The PCF Young Investigator Award-Class of 2015 recipients are:
2015 David H. Koch–PCF Young Investigator
Wassim Abida, MD, PhD
Memorial Sloan Kettering Cancer Center
Mentors: Howard Scher, MD; Charles Sawyers, MD
Proposal Title: Investigating Treatment Selection and Resistance Using Prostate Cancer Genomics
- Genomic profiling of primary and metastatic treatment-resistant prostate cancer (CRPC) allows precise molecular classification of the disease. Identifying mechanisms of resistance to current therapies will lead to novel precision medicine treatment options.
- Dr. Abida will use genetic data obtained from the PCF International Prostate Cancer Dream Team to correlate molecular signatures of CRPC cells with patient outcomes to identify mechanisms driving treatment-resistance and disease progression in men with lethal forms of the disease.
- Targeted genomic profiling of tumor DNA directly from the blood CTCs of these patients may lead to development of clinical tools to detect mutations in patients with CRPC without the pain and expense of an invasive tumor biopsy.
- Dr. Abida’s research lays a crucial foundation for development of precise diagnostic and prognostic tools—advancing personalized treatment options for men with CRPC.
What this means for patients: Prostate cancer patients will invariably become resistant to standard treatments. Targeting specific genomic alterations represents an innovative strategy for earlier diagnosis of aggressive prostate cancer and precise and personalized treatment for patients with CRPC.
2015 John Paulson–PCF Young Investigator
Rahul Aggarwal, MD
University of California, San Francisco
Mentor:Eric Small, MD
Proposal Title:Targeting MYC-Driven Cell Cycle Progression in Neuroendocrine Prostate Cancer with Gallium Citrate PET as a Novel Biomarker of MYC Transcriptional Activity
- The development of androgen axis inhibitors Zytiga® and Xtandi® has improved treatment of metastatic treatment-resistant prostate cancer (mCRPC). Often, these patients become treatment-resistant. Some of these men develop prostate cancer with features of neuroendocrine disease, a highly aggressive form of prostate cancer.
- MYC-driven cyclin-dependent kinases (CDK) 4/6 is a potential therapeutic target for CRPC. Dr. Rahul Aggarwal will clinically evaluate the effects of a 6-month trial treating patients whose tumors express features of neuroendocrine disease with a CDK 4/6 inhibitor in combination with docetaxel chemotherapy.
- Once a novel biomarker of MYC transcriptional activity is identified, Dr. Aggarwal will investigate use of gallium citrate PET imaging to gauge MYC target inhibition and clinical response during treatment
- Dr. Aggarwal’s research builds on preliminary pre-clinical data that supports the use of gallium citrate PET as a biomarker for MYC target inhibition.
What this means for patients: There is a critical and growing unmet medical need to develop more effective treatment strategies to improve outcomes in men suffering from neuroendocrine evolved prostate cancer. If successful, this research will provide strong proof of concept for integration of these novel targeted therapies in clinical care.
Heather Cheng, MD, PhD
University of Washington
Mentor: Peter Nelson, MD
Proposal Title: Identifying High-Penetrance Prostate Cancer Risk Genes: Leveraging Families for Next Generation Discovery and Prevention
- Although family history is well-established as a risk factor for development of prostate cancer, scientists currently lack a comprehensive understanding of underlying genetic causes.
- Dr. Heather Cheng is coordinating a large-scale program to identify potential highly hereditable genes that may only run in one in 200 families or less, but are exceptionally powerful and carry a high risk of developing prostate cancer—comparable to the BRCA genes implicated in families with frequent occurrence of breast and ovarian cancer.
- After recruiting families with multiple relatives with early-onset or aggressive prostate cancer, gene and whole exome sequencing techniques will help detect shared genes and mutations.
- In order to leverage this project’s potential immediate clinical impacts, Dr. Cheng is developing and sharing a first-in-field, web-based educational and counseling resources and information about research opportunities for these men, their families, and related healthcare providers.
What this means for patients: Prostate cancer is well known to have a strong inherited component, yet the causative genes are incompletely known. This unique project is poised to identify specific high-risk genes, offering a novel path to enhanced screening (i.e. early PSA screening for men in their 40s) and prevention of prostate cancer in family members.
2015 Adrianne & Jerry Cohen, Larry Gagosian, and Pablo Legorreta–PCF Young Investigator
Justin Drake, PhD
Rutgers University Cancer Institute of New Jersey
Mentor: Robert DiPaola, MD
Proposal Title: Elucidating Kinase Activation Pathways in Advanced Prostate Cancer
- Men with progressive metastatic prostate cancer are often treated with medicines that target androgen receptor (AR) pathways. These patients invariably develop resistance to current AR treatments (e.g., Lupron, Zytiga®, Xtandi®).
- Dr. Justin Drake will use bioinformatics and a computational model of CRPC tumors to identify other pathway targets for therapy. Specifically, he will focus on several mutations of tyrosine kinase enzymes, which are the “on” or “off” switches for many cellular functions.
- Activated kinase pathways may drive metastatic CRPC cell growth despite use of AR inhibitors.
- Evaluation of clinical tissues and mouse models of human CRPC will allow Dr. Drake to identify specific combinations of pathways that allow metastatic CRPC cells to proliferate, and test combinations of existing therapies that suppress these growth signals.
- Dr. Drake’s research may lead to personalized treatment strategies that combine currently-available inhibitors of kinase signaling to significantly improve outcome in patients with CRPC.
What this means for patients: New targets for the treatment of AR medicine-resistant prostate cancer represents an unmet medical need. Dr. Drake’s investigation of kinase inhibitor targets holds promise of filling this therapeutic goal.
2015 Brent Nicklas–PCF Young Investigator
Amanda Hargrove, PhD
Mentors: Hashim Al-Hashimi, PhD; Peter Dervan, PhD
Proposal Title:Targeting the lncRNA SChLAP1 in Aggressive Prostate Cancer by the Assembly of Multivalent Small Molecule Inhibitors
- Long noncoding RNAs (lncRNAs) play a critical role in cell development by activating other molecules in charge of shaping gene expression. Recent research suggests that lncRNAs may be the most active driver of aggressive prostate cancer.
- Specifically, the lncRNA SChLAP1 might play a prominent role in metastasis by inhibiting the SWI/SNF complex, a group of proteins that suppress tumor growth in healthy men.
- Dr. Amanda Hargrove will use a library of RNA sequences to identify parts of SChLAP1 that can be targeted with engineered ligands (binding molecules) in order to prevent its interaction with SWI/SNF.
- Investigating engineered ligand binding to SChLAP1 in clinical prostate cancer tissues may lead to identification of promising compounds for SChLAP1-targeted medication development.
- Dr. Hargrove’s research will lay the groundwork for the first clinical trial evaluating the use of SChLAP1-targeting therapies to treat men with advanced prostate cancer.
What this means for patients: Prevention of metastasis of prostate cancer is an unmet medical need. This lncRNA basic research could lead to a novel class of medication to prevent early prostate cancer or treat prostate cancer metastasis.
2015 Victoria & Vinny Smith, Eustace Wolfington,
and Ali & Joe Torre–PCF Young Investigator
Joseph Ippolito, MD, PhD
Washington University School of Medicine in St. Louis
Mentors: Jeffrey Arbeit, MD; Farrokh Dehdashti, MD
Proposal Title:Characterizing and Imaging Metabolic Symbiosis in Castrate- Resistant Prostate Cancer
- Metabolic oxidative phosphorylation (OXPHOS) is a biochemical process that may lead to therapy resistance and tumor recurrence in men with prostate cancer. Characterizing the metabolism of treatment-resistant prostate cancer (CRPC) tumors will validate potential use of OXPHOS for diagnosis, imaging, and treatment in men suffering from the disease.
- Dr. Joseph Ippolito will model metabolism in CRPC cells to evaluate the effects of OXPHOS on tumor growth and survival and determine if inhibiting OXPHOS will decrease tumor burden.
- Another challenge to managing CRPC is the present lack of precise imaging techniques to measure tumor burden in metastatic prostate cancer. Dr. Ippolito will use a mouse model of CRPC treated with OXPHOS inhibitors to test the feasibility of imaging decreased tumor metabolism.
- If successful, Dr. Ippolito’s research will lead to development of a novel medication, as well as innovative tools for identifying more lethal types of prostate cancer during the crucial early phase of a man’s disease and monitoring the effects of treatment on CRPC tumors.
What this means for patients: Characterizing the metabolic activity of CRPC cells will lay the groundwork for a new paradigm of research targeting prostate cancer. This research may lead to development of new treatments that improve outcome for patients.
2015 Neal Rodin–PCF Young Investigator
Won Kim, MD
University of California, San Francisco
Mentors: Charles Ryan, MD; Eric Small, MD
Proposal Title:Dissecting Variant Androgen Signaling Phenotypes to Guide Treatment Selection in Abiraterone Acetate and Enzalutamide-Resistant Prostate Cancer
- The emergence of treatment-resistant prostate cancer (CRPC) is an inevitable outcome for men treated with androgen receptor (AR) targeted therapies. At present, the biology of prostate cancer treatment resistance is poorly understood.
- Dr. Won Kim hypothesizes that specific genetic changes in the AR are key drivers of resistance to androgen deprivation therapy (ADT) medications such as Xtandi® and Zytiga®.
- Androgen levels measured in patients enrolled in a long-term study with the Prostate Cancer West Coast Dream Team will enable Dr. Kim to explore interactions between androgen levels, AR genetic expression, prior treatments, and other clinical co-variables.
- Dr. Kim’s research will fill several crucial gaps in our current understanding of the molecular interactions driving treatment resistance and will evaluate the use of androgen level as a predictive biomarker for patient response to ADT.
What this means for patients: Characterizing the specific molecular interactions between androgen levels, ARs, ADT, and other clinical factors may lead to development of novel diagnostic and prognostic tools that, improve survival for men with CRPC.
2015 Gerry Lenfest–PCF Young Investigator
Vishal Kothari, PhD
University of Michigan
Mentors: Arul Chinnaiyan, MD, PhD; Felix Feng, MD
Proposal Title:Investigating DNAPK as a Therapeutic Target and a Prognostic Biomarker in Castration-Resistant Prostate Cancer
- New therapeutic targets and prognostic biomarkers for treatment-resistance prostate cancer (CRPC) would greatly improve outlook and decrease mortality rates for men with advanced forms of this disease. Recent research has identified DNA-dependent protein kinase (DNAPK), a molecule that regulates cell function, as a key driver in CRPC metastatic progression.
- Dr. Vishal Kothari will use gene sequencing of clinical tissue from CRPC patients to investigate how DNAPK increases Wnt signaling. Overexpression of Wnt signaling is implicated in onset of 30% of patients with treatment resistance and is induced by androgen deprivation therapies (ADT).
- Defining the DNAPK interaction network will allow Dr. Kothari to determine the effectiveness of using a DNAPK inhibitor combined with standard ADT medicines in treating men with CRPC.
- Dr. Kothari’s study is poised to make significant advancements toward using DNAPK activity as a biomarker for prognostic tools and targeted therapies to treat men suffering from CRPC.
What this means for patients: Early diagnosis of aggressive, lethal types of prostate cancer is a critical unmet clinical need. Validating DNAPK as a prognostic marker will provide a novel clinical tool to guide early treatment intensification, and may guide personalization of treatment for men with prostate cancer.
2015 Lori Milken–PCF Young Investigator
John Kyung Lee, MD
University of California, Los Angeles
Mentor: Owen Witte, MD
Proposal Title:Therapeutic Targeting of N-Myc-Driven Human Small Cell Neuroendocrine Prostate Cancer
- A highly aggressive subtype of treatment-resistant prostate cancer has been increasingly diagnosed in men who have suffered from the disease and were treated with androgen deprivation therapy. Small cell neuroendocrine prostate cancer (SCNPC) carries an extremely poor prognosis, and targeted treatments are an unmet medical need.
- Dr. John Lee will use a novel human model system of prostate cancer to evaluate the function of N-Myc, a protein that is often overexpressed in cancer cells, in driving the onset of SCNCP. He will use a panel of N-Myc-driven SCNPC cell lines to profile molecular signaling.
- Profiling the molecular signaling of N-Myc-driven SCNPC cell lines will allow Dr. Lee to evaluate efficacy of using several currently available inhibitors to target cell cycle regulators and slow growth of these aggressive tumors.
- If successful, Dr. Lee’s research will harness the power of his team’s first-in-field SCNPC human model and cell lines to develop a breakthrough treatment strategy for this disease.
What this means for patients: Standard chemotherapy for SCNPC is highly toxic and offers short-lived benefits. This innovative therapy will precisely target dangerous prostate cancer cells, avoiding unnecessarily harsh treatments and improving outlook and quality of life for men suffering from this lethal form of prostate cancer.
2015 Stephen A. Schwarzman–PCF Young Investigator
Zhenfei Li, PhD
Cleveland Clinic Foundation
Mentors: Nima Sharifi, MD; Eric Klein, MD
Proposal Title: A Novel Abiraterone Metabolite as a Predictive Biomarker for Clinical Response to Abiraterone
- While most men with prostate cancer initially respond well to androgen deprivation therapies (ADT) such as Zytiga®, some do not, and patients inevitably develop resistance to treatment. Recent research has identified a specific molecular interaction—conversion of Zytiga® into the metabolic product D4A—as an essential part of a patient’s positive clinical response.
- Dr. Zhenfei Li hypothesizes that D4A has potent anti-tumor activity against prostate cancer tumors and that the conversion rate of Zytiga® to D4A is a biomarker for predicting patient response to Zytiga® early during treatment.
- Establishing the clinical significance of D4A production in patients with CRPC will lead to potential identification of other steroidal metabolites of Zytiga®.
- Dr. Li’s research may provide the first instance of the metabolite of a medication (D4A) being used as a biomarker of patient response and may provide a rapid, non-invasive approach for determining effectiveness of treatment with Zytiga®.
What this means for patients: The presence of D4A in the blood or tissue of CRPC patients might predict response to Zytiga®. If successful, this project will lead to the identification of a predictive biomarker in a routine blood test that informs clinicians early in the treatment whether Zytiga® is inducing a long-term remission.
2015 National Cancer Institute–
PCF Young Investigator
Ravi Madan, MD
National Cancer Institute
Mentor: James Gulley, MD, PhD
Proposal Title:Using A Therapeutic Cancer Vaccine to Enhance Anti-PD-1 Therapy Prior to Prostatectomy
- Immune checkpoint inhibitors “take the brakes” off a patient immune response, resulting in immune elimination of the cancer. Patients with melanoma, renal, bladder, lymphoma and lung cancers have been successfully treated with checkpoint immunotherapy, but clinical results in prostate cancer have been modest to date.
- It is possible that newer cancer vaccine biotechnology can amplify a patient’s immune response and might significantly increase the efficacy of immune checkpoint therapy.
- Dr. Ravi Madan will evaluate data from a clinical trial treating patients with combinations of prostvac, a promising new prostate cancer vaccine, and nivolumab, an anti-PD-1 immune checkpoint inhibitor. Investigating changes in T-cell infiltration of prostate tumors will predict if this combination therapy is successful.
- If successful, Dr. Madan’s research will inform immunotherapy strategies for the treatment of prostate cancer.
What this means for patients: The development of immunotherapy strategies for advanced prostate cancer is a medical priority. This work may define a novel first-in-class immunotherapy capable of overcoming the intrinsic immunoresistance of prostate cancer.
2015 John Paulson–PCF Young Investigator
Sean McGuire, MD, PhD
Baylor College of Medicine
Mentor: Bert O’Malley, MD
Proposal Title:Targeting the Mitochondrial Pyruvate Carrier in Castration- Resistant Prostate Cancer
- New hormonal treatments for prostate cancer such as Xtandi® and Zytiga® are effective, but patients invariably become resistant to these medications.
- Dr. Sean McGuire’s innovative research is evaluating potential therapeutic value of a molecular target downstream of AR signaling, the indirect targets of Xtandi® and Zytiga®.
- One unique aspect of prostate cancer is that the cells preferentially synthesize lipids compared to glucose. This process provides several specific molecular targets that if inhibited could disrupt cancer cell growth.
- Dr. McGuire is using experimental manipulations of prostate cancer cells to determine if the mitochondrial pyruvate carrier (MPC), a key function of CRPC metabolism that increases during prostate cancer tumor growth, is a reliable target.
- The metabolic consequences of changes to MPC are currently unknown. A better understanding of this process will provide a foundation for the development of therapies targeting prostate cancer metabolic processes downstream of targets of Xtandi® and Zytiga® for patients with CRPC.
What this means for patients: There is an urgent clinical need to develop new therapies for patients resistant to Xtandi® and Zytiga®. Characterizing metabolic alterations specific to prostate cancer cells may lead to novel personalized therapies for men with advanced forms of the disease.
2015 Lori Milken–PCF Young Investigator
Saul Priceman, PhD
City of Hope National Medical Center
Mentor: Stephen Forman, MD
Proposal Title:Targeting Metastatic Prostate Cancer with PSA-Specific Chimeric Antigen Receptor-Engineered T-Cells
- Supplementing a patient’s immune response by engineering their killer white blood cells (CAR T-cells) to recognize, bind to, and eliminate the tumor is a new and transformational area of cancer immunotherapy in other forms of chemotherapy-resistant cancers.
- Dr. Saul Priceman will use laboratory models of prostate cancer to evaluate how engineered CAR T-cells bind to prostate cancer cells and cause their death.
- Further, combining CAR T-cells that bind with PSA (prostate specific antigen) and PSCA (prostate stem cell antigen) may improve efficacy of immunotherapies in treating patients with advanced metastatic prostate cancer.
- If successful, Dr. Priceman’s research will lead to an innovative clinical trial testing engineered patient CAR T-cells as a new treatment for advanced, treatment-resistant prostate cancer.
What this means for patients: Development of a highly specific T-cell therapy for prostate cancer is a critical objective for advanced prostate cancer treatment. The path to the clinic for this project has all its milestones defined. This science will support and inform the appropriate clinical translation of this first-in-field treatment.
2015 Kelsey Dickson–PCF Young Investigator
Michael Schweizer, MD
University of Washington
Mentor: Peter Nelson, MD
Proposal Title: Bipolar Androgen Therapy (BAT): Molecular Drivers of Response and Resistance
- As prostate cancer cells adapt to lower levels of testosterone (T) induced by androgen deprivation therapy (ADT), increased androgen receptor (AR) activity leads to treatment resistance. Pilot studies show that rapid cycling between high and low T levels in men with treatment-resistant prostate cancer (CRPC) can improve patient outcome and quality of life.
- Dr. Michael Schweizer will obtain blood and tumor biopsy samples from patients enrolled in a Phase II trial testing Bipolar Androgen Therapy (BAT; induction of supraphysiological levels of T), and will test for changes in AR related to this novel therapy.
- Dr. Schweizer’s work will help scientists better understand how BAT works, what type of patients are ideal candidates for BAT, which might lead to BAT as a standard treatment option.
What this means for patients: While recent developments in ADT medications have improved the ability to slow progression of CRPC, patients inevitably become resistant. BAT represents an innovative therapy that can potentially save lives of men resistant to other treatments.
2015 David Yurman–PCF Young Investigator
Shabnam Shalapour, PhD
University of California, San Diego
Mentors: Michael Karin, PhD
Proposal Title: Development of Immunosuppressive Plasmocytes that Interfere with T-Cell-Dependent Immunogenic Chemotherapy in Prostate Cancer
- Cancer is characterized by accumulation and loss of normal cellular regulatory processes, leading to expression of tumor-specific molecules (antigens). The tumor microenvironment also causes exhaustion of the patient’s immune response to their cancer.
- Dr. Shabnam Shalapour will use a clinical study to investigate the exact mechanism through which prostate cancer cells cause the exhaustion of prostate cancer patient immune cells that were once capable of eliminating tumors.
- Treatments to reverse immune exhaustion will be studied in a mouse model of human prostate cancer.
- Analyzing biopsies of prostate cancer tumors both before and after patient treatment will allow Dr. Shalapour to determine the exact role that immune cells play in controlling cancer growth and invasion.
What this means for patients: Many immunotherapies that have been successful treating other cancers have had little impact on prostate cancer. Defining mechanisms driving immune cell suppression will lay the groundwork for a clinical trial that test combination therapy in patients with the goal of reversing this resistance.
2015 Howard Shore–PCF Young Investigator
Prasanna Sooriakumaran, MBBS, PhD
University of Oxford
Mentor: Freddie C. Hamdy, MD
Proposal Title: Testing Radical Prostatectomy in Men with Prostate Cancer and oligoMetastases to the Bone: A Randomized Controlled Feasibility Study (TRoMbone)
- As life expectancy rises, greater numbers of older men with skeletal metastases from prostate cancer suffer higher treatment burdens. The current standard-of-care, androgen deprivation therapy (ADT), causes morbidity and might pose significant damage to bone and mental health. Better definition of burden-of-treatment from ADT will enable appropriate multi-disciplinary management and directly improve quality of care.
- Dr. Prasanna Sooriakumaran is exploring an approach to the management of advanced, metastatic prostate cancer without compromising quality-of-life.
- Dr. Sooriakumaran will launch a three-year observational study of 200 men with mCRPC to assess a model considering severity of bone lesions, age, anxiety and depression symptoms, co-morbidities, and treatment choices. Testing this model may lead to a predictive tool to guide clinicians in selecting personalized treatment.
What this means for patients: A model predicting quality-of-life for men with advanced metastatic prostate cancer will enable doctors to prescribe treatments on a personalized basis.
2015 National Cancer Institute–PCF Young Investigator
Adam Sowalsky, PhD
National Cancer Institute
Mentors: Kathleen Kelly, PhD; William Dahut, MD
Proposal Title:Investigations into the Mechanisms of Resistance to Enzalutamide in CRPC
- Genomic analysis of cancer tissue has enabled investigators to study mechanisms of resistance to the androgen receptor (AR) inhibitor Xtandi® in men with prostate cancer.
- Dr. Adam Sowalsky will use tissue samples taken from men progressing on Xtandi® and generate six new Xtandi®-resistant cell cultures. These cultures will potentially preserve the complexity and diversity of treatment resistance prostate cancers, allowing advanced mechanistic studies.
- Treatment-resistant prostate cancer (CRPC) emerges as tumor cells respond to the stress of therapy and change in order to survive. The cancer now survives in an environment of low hormonal concentration.
- This developed model will allow him to determine if alterations to the DNA damage repair machinery render CRPC cells susceptible to PARP (DNA-repairing protein) medicines.
- If successful, Dr. Sowalsky’s study will provide critical data to support the management of patients whose cancers progress during treatment with Xtandi®.
What this means for patients: Comprehensive understanding of the biology and molecular interactions driving treatment resistance allows scientists to develop innovative strategies to treat men with CRPC. Creating new cell lines based on resistance to new drugs can be invaluable tools to the entire prostate cancer research community.
2015 Genomic Health–PCF Young Investigator
Rendong Yang, PhD
University of Minnesota
Mentor: Scott Dehm, PhD
Proposal Title:Delineating Coding and Regulatory Indels in Prostate Cancer
- Next generation sequencing (NGS) is a growing class of innovative new gene sequencing techniques that can sequence millions of fragments of DNA simultaneously. NGS results expand our understanding of complex genetic aberrations that drive the development and growth of both primary and metastatic prostate cancer.
- Dr. Rendong Yang will develop novel computational tools that use data generated by NGS to identify and genotype indels, the insertions and deletions in the “door” (Indel) DNA coding change that drive malignancy.
- Prostate cancer is a clinically heterogeneous disease. Understanding the coding and non-coding sequence variations of the prostate cancer genome at various stages of disease progression is critical for discovery of novel diagnostic and prognostic biomarkers, as well as therapeutic targets.
- Prior genomic research has focused on protein-coding variants, yet non-coding variants are the second most common source of genetic alteration in prostate cancer.
- Dr. Yang’s research will provide cancer researchers with a more complete encyclopedia of non-coding alterations in the prostate cancer genome.
What this means for patients: Identifying specific subtypes of prostate cancer and the distinct pattern of indels associated with them will enhance development of precise diagnostic tools that detect specific genetic aberrations, allowing doctors to reliably predict a patient’s outcome and prescribe personalized treatment.
2015 James Litinsky–PCF Young Investigator
Shuang Zhao, MD
University of Michigan
Mentors: Arul Chinnaiyan, MD, PhD; Felix Feng, MD
Proposal Title: Investigating Long Noncoding RNAs in Aggressive Prostate Cancer
- Long non-coding RNAs (lncRNAs) such as PCAT1 and SChLAP1 have emerged as key molecular drivers, biomarkers, and potential therapeutic targets in aggressive prostate cancer. Currently only a small number of lncRNAs have been identified, which limits the understanding of their overall significance.
- Dr. Shuang Zhao will use data from a library of 50,000 recently discovered lncRNAs to identify specific lncRNAs associated with prostate cancer patients who have poor prognoses and develop treatment resistance.
- Specifically, he will focus on whether the lncRNA AC009478.1, which has been independently validated as a biomarker for metastatic prostate cancer, is also related to treatment resistance.
- This detailed genetic exploration will allow identification of potential mechanisms and pathways through which AC009478.1 drives aggressive prostate cancer progression.
- Dr. Zhao’s study will build upon first-in-field data sets to develop a detailed understanding of clinically-relevant lncRNAs in prostate cancer.
What this means for patients: Comprehensively profiling all known lncRNAs will provide the foundation for developing novel strategies that predict which prostate cancer patients will respond to specific therapies, which in turn will help personalize treatment for each unique tumor.
Imperial College London
Mentors: Johann De Bono, MD, PhD, Charlotte Bevan, PhD
Proposal Title: Systematic Identification of MicroRNA Drivers of Resistance to Novel Therapeutics in Advanced Prostate Cancer – Exploitation as Stratification Biomarkers and Drug Targets
- MicroRNAs are a class of RNA molecules that regulate gene expression and can function as oncogenes or tumor suppressors. Understanding the role of microRNAs in prostate cancer may lead to development of new predictive biomarkers and therapies.
- Claire Fletcher will generate prostate cancer cell lines that are resistant to various therapies used to treat patients with castrate resistant prostate cancer (CRPC), and screen these cell lines to identify microRNAs that are associated with drug resistance. The genes and molecular pathways regulated by the microRNAs will be identified to provide insight into the mechanisms of drug resistance.
- Biomarker tests will be developed that evaluate the expression of microRNAs associated with general drug resistance and with docetaxel-specific resistance. The utility of the biomarker tests in predicting therapeutic resistance will tested in a cohort of CRPC patients undergoing treatment with docetaxel.
- Is successful, this project will result in the identification of new potentially targetable drug resistance mechanisms and the development of biomarker tests that predict responses to various therapies.
What this means for patients: Identifying mechanisms of treatment resistance is critical for developing new therapeutic approaches. Dr. Fletcher will identify microRNA genes that confer resistance to therapies and develop biomarker tests to predict therapeutic resistance. This will enable stratification of patients to receive therapies most likely to be of benefit and may lead to the development of new targeted therapies for CRPC patients.
2015 David Yurman-PCF Young Investigator Award
Rana McKay, MD
Dana-Farber Cancer Institute
Mentor: Philip Kantoff, MD
Proposal Title: Understanding Defects in the DNA Repair Pathway and Assessing Sensitivity to PARP Inhibition in Patients with Metastatic Castration Resistant Prostate Cancer
- Mutations in genes that fix damaged DNA have been found in 20-30% of patients with metastatic castration resistant prostate cancer (mCRPC). These mutations may render tumors sensitive to treatment with PARP-inhibitors. However, numerous mutations in these gene can occur and the clinical relevance of each mutation needs to be determined in order to identify patients who will benefit from treatment with PARP-inhibitors.
- Rana McKay is assessing the clinical relevance of alterations in the DNA repair pathway in men with mCRPC.
- mCRPC patients whose tumors harbor mutations in DNA repair genes will be identified and enrolled in PARP-inhibitor clinical trials and evaluated for clinical responses.
- Approximately 12% of metastatic prostate cancer patients have inherited (germline) mutations in DNA repair genes that likely caused their disease. Men who carry these mutations are more likely to have more aggressive prostate cancer and their family members are at increased risk for multiple cancer types including prostate, breast and ovarian cancers.
- To determine family genetic cancer susceptibility, the family histories of CRPC patients with inherited mutations in DNA repair genes will be evaluated and family members will be screened for the presence of hereditary mutations.
- If successful, this study will result in the development of optimal treatment plans for patients and cancer risk-management plans for families.
What this means for patients: The presence of DNA repair gene mutations in prostate cancer has implications for both patients’ treatment, and for their families if mutations were inherited. Dr. McKay is studying the relationship between specific mutations and response to treatment with PARP-inhibitors and also determining the relationships between the presence of inherited mutations and cancer risk in families. This project will result in the identification of patients who will benefit from treatment with PARP-inhibitors and optimal cancer risk-management plans for families.
2015 John Paulson-PCF Young Investigator Award
Yuanyuan Qiao, PhD
University of Michigan
Mentor: Arul Chinnaiyan, MD, PhD
Proposal Title: Development of a Rational Triple Combination Therapy for Castrate-Resistant Prostate Cancer
- Castrate resistant prostate cancer (CRPC) is a lethal prostate cancer phenotype that arises following tumor development of resistance to androgen deprivation therapy. New treatments are urgently needed for these patients.
- Yuanyuan Qiao is studying the therapeutic efficacy of a novel triple-combination therapy for the treatment of CRPC patients.
- Preclinical studies will be done to evaluate the safety and potential therapeutic efficacy of combining androgen-targeted therapy, c-Met-inhibitors, and proteasome-inhibitors for the treatment of CRPC. c-Met is a molecule that appears to drive some forms of CRPC. Inhibition of the proteasome, the cellular organelle responsible for breaking down proteins, has been found to enhance the anti-tumor effects of c-Met-inhibitors.
- The efficacy of c-Met-inhibitors as a monotherapy or in combination with proteasome inhibitors for the treatment of androgen receptor-negative prostate cancer, will also be evaluated in preclinical models.
- Finally, several FDA-approved and experimental c-Met-inhibitors and proteasome-inhibitors will be compared to identify the best candidates for forwarding to clinical trials in CRPC.
- If successful, this project will result in the development of a new rational triple combination therapy for the treatment of CRPC.
What this means for patients: Combination therapies that target multiple drivers of castrate resistant prostate cancer (CRPC) may prevent the progression of this lethal disease. Dr Qiao is developing a new triple combination therapy that targets the androgen receptor plus c-Met, a driver of CRPC. This will lead to the development of a promising new therapeutic strategy for patients with CRPC.
2015 Peter Grauer-PCF Young Investigator Award
Ashley Ross, MD, PhD
Johns Hopkins University
Mentor: Charles Drake, MD, PhD
Proposal Title: Effects of Local therapy on the Systemic Anti-Tumor Response: Exploration of the Abscopal Effect in Mouse Models for Prostate Cancer
- Immunotherapy can produce apparent cures in patients with certain cancer types, but has not yet demonstrated curative potential for prostate cancer patients. Identifying methods to better activate anti-tumor immune responses may lead to more effective treatment strategies for patients.
- Ashley Ross is studying whether treatment of tumors with local therapies can activate systemic anti-tumor immune responses.
- Mouse models of prostate cancer will be used to determine whether local therapies including surgical excision, complete cauterization, radiation, and cryo-ablation, are able to activate anti-tumor immune responses that attack tumors at distant sites. The immune responses in distant tumors will be characterized and compared following different local therapies.
- Immune checkpoint immunotherapy works by reactivating anti-tumor immune cells that have been turned off by tumor cells. Whether combining local therapies with immune checkpoint immunotherapy will induce more effective anti-tumor immune responses will be examined in preclinical models.
- If successful, this project will result in new treatment strategies to activate anti-tumor immune responses that can cause dramatic and sustainable tumor regression.
What this means for patients: Identifying new ways to potentiate immunotherapy and anti-tumor immune responses will allow clinicians to harness the power of the immune system to eliminate cancer. Dr. Ross is studying whether local tumor treatments can activate anti-tumor immune responses or can synergize with immunotherapy to induce regression of distant metastases. This project will lead to new immunotherapeutic treatment strategies for prostate cancer patients.