pathway activity in tumors.
- Pilié will conduct a phase 1/2 clinical trial to test the efficacy of an ATR-inhibitor in combination with the anti-androgen therapy darolutamide in patients with metastatic prostate cancer.
- Whether and how treatment with an ATR-inhibitor impacts the immune system will also be evaluated in patients and in preclinical models.
- If successful, this project will determine how RSR gene defects and RSR-inhibitors may inform new prostate cancer precision medicine strategies.
What this means to patients: Dr. Pilié will determine whether defects in RSR genes may render prostate cancer sensitive to treatment with PARP-inhibitors and platinum chemotherapy, and will determine the biological and clinical impact of treatment with ATR-inhibitors.
Raffaella Pippa, PhD
Sanford Burnham Prebys Medical Discovery Institute
Mentors: Karen Knudsen, William Kelly, Josep Domingo-Domenech
Mechanistic study of the tumor suppressor role of MITF uncovers actionable translation targeting for prostate cancer
- New therapies are urgently needed for men with advanced prostate cancer. The identification of novel therapeutic targets and pathways that contribute to prostate cancer lethality is necessary for improving clinical outcomes.
- Raffaella Pippa has discovered that microftalmia transcription factor (MITF), a transcription factor that regulates the expression of protein synthesis machinery, acts to prevents prostate cancer aggressiveness, and that MITF may become dysregulated in prostate cancer.
- In this project, Dr. Pippa will investigate the mechanisms by which MITF acts to limit prostate cancer progression in preclinical models.
- Whether MITF pathway activities may act as biomarkers to predict patient outcomes will be investigated.
- Pippa will also investigate the therapeutic potential for targeting protein synthesis machinery regulated by the MITF pathway in preclinical models of advanced prostate cancer, particularly in prostate cancer in which MITF is dysregulated.
- If successful, this project will determine the role of MITF in the pathogenesis of advanced prostate cancer and may lead to novel therapeutic approaches.
What this means to patients: Dr. Pippa will investigate the role of a novel protein MITF, in prostate cancer and establish whether activities regulated by the MITF pathway have potential as biomarkers or novel actionable therapeutic targets.
Pasquale Rescigno, MD
Institute of Cancer Research (ICR)
Mentors: Johann de Bono
Defining biomarkers of response/resistance to immunotherapy in mCRPC with DNA repair defects, high mutational load and/or with high tumor-infiltrating lymphocytes.
- Cancers with a high tumor mutational burden (TMB), which can be caused by genomic alterations such as microsatellite instability (MSI) and defects in mismatch repair (MMR) or CDK12 genes, are more likely to activate anti-cancer immune responses and be responsive to treatment with checkpoint immunotherapy.
- Tumor infiltration by high levels of immune cells is also thought to be an indicator of increased likelihood to benefit from checkpoint immunotherapy
- Despite these findings, it remains unclear how to best identify prostate cancer patients who will benefit from checkpoint immunotherapy.
- Pasquale Rescigno will investigate mechanisms and biomarkers of response to checkpoint immunotherapy in prostate cancer patients.
- Rescigno will determine mechanisms that impact levels of immune cell infiltration in advanced prostate cancers, specifically evaluating why some prostate cancers with MMR and CDK12 defects have low levels of infiltrating immune cells.
- Novel genomic alterations that associate with high levels of immune cells in cancers lacking MMR or CDK12 gene defects will be identified.
- Biomarkers and mechanisms of response and resistance to pembrolizumab checkpoint immunotherapy will be evaluated using samples from patients on a phase 2 clinical trial.
- If successful, this project will advance precision medicine for prostate cancer patients by developing biomarkers to determine which patients are most likely to benefit from checkpoint immunotherapy.
What this means to patients: Dr. Rescigno will identify biomarkers and mechanisms of response and resistance to checkpoint immunotherapy, which will accelerate the use of this highly promising class of treatments in prostate cancer patients.
Joshua Scurll, PhD
University of British Columbia (UBC)
Mentors: Amina Zoubeidi
Deciphering mechanisms by which BRN2 mediates the development of neuroendocrine prostate cancer in response to hormone therapy.
- Neuroendocrine prostate cancer (NEPC) is a highly aggressive and lethal form of prostate cancer that is resistant to hormone therapy.
- NEPC most often develops in response to hormone therapy and rarely occurs otherwise.
- The Zoubeidi lab identified BRN2 as a critical driver of NEPC and is exploring the effects of inhibiting BRN2 in preclinical models of NEPC.
- In this project, Dr. Scurll will investigate the molecular and epigenetic mechanisms by which BRN2 mediates the transition from treatable prostate cancer to hormone-therapy–resistant NEPC.
- Dr. Scurll will also explore how these mechanisms are disrupted by novel BRN2 inhibitors, potentially re-sensitizing cancer cells to hormone therapy.
- If successful, this project will provide essential foundations for clinical studies of biomarkers to identify NEPC patients who may benefit from therapeutic inhibition of BRN2.
What this means to patients: Dr. Scurll will uncover mechanisms of hormone therapy failure mediated by BRN2 in prostate cancer and how these mechanisms are disrupted by inhibition of BRN2. This will yield important insights into why and how some prostate-cancer patients progress to NEPC and could ultimately help to identify patients who may benefit from new drugs targeting BRN2.
Jeremy Shelton, MD
University of California, Los Angeles (UCLA)
Mentors: Matthew Rettig
Developing a prostate cancer data repository to support implementation of precision oncology care and research in VA
- Prostate cancer is the most common solid tumor diagnosis among U.S. veterans, accounting for 31.8% of all cancer diagnoses at the VA in 2012. 8% of men with new prostate cancer diagnoses in the VA have advanced disease.
- The PCF and the VA have developed a novel partnership to drive rapid implementation of precision medicine for veterans with prostate cancer.
- Jeremy Shelton will create a prostate cancer data core to serve the operational and research objectives of the VA/PCF partnership. This data core will contain clinical, genomic, and research data for prostate cancer patients seen in the VA.
- Clinical infrastructures will be developed to streamline delivery of optimal individualized care to VA patients and match patients with precision medicine clinical trials. These infrastructures will include operational structures, advisory committees, decision support tools, and pathways to integrate with non-VA institutions.
- If successful, this project will result in the establishment of a rich data core and precision medicine delivery system that will significantly improve outcomes for veterans with prostate cancer and will drive new research into prostate cancer biology and treatment.
What this means to patients: Dr. Shelton will establish a data core and clinical infrastructure at the VA to accelerate widespread adoption of precision oncology for veterans with prostate cancer, and create a roadmap for improving care for the treatment of many other diseases at the VA.
Eugene Shenderov, MD, PhD
Sidney Kimmel Cancer Center / Johns Hopkins University
Mentors: Drew Pardoll, E. Antonarakis, Charles Drake
Understanding Antitumor Immunity in High-Risk Localized Prostate Cancer: A Neoadjuvant Trial using Enoblituzumab to Target the B7-H3 Checkpoint
- Checkpoint immunotherapy is a type of treatment that activates a patient’s own immune system to fight their cancer by blocking immune-suppressive “checkpoint” signals.
- This type of therapy has been highly effective and even curative in some patients with melanoma and other cancers, but has had limited activity in prostate cancer.
- Eugene Shenderov is working with a novel immune checkpoint (B7-H3) that is highly expressed in prostate cancer, and can be targeted by an existing experimental checkpoint immunotherapeutic, enoblituzumab.
- Shenderov is conducting a clinical trial to determine the immunological, biological and clinical effects of enoblituzumab in patients with high-risk localized prostate cancer.
- If successful, this project will establish a new immunotherapy treatment for men with high-risk prostate cancer.
What this means to patients: Dr. Shenderov’s project will determine the clinical efficacy and biological effects of a novel immunotherapy treatment in men with high-risk localized prostate cancer.
Daksh Thaper, PhD
University of British Columbia (UBC)
Mentors: Amina Zoubeidi
Deciphering and targeting the multifaceted roles of BRN2 in neuroendocrine prostate cancer
- Neuroendocrine prostate cancer (NEPC) is a highly aggressive and lethal form of hormone therapy-resistant prostate cancer, for which there are currently no effective treatments.
- The Zoubeidi lab has identified BRN2 as a critical driver of NEPC and is developing a new drug that targets BRN2.
- In this project, Dr. Daksh Thaper will investigate the role of BRN2 as a driver and therapeutic target in NEPC.
- The mechanisms by which BRN2 drives the development of NEPC in the context of androgen-targeted therapy will be investigated.
- The efficacy of BRN2-inhibitors will be tested in preclinical models of human NEPC.
- If successful, Dr. Thaper’s project will provide preclinical data necessary to advance BRN2-inhibitors into clinical trials, and may ultimately result in a new treatment for NEPC.
What this means to patients: Dr. Thaper will establish the biology and therapeutic potential for targeting BRN2 in NEPC, and will provide rationale for advancing a novel BRN2-inhibitor into clinical trials for this highly aggressive and currently untreatable form of prostate cancer.
Xiao Wei, MD
Harvard: Dana-Farber Cancer Institute (DFCI)
Mentors: Mary-Ellen Taplin
Chemo-Hormonal-Immunotherapy in Metastatic Hormone Sensitive Prostate Cancer
- There have been significant advances in cancer immunotherapy in recent years, specifically with immune checkpoint inhibitors. However, while these agents are effective and can even be curative in a variety of malignancies, their use has not yet been optimized in prostate cancer.
- Xiao Wei hypothesizes that combining upfront docetaxel chemotherapy and androgen deprivation therapy (ADT) with checkpoint immunotherapy will improve outcomes in some patients with newly diagnosed metastatic prostate cancer.
- Wei is conducting a phase 2 clinical trial testing the clinical efficacy of docetaxel + ADT + the checkpoint immunotherapy nivolumab in patients with newly diagnosed metastatic prostate cancer.
- Wei further hypothesizes that this treatment combination may work better in patients with DNA damage repair (DDR) gene mutations or in tumors with an inflamed tumor microenvironment. To test these hypotheses, the trial will prospectively enroll patients into 3 biomarker-based cohorts: 1) patients with mutations in DDR genes; 2) patients with tumors that have high PD-L1 expression or T cell infiltration and do not have DDR mutations; and 3) patients with neither of these biomarkers.
- Samples from patients on this trial will be used to identify improved biomarkers of DNA repair defects that predict responses to this treatment combination.
- Additionally, whether changes in levels of circulating tumor cells (CTCs) may predict clinical efficacy or inform on mechanisms of therapeutic resistance during treatment with immunotherapy will be studied.
- If successful, this project will support a new precision medicine treatment regimen for men with newly diagnosed metastatic prostate cancer.
What this means to patients: Dr. Wei’s project will establish the therapeutic potential for upfront treatment of newly diagnosed metastatic prostate cancer patients with docetaxel + ADT + checkpoint immunotherapy, and establish biomarkers to identify which patients are most likely to benefit.
Yukiko Yamaguchi, PhD
City of Hope
Mentors: Stephen Forman, Saul Priceman
Novel multi-targeting shRNA engineering platform for inhibition of PSCA-CAR T cell exhaustion in the prostate tumor microenvironment
- Chimeric antigen receptor (CAR) T cell therapy is a promising new type of immunotherapy that has been highly effective for the treatment of certain leukemias and lymphomas. This type of treatment engineers a patient’s own immune cells to recognize and kill their tumors. CAR T cells are now being developed for the treatment of solid tumors.
- Yukiko Yamaguchi is developing and optimizing CAR T cells for the treatment of prostate cancer patients. This project builds on previous PCF-funded work to develop a CAR T cell that targets the prostate cancer associated protein PSCA, and which is now being tested in a phase I clinical trial.
- Yamaguchi hypothesizes that turning off immune suppressive signaling pathways in CAR T cells will improve their anti-tumor efficacy.
- The mechanisms by which immune suppressive signaling pathways such as PD1/PD-L1 suppress the activities of CAR T cells will be determined in preclinical models.
- PSCA-targeting CAR T cells that are resistant to immune suppressive signaling pathways including PD1, TIM3 and LAG3 will be developed and tested in preclinical models.
- If successful, this project will result in a clinically translatable strategy to improve the therapeutic efficacy of PSCA-CAR T cells for the treatment of prostate cancer patients.
What this means to patients: Dr. Yamaguchi is developing CAR T cells that can resist immune-suppressive signals and will have improved overall activity and durability for the treatment of prostate cancer and other solid tumors.