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Young Investigator Award-Class of 2014

The PCF Young Investigator Award-Class of 2014 recipients are:

2014 Clay and Lynn Hamlin-PCF Young Investigator

W. Nathaniel Brennen, PhD
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Mentors: John Isaacs, PhD, Charles Drake, MD, PhD

Proposal Title: T cells Engineered to Selectively Deliver a PSA-activated Protoxin to Sites of Advanced Prostate Cancer






T cells are a type of immune cell with significant tumor cell seeking and killing capabilities, but tumor survival mechanisms cause T cell inactivation. Methods for re-arming these specialized killing cells provides powerful treatment opportunities.

Dr. Nathaniel Brennen will engineer a patient’s T cells to act as “Trojan horses”: specifically targeting tumor cells and releasing a cell wall-damaging bacterial toxin, proaerolysin (PA), to kill the tumor cells.

A patient’s T cells will be transformed with a CAR molecule, an engineered T cell-activating and targeting molecule that recognizes a tumor-associated protein, PSMA. When the CAR-T cell locates its target (PSMA), the T cell will be activated to release the toxin.

PSMA can be expressed by normal brain and kidney cells. To avoid non-specific toxicity, the toxin will be delivered in a modified inactive form, and can only be converted to its active form by a prostate-specific enzyme, prostate-specific antigen (PSA).

Dr. Brennen’s strategy will result in the development of a highly specific and highly toxic live cell therapy for the treatment of prostate cancer.

What this means for patients: What this means for patients: While significant advances have been made in the development of prostate cancer therapies, patients will eventually become resistant and progress to a lethal disease state. If successful, this project will develop an innovative and powerful new treatment strategy that uses the patient’s immune system to kill tumor cells.

2014 Stewart Rahr-PCF Young Investigator

Marcin Cieslik, PhD
University of Michigan
Mentors: Arul Chinnaiyan, MD, PhD

Proposal Title: Clinical Implications of Expressed Pseudogene Transcripts in Metastatic Castration-Resistant Prostate Cancer






Differentiating indolent from aggressive prostate tumors is critical for early detection of aggressive tumors and prevention of overtreatment.

Pseudogenes are dysfunctional relatives of genes that have lost their ability to code important proteins due to an accumulation of mutations. These molecules are expressed in many cancers, contribute to disease biology, and may serve as diagnostic biomarkers.

Dr. Cieslik will use gene expression databases to correlate pseudogene expression in prostate cancer to the presence of potentially lethal disease.

If successful, a panel of pseudogenes will serve as a new and innovative biomarker for lethal prostate cancer.

What this means for patients: The current prostate cancer screening method (PSA testing) is nonspecific and leads to unnecessary prostatic biopsies and mass overtreatment. Dr. Cieslik aims to identify a new class of aberrantly expressed genes that can be used as biomarkers for improved diagnosis of prostate cancers that need urgent therapy.

2014 Joshua J. Harris-PCF Young Investigator

Jeremy Durack, MD, MS
Memorial Sloan Kettering Cancer Center
Mentors: Howard Scher, MD

Proposal Title: Rapid Spectroscopic Assessment of Targeted Prostate Cancer Biopsy Sufficiency at the Point-of-Care






Prostate cancer diagnosis and precision medicine treatment decisions currently rely on results from invasive biopsy procedures. Current biopsy methods do not ensure that the quality of the sample collected is sufficient for diagnosis and molecular and genomic characterization.

Dr. Jeremy Durack is developing a unique biopsy instrument that uses specialized integrated spectroscopy to differentiate tumor from normal prostate tissues and to assess the quantity of collected DNA.

This instrument will enable interventional radiologists to assess the quality of biopsies as they are being performed, which will ultimately lead to a reduction in the number of cores that need to be taken for each patient, thereby improving patient safety and guaranteeing the sufficiency of sample quality for genomic characterization.

What this means for patients: Prostate cancer patient diagnosis and treatment decisions rely on results gained from invasive biopsies. Current procedures do not ensure that the biopsy specimen is sufficient. Dr. Durack will develop an instrument that will immediately inform interventional radiologists when sufficient biopsy specimens have been collected, thus accelerating and improving diagnosis and treatment decisions and reducing patient morbidity.

2014 Stewart Rahr-PCF Young Investigator

Leigh Ellis, PhD
Roswell Park Cancer Institute
Mentors: Roberto Pili, MD, Irwin Gelman, PhD

Proposal Title: Interrogation of MYC as a Therapeutic Target and Genetic Platform to
Identify Aggressive Prostate Cancers






Identification of molecular drivers of prostate cancer development and progression are critical for understanding prostate cancer biology and generating new treatments.

Dr. Leigh Ellis is studying the role and therapeutic potential of targeting MYC, an oncogene implicated in many types of cancers including prostate cancer.

In this study, a recently developed, novel MYC inhibitor will be assessed for efficacy in pre-clinical prostate cancer models, administered alone and in combination with current FDA approved treatments for advanced prostate cancer: docetaxel and androgen deprivation therapy (ADT). Molecular mechanisms of MYC in promoting prostate cancer will be studied.

If successful, this study will credential MYC as a therapeutic target in prostate cancer progression.

What this means for patients: Novel therapeutic strategies for the treatment of patients with aggressive prostate cancers are urgently needed. This study will delineate the biology and effectiveness of targeting the MYC oncogene with a novel drug and may lead to new, more effective treatments for patients.

2014 Bonnie Pfeifer Evans-PCF Young Investigator

Christopher Heaphy, PhD
Johns Hopkins University School of Medicine
Mentors: Alan Meeker, PhD, Angelo De Marzo, PhD, Elizabeth Platz, PhD

Proposal Title: The Telomere Biomarker for Individualized Prostate Cancer Risk Stratification and Prognostication






Telomeres are repeating sequences of DNA located at the ends of chromosomes that act as a buffer to protect chromosomes from deterioration or abnormal fusions during DNA replication. Telomeres are shortened with every cell division and once too short, chromosomes become unstable and normal cells activate protective cell death mechanisms. These mechanisms are commonly inactivated in cancer cells, allowing for the development of genomic mutations.

Dr. Christopher Heaphy is studying telomere length in prostate biopsy specimens as a diagnostic and prognostic biomarker of prostate cancer. Telomere lengths will be compared in normal prostate cells, prostate cancer cells, and stromal cells (the complex tissue surrounding normal and malignant prostate glands) from prostate needle biopsies from men with and without prostate cancer. They will determine if shorter telomere lengths in various cell types predict the severity of disease.

Finally, telomere lengths will be assessed in tumor specimens from prostate cancer patients who have undergone hormone therapy to determine if they predict therapeutic response, duration, and disease recurrence.

If successful, this project will identify new diagnostic and prognostic biomarkers of prostate cancer outcome and response to hormone therapy.

What this means for patients: It is critical to discover and validate biomarkers that can be used to improve diagnosis, prognosis, and individual risk stratification. Dr. Heaphy will assess the utility of a novel biomarker for predicting prostate cancer aggressiveness and responsiveness to hormone therapy, leading to better selection of treatment for individual patients and new understandings of disease biology.

2014 Stewart Rahr-PCF Young Investigator

Franklin Huang, MD, PhD
Dana-Farber Cancer Institute
Mentors: Levi Garraway, MD, PhD

Proposal Title: Investigating the Genomics of African-American Prostate Cancer






African-American men have higher incidence and death rates from prostate cancer compared to Caucasian men. Disease grade at presentation is more advanced and cancers are diagnosed at a younger age in African-American men.

The precise reason(s) for this disparity are generally unknown but might be related to various lifestyle, environmental, socioeconomic, and genomic factors.

Dr. Franklin Huang will systematically assess genomic alterations that occur in prostate cancers from African-American men and identify and characterize novel cancer-associated genes.

His preliminary studies have identified a novel putative tumor suppressor gene which is mutated in a subset of African-American patients, and these studies will evaluate the tumor suppressor functions of this gene.

If successful, this project will identify new therapeutic targets for prostate cancer in African-American men and expand the understanding of prostate cancer biology.

What this means for patients: African-American men have a higher risk for lethal prostate cancer. Characterizing the unique biology of prostate tumors in these patients will lead to discoveries of new therapies and improve patient outcome.

2014 Stewart Rahr-PCF Young Investigator

Neema Jamshidi, MD, PhD
University of California, Los Angeles
Mentors: Michael Kuo, MD, Robert Reiter, MD

Proposal Title: Identifying Gen-Rad-Path (Genomic-Radiology-Pathology) Correlates in Patients with Indolent versus Aggressive Prostate Cancer






The ability of physicians to more accurately differentiate indolent from aggressive prostate tumors is critical to eliminate the current problem of overdiagnosis and overtreatment of many patients while missing aggressive disease in others.

Multi-parametric MRI is a powerful new imaging method that provides anatomic and functional information, but its use in prostate cancer diagnosis is not yet validated.

Dr. Neema Jamshidi will evaluate tumor characteristics and patient outcome to develop a strategy for applying multi-parametric MRI in the diagnosis of prostate cancer.

Pre-operative multi-parametric MRI images, histological features, and gene expression of surgically resected prostate tumors will be correlated to clinical outcomes to determine which MRI features can refine differentiation of indolent vs. aggressive disease.

If successful, this project will establish a link between multi-parametric MRI and genomic alterations in prostate cancer diagnosis.

What this means for patients: Proper differentiation of indolent vs. aggressive disease is important for determining appropriate treatment plans for patients – sparing many from overtreatment. This project will establish a mechanism for employing powerful emerging imaging and genomic technologies for the refinement of patient diagnostic procedures.

2014 David S. Blitzer-PCF Young Investigator

Charalambos Kaittanis, PhD
Memorial Sloan Kettering Cancer Center
Mentors: Jan Grimm, MD, PhD, Steven M. Larson, MD

Proposal Title: Overcoming Drug Resistance in Advanced Prostate Cancer with Multifunctional Nanosponges






The poor solubility and bioavailability of many prostate cancer medicines forces physicians to prescribe higher doses to patients to obtain a clinical response. Targeted delivery of drugs to tumors could reduce patient side effects and drug costs.

Dr. Charalambos Kaittanis is studying iron oxide nanoparticles that can act as drug delivery vehicles. These “nanosponges” bind to drugs and release them only in the acidified environment of tumors. Nanosponges emit MRI signals that are selectively quenched by drug-binding, allowing imaging of nanosponge location upon drug deposition.

This project will develop the use of nanosponges as vehicles for individual and co-delivery of enzalutamide and several experimental drugs. Additional tumor imaging technologies will be integrated to measure drug response and resistance.

If successful, this project will develop iron oxide nanoparticles as targeted drug delivery vehicles for prostate cancer treatment and evaluate multiple drug combination activities.

What this means for patients: Dr. Kaittanis will develop nanoparticles as vehicles for the targeted delivery of individual drugs and drug combinations, which might reduce patient morbidity and medical costs, and help to overcome drug resistance.

2014 William B. Finneran-PCF Young Investigator

Haydn Kissick, PhD
The Emory Vaccine Center and the Department of Urology, Emory University
Mentors: Martin Sanda, MD, Rafi Ahmed, PhD

Proposal Title: Vaccination against Patient Specific Coding Mutations to Treat Prostate Cancer






T cells are immune cells with a specialized and powerful ability to recognize dangerous cells and kill them. This occurs by T cell recognition of antigens, i.e. small segments of proteins that are uniquely expressed by the dangerous cell. Tumor cells express many unique and mutated proteins which are ideal killer T cell targets.

Dr. Haydn Kissick is developing methodologies to discover mutated prostate cancer antigens that are recognized by patient T cells.

These antigens can be used to create patient-specific vaccines to expand existing anti-tumor T cell populations and enhance their activity. Efficacy of this cancer vaccine approach and mechanisms of immune resistance will be studied in pre-clinical mouse models.

If successful, this project will create and validate a methodology for generating personalized vaccines that activate the immune system to kill prostate cancer cells.

What this means for patients: The immune system has powerful tumor-killing capabilities but these responses are sub-optimal in cancer patients. This project will develop a methodology for creating personalized vaccines to expand and activate existing anti-tumor T cells, enabling life-long immune surveillance and control of tumors.

2014 Bari Milken Bernstein and Fred Bernstein-PCF Young Investigator

Rajan Kulkarni, MD, PhD
David Geffen School of Medicine at UCLA
Mentors: Matthew Rettig, MD, Dino Di Carlo, PhD

Proposal Title: Utilizing Vortex Chip for Enumeration and Determination of Single-Cell Heterogeneity of Circulating Tumor Cells in Prostate Cancer






Prostate cancer diagnosis and precision medicine decisions are currently informed by analysis of tissues obtained by invasive biopsy procedures. Circulating tumor cells (CTCs) are cells that have been shed from tumor sites and can be obtained from blood draws. Enumeration of CTCs have been shown to possess prognostic significance in clinical studies.

Dr. Rajan Kulkarni is developing a highly innovative microfluidic chip, termed ‘Vortex Chip,’ for improved efficiency of isolation of CTCs from patient blood.

CTCs can also serve as proxies for studying molecular and genomic features of a patient’s tumor. Dr. Kulkarni will assess CTCs for expression of oncogenic and metastatic proteins, genomic aberrations, and gene expression profiles.

If successful, this project will generate a new CTC isolation technology and validate the use of CTCs for diagnostic, prognostic, and precision medicine determinations.

What this means for patients: Prostate cancer diagnosis, prognosis, and treatment decisions require invasive biopsies which can cause patient morbidity and often result in insufficient specimens. This project will create a new technology and validate methodologies that will allow this information to be gained from tumor cells obtained by a simple blood draw.

2014 Stewart Rahr-PCF Young Investigator

Everardo Macias, PhD
Duke University
Mentors: Stephen Freedland, MD, Jen-Tsan Chi, MD, PhD

Proposal Title: Kinase Signaling in Prostate Cancer Associated with Obesity






Development and progression of prostate cancer is associated with obesity, suggesting that therapeutic targeting of metabolic factors may represent a novel treatment strategy. However, caloric restriction to target the metabolic consequences of obesity has not shown a significant clinical benefit in preventing disease progression.

Dr. Everardo Macias will employ a novel screening method in mouse models to identify genes that are essential for prostate cancer progression during dietary interventions including caloric restriction in the setting of obesity. Identified genes will be targeted in pre-clinical models to validate synergy with caloric restriction for maximally limiting tumor growth and progression.

If successful, this project will identify molecular pathways that can be targeted to enhance the effects of caloric restriction in preventing prostate cancer progression.

What this means for patients: Poor diet and lifestyle factors contribute to prostate cancer progression. This project will identify novel therapeutic targets that will enhance the anti-tumor effects of dietary intervention in obese patients, and may create new treatment paradigms.

2014 Stewart Rahr-PCF Young Investigator

Rohit Malik, PhD, MSc
Research fellow, University of Michigan
Mentors: Arul Chinnaiyan, MD, PhD

Proposal Title: Characterization and Therapeutic Targeting of Androgen Receptor Co-activators in Castration Resistant Prostate Cancer






Therapies targeting the androgen receptor (AR) are the primary treatment approach for metastatic prostate cancer. Patients eventually progress to an aggressive drug-resistant disease state termed castrate-resistant prostate cancer (CRPC).

Dr. Rohit Malik will study a protein called MLL that interacts with AR and will attempt to credential MLL as a novel target to prevent or treat cancers resistant to AR-targeting drugs.

Small molecules that inhibit MLL activity will be identified and tested in pre-clinical AR-dependent and independent prostate tumor models.

If successful, a new therapeutic target will be credentialed, drug candidates will be discovered, and the potential efficacy of targeting MLL in drug-sensitive and CRPC patients will be determined.

What this means for patients: The identification of drugs that can inhibit the development of or be used to treat CRPC is critical to prevent the otherwise inevitable deaths of these patients. This project will characterize the biology and impact of therapeutically targeting a promising candidate gene, MLL, and may lead to new treatments that prolong the lives of patients.

2014 Stewart Rahr-PCF Young Investigator

Todd Morgan, MD
University of Michigan
Mentors: Arul Chinnaiyan, MD, PhD, Russell Taichman, DMD, DMSc

Proposal Title: Defining the Role of the HGF/c-MET Axis as a Mediator of Therapeutic Resistance in Advanced Prostate Cancer






The androgen receptor (AR) is the engine that drives prostate cancer progression and survival and is the primary therapeutic target for this disease. Resistance to AR medicines is inevitable and new treatments for drug resistant patients are urgently needed.

Dr. Todd Morgan hypothesizes that the HGF/c-MET cell growth pathway is a potential mediator of resistance to AR-targeting therapies. In this project, HGF/c-MET activity will be assessed in prostate cancer cell lines and in patients receiving enzalutamide and other AR-targeting therapies to determine mechanisms of drug-resistance.

c-MET inhibitors are being tested in phase 2 and 3 clinical trials in patients with AR-targeting drug resistant tumors. c-MET activity will be correlated to treatment response in patients with an experimental c-MET drug (Cabozantinib) and mechanisms of resistance will be studied in these patients.

If successful, this study will identify a mechanism of AR-targeting drug resistance and treatment implications for c-MET inhibitors.

What this means for patients: Resistance to standard and next generation AR-targeting therapies leads to development of untreatable lethal disease. This study will assess the biology of treatment resistance mechanisms and may lead to new combinatorial therapies and therapeutic strategies to treat or prevent this disease state.

2014 Stewart Rahr-PCF Young Investigator

David Olmos, MBBS, MSc, PhD
Spanish National Cancer Research Centre
Mentors: Johann de Bono, MD, PhD, Manuel Hidalgo, MD, PhD

Proposal Title: Integration of Clinical, Molecular and Biological Characteristics to Define an Aggressive Subtype of Prostate Cancer Based on Deficient Homologous Recombination






BRCA is a gene that mediates DNA repair. Mutations in BRCA cause genomic instability and greatly enhance risks for developing breast, ovarian, and other cancers.

Dr. David Olmos has found that men carrying inherited mutations in BRCA genes develop more aggressive prostate cancers and earlier resistance to androgen receptor (AR)-targeted therapies.

In this project, the mechanisms by which BRCA mutations and genomic instability contribute to aggressive prostate cancer and resistance to AR-targeted therapies will be studied in patients and experimental models. Biomarkers that identify disabled BRCA functions in tumors will also be discovered.

If successful, molecular mechanisms by which inherited BRCA mutations contribute to aggressive prostate cancer will be characterized.

What this means for patients: The acquisition of genetic aberrations is a hallmark of cancer and contributes to disease progression and drug resistance. Dr. Olmos will discover disease mechanisms and biomarkers of inherited BRCA mutations in prostate cancer which may lead to the development of new therapies in this subset of patients with more aggressive disease.

2014 Stephen A. Schwarzman-PCF Young Investigator

Brian Olson, PhD
University of Wisconsin Carbone Cancer Center
Mentors: Douglas McNeel, MD, PhD, Glenn Liu, MD

Proposal Title: Targeting Resistance to Androgen Deprivation Therapies using Immunotherapies Targeting the Androgen Receptor






The androgen receptor (AR) is the engine driving prostate cancer and is the treatment target for metastatic disease. Resistance mechanisms to AR-targeting drugs commonly develop and lead to untreatable disease states, which can be accompanied by enhanced expression of AR.

T cells are an immune cell type with potent tumor-killing capabilities. Therapies to promote the ability of T cells to recognize and kill various tumors types are promising.

Dr. Brian Olson has found that T cells that recognize AR arise in prostate cancer patients and vaccination against AR induces potent anti-tumor T cell responses in mice.

In this project, the utility of combinations of AR-targeted drugs and vaccination against AR will be evaluated in pre-clinical models and first-in-human clinical trials. Methodologies will be developed to predict patients that will benefit from this combinatorial therapy.

If successful, this project will lead to a novel combination therapy to avoid lethal drug-resistance.

What this means for patients: Development of therapies that overcome resistance to AR-targeted medicines is critical for finding a cure to this lethal disease. This project will develop a unique therapeutic regimen that takes advantage of AR-targeted drug resistance mechanisms and the power of the immune system for treatment of patients with advanced disease.

2014 Stewart Rahr-PCF Young Investigator

Anirban Sahu, PhD
University of Michigan
Mentors: Arul Chinnaiyan, MD, PhD

Proposal Title: The Role of Long Noncoding RNA SChLAP1 in Aggressive Prostate Cancer






Long non-coding RNAs (lncRNA) are a recently appreciated class of RNA molecules that are transcribed from exons in the genome, but are not translated into proteins. Some lncRNAs are differentially expressed in normal and malignant tissue, suggesting cancer-associated functions.

Dr. Anirban Sahu is studying a prostate cancer-specific lncRNA, SChLAP1, which associates with poor patient outcome and promotes metastasis.

In this study, the molecular mechanisms by which SChLAP1 mediates aggressive prostate cancer and the utility of SChLAP1 as a biomarker for aggressive prostate cancer will be assessed.

If successful, this study will enrich the understanding of prostate cancer biology and establish new biomarkers of aggressive disease.

What this means for patients: Understanding the biology and identifying biomarkers of aggressive prostate cancer is important for treatment of this subset of patients who will progress to lethal disease. This project will uncover new mechanisms of aggressive disease and a means to identify these patients, which will lead to new treatments and improved clinical management.

2014 John A. Paulson-PCF Young Investigator

Nikolaus Schultz, PhD
Memorial Sloan Kettering Cancer Center
Mentors: Charles Sawyers, MD, Chris Sander, PhD

Proposal Title: A Genomics-Guided Decision Support System for the Treatment of Prostate Cancer






Precision medicine is the generation of individualized patient treatment plans based on their unique tumor biology. A plethora of genomic, molecular, pathological, and clinical information is used to guide the decisions that will be made in this emerging strategy for clinical management of patients. Lack of information analysis and management tools however, are hindering the establishment of refined precision medicine methods.

Dr. Nikolaus Schultz is developing software and an infrastructure to integrate all relevant patient information databases and is creating a decision support system that will enable researchers and clinicians to visualize and interpret data to guide patient treatment plans.

This project will address a critical need for the advancement of the field of precision medicine for prostate cancer patients.

What this means for patients: Precision medicine is an emerging clinical strategy to match treatment with genomic alterations in a patient’s tumor. This strategy requires a robust infrastructure for data collection, analysis, and interpretation to generate a decision support system, which this project will establish.

2014 J. Eustace Wolfington-PCF Young Investigator

Jinjun Shi, PhD
Brigham and Women’s Hospital, Harvard Medical School
Mentors: Omid Farokhzad, MD, Ulrich von Andrian, MD, PhD

Proposal Title: mRNA-Based Immuno-Nanotherapeutics for Advanced Prostate Cancer Treatment






The immune system has the power to recognize and kill cells that are dangerous to host homeostasis. Vaccination against tumor antigens has appreciated limited success in inducing anti-tumor immune responses, and refinement of this methodology will create powerful new treatment approaches.

Dr. Jinjun Shi is developing a novel vaccination strategy for prostate cancer in which specialized nanoparticles with controlled-release capabilities will deliver RNA molecules that encode prostate cancer-associated antigens. Potent immune-activating adjuvants, will also be delivered to immune cells, in order to elicit anti-tumor immune responses.

These vaccines will be tested and optimized in prophylactic and therapeutic pre-clinical prostate cancer models.

If successful, this research will create a new method for immunizing patients against their own tumor and may lead to new treatments.

What this means for patients: The immune system has significant tumor-killing capabilities but becomes inactivated in cancer patients. This project will develop a new therapeutic strategy to vaccinate patients and elicit their immune system to target and kill tumor cells.

2014 Rebecca and Nathan Milikowsky-PCF Young Investigator

Daniel Spratt, MD
Memorial Sloan Kettering Cancer Center
Mentors: Charles Sawyers, MD

Proposal Title: Androgen Receptor Signaling Post-Radiotherapy: A Novel Non-Invasive Predictive Biomarker for Locally Advanced and Castrate Resistant Prostate Cancer






Some prostate cancer patients who undergo radiation therapy do not derive a significant benefit from this treatment.

The androgen receptor (AR) is the primary factor mediating growth and survival in prostate cancer cells. Levels of AR can be enhanced by radiation therapy and thereby limit the effects of radiation therapy by promoting cancer cell survival.

Dr. Daniel Spratt will compare serum biomarkers and imaging technologies to create a non-invasive predictive tool that determines the activity of AR in patients undergoing radiation therapy. This tool will be tested in phase 0 clinical trials for validation and optimization.

If successful, this project will create a clinical tool to determine whether a patient undergoing radiation therapy may benefit from the addition of androgen deprivation therapy (ADT).

What this means for patients: The practice of personalized medicine requires the development of tools that enable optimal prescription of treatment regimens based on an individual’s unique tumor characteristics. This research will create a tool to non-invasively monitor tumor responses to radiation therapy and identify patients who will need more aggressive therapeutic interventions.

2014 Lori Milken-PCF Young Investigator

Matthias Stephan, MD, PhD
Fred Hutchinson Cancer Research Center
Mentors: Peter Nelson, MD

Proposal Title: In Vivo Programming of Prostate Tumor-Specific T cells using Synthetic Nanoparticles






The immune system is a powerful natural defense system that targets and kills cells considered by the host to be dangerous. Tumors survive because of their ability to evade or inactivate T cells, a main immune cell type that kills tumor cells.

Dr. Matthias Stephan will create a therapy to program T cells to kill prostate cancer cells. Nanoparticles that can act as targeted delivery vehicles will be engineered to deliver DNA encoding tumor cell recognition genes to T cells. Expression of the gene by the T cell will enable specific recognition and killing of prostate cancer cells.

If successful, this project will develop a therapeutic approach to generate anti-tumor T cells, thereby reprogramming the immune system for tumor elimination.

What this means for patients: The immune system is naturally equipped to recognize and kill dangerous cells. This project will create a novel off-the-shelf therapy to reprogram killer T cells to eliminate prostate cancer cells.

2014 Stewart Rahr-PCF Young Investigator

Tanya Stoyanova, PhD
University of California at Los Angeles
Mentors: Owen Witte, MD

Proposal Title: Proteolytically Cleaved Receptors as Oncogenes and Therapeutic Targets in Advanced Castration Resistant Prostate Cancer






Few options remain for prostate cancer patients who have failed to respond to androgen deprivation therapy. New therapeutic targets and treatments are desperately needed.

Dr. Tanya Stoyanova is investigating two oncogenic molecules, Trop2 and Notch1, which are highly expressed and activated in advanced prostate cancer and may represent new drug targets.

In this project, the roles of Trop2 and Notch1 in prostate cancer will be characterized. The therapeutic efficacy of targeting these molecules will be tested in pre-clinical prostate cancer models.

If successful, this project will lead to the discovery of new biological mechanisms and therapeutic targets in advanced prostate cancer.

What this means for patients: Castrate-resistant prostate cancer (CRPC) is a lethal form of advanced disease with few therapeutic options for extending survival and no means for enacting cures. This project will explore the biology and therapeutic targeting of two oncogenes with roles in CRPC and may lead to new treatments for these patients.

2014 Stewart Rahr-PCF Young Investigator

Sumit Subudhi, MD, PhD
M. D. Anderson Cancer Center
Mentors: James Allison, PhD, Padmanee Sharma, MD, PhD

Proposal Title: Improving Patient Selection for Immune Checkpoint Therapy: Maximizing Benefit and Minimizing Toxicities






Ipilimumab is a cancer immunotherapy that has recently been FDA approved for treatment of metastatic melanoma. A phase 3 clinical trial in metastatic prostate cancer patients failed to demonstrate an effect on overall survival but a small subset of patients did respond.

Ipilimumab works by removing an inhibitory signal from T cells, enabling these immune cells to kill tumor cells.

Dr. Sumit Subudhi will examine the tumor and immune biology and clinical outcomes of advanced prostate cancer patients who participated in phase 3 clinical trials with ipilimumab to identify biomarkers for patients that responded to therapy.

Experimental models will be studied to characterize the mechanisms that regulate ipilimumab-elicited anti-tumor responses.

If successful, this project will lead to the identification of biomarkers that predict response to ipilimumab and can be used to select prostate cancer patients who may benefit from this therapy in future clinical trials.

What this means for patients: Cancer immunotherapeutic agents such as ipilimumab can induce durable and potentially curative anti-tumor immune responses, but can be highly toxic. This research will result in discovery of biomarkers to identify patients that will benefit from ipilimumab treatment and enable the use of this drug in selected prostate cancer patients.

2014 Richard and Ellen Sandler-PCF Young Investigator

Li Wang, PhD
Icahn School of Medicine at Mount Sinai
Mentors:: William Oh, MD and Eric Schadt, PhD

Proposal Title: Integrative Genomics Study of Immune Signatures in Blood and Tumor Tissue for Prostate Cancer






The identification of biomarkers to stratify risk for prostate cancer patients remains an unmet medical need.

Dr. Li Wang is using bioinformatics methods to identify immune cell gene expression signatures in blood samples from castrate-resistant prostate cancer patients that predict clinical outcomes to develop a prognostic biomarker that can be used to monitor patients.

In addition, the associations between the blood-based immune signature, gene expression of immune cells that infiltrate tumors, tumor genetic mutations, and other diagnostic and prognostic patient biomarkers will be assessed to identify mechanisms that regulate the immune signature.

Is successful, this project will result in the development of a blood-based biomarker to stratify a patient’s risk for lethal prostate cancer.

What this means for patients: Developing minimally invasive methods to prognosticate and monitor patients is a critical need.Dr. Wang will generate a blood-based immune biomarker to predict survival of patients with advanced, metastatic prostate cancer, which will improve clinical management of the disease.

2014 Thomas H. Lee-PCF Young Investigator

Yu Wang, MD, PhD
New York University Lagone Medical Center
Mentors:: Susan Logan, PhD, Michael Garabedian, PhD

Proposal Title: Multivalent Peptidomimetic Conjugates in CRPC Treatment






Castrate-resistant prostate cancer (CRPC) is an aggressive, lethal form of prostate cancer that recurs after initial treatment with androgen deprivation therapy (ADT). ADT targets the androgen receptor (AR), the primary driver of prostate cancer growth and survival.

While CRPC is resistant to current ADT regimens, it is common for tumor cells to continue to rely on AR through various escape mechanisms.

Dr. Yu Wang is developing a novel class of drugs that can target AR-dependent escape mechanisms in CRPC patients.

Synthetic molecules called “peptidomimetic conjugates” that antagonize the AR pathway will be developed and tested in preclinical CPRC models for anti-tumor activity.

What this means for patients: The development of new drugs to treat therapy-resistant prostate cancers is critical. This research may result in the discovery and development of novel drugs to treat patients with tumors that have developed resistance to androgen deprivation therapies but still rely on androgen receptor pathways for growth and survival.

2014 Heritage Medical Research Institute-PCF Young Investigator

Kathryn Wilson, ScD
Harvard School of Public Health
Mentors: Lorelei Mucci, ScD, Matthew Smith, MD, PhD

Proposal Title: Bone Metabolism and Bone Metastases in Prostate Cancer






Metastatic prostate cancer is essentially incurable and the most common metastatic site for prostate cancer is the bone. Understanding the interactions between prostate cancer cells and the
bone environment will lead to new treatments to prevent this painful and lethal disease state.

Dr. Kathryn Wilson is studying whether prostate cancer cells exhibit bone-like features or bone-generating capabilities that promote their ability to colonize bones. The expression of genes related to these features will be assessed in primary prostate tumor specimens and their association with patient clinical parameters including bone metastasis and disease outcome will be determined.

The hypothesis that patients with higher rates of bone regeneration are more susceptible to bone metastasis by providing a more conducive bone environment will be explored. The levels of molecules associated with bone regeneration in patient blood will be determined for their association with disease outcome.

Finally, whether obesity and cadmium exposure, both of which impact bone metabolism, might influence prostate cancer bone metastasis will be studied. Patient BMI and cadmium levels in toenails and prostate tissues will be determined and assessed for their association with the risk of bone metastasis and disease outcome.

If successful, this project will discover mechanisms of prostate cancer bone metastasis and lead to the identification of new therapeutic targets.

What this means for patients: Prostate cancer metastases most frequently occurs in bone and results in significant patient morbidity and potential mortality. Dr. Wilson will identify features of prostate cancer cells, the bone environment, and patient factors that contribute to the ability of prostate cancer cells to colonize the bone which will lead to the identification of new therapies to treat or prevent prostate cancer bone metastases.

2014 The LeFrak Family-PCF Young Investigator

Kamlesh Yadav, PhD
Icahn School of Medicine at Mount Sinai
Mentors: Ash Tewari, MD

Proposal Title: Rational Design of Effective Prostate Cancer Combination Therapies






Understanding the biology of how prostate cancer cells develop resistance to drugs, and how different drugs interact with one another will lead to the development of drug combinations that significantly delay or even prevent drug resistance and disease progression.

Dr. Kamlesh Yadav will test the hypothesis that resistance emerges faster against synergistic drug combinations compared with antagonistic drug combinations. He will test the efficacy of pair-wise combinations of commonly used drugs in prostate cancer cell lines to determine which drug-pairs are synergistic or antagonistic (the combined effect of the drugs being respectively greater or less than the sum of the inhibitory activities of the individual drugs), and how these combinations affect the emergence of drug resistant tumors.

Cell lines that develop resistance to single drugs or combinations will be assessed for genomic mutations to identify the involved genes. Combinations of drugs to which resistance emerges through non-overlapping mechanisms will be tested for their efficacy in cell lines and mouse models.

Finally, clinical trials will be initiated to test the most promising combinations in castration-resistant prostate cancer patients.

What this means for patients: The development of drug resistance by prostate cancer cells leads to an untreatable form of this disease. Dr. Yadav will identify drug resistance mechanisms to commonly prescribed prostate cancer medications to develop therapeutic combinations that will delay or prevent the development of lethal, drug-resistant prostate cancer.

2014 J. Eustace Wolfington-PCF Young Investigator

Kosj Yamoah, MD, PhD
Thomas Jefferson University
Mentors: Adam Dicker, MD, PhD, Timothy Rebbeck, PhD

Proposal Title: Identification and Validation of a Biomarker Signature that can Improve Predictability of Aggressive Disease in Men of African Descent with Prostate Cancer






The risk of developing and dying from prostate cancer is higher in men of African descent. A genomic classifier test has been developed to identify men with prostate cancers that have increased aggressive and metastatic potential. This test was developed using men of European descent and its relevance in men of other ethnic backgrounds is unknown.

Dr. Kosj Yamoah will assess prostate cancer gene expression profiles in men of African descent to identify biomarkers of increased risk for aggressive disease.

If successful, this project will identify biomarkers that detect men of African descent with more aggressive tumors to direct treatment regimens and lead to further insight in prostate cancer biology.

What this means for patients: A critical factor in patient management is the successful stratification of patients who need aggressive treatment from patients for whom watchful waiting is appropriate. This project will identify biomarkers that differentiate indolent from aggressive tumors in men of African descent to guide selection of appropriate treatment strategies.

2014 Stewart Rahr-PCF Young Investigator

Huihui Ye, MD
Harvard Medical School: Beth Israel Deaconess Medical Center
Mentors: Steven Balk, MD, PhD

Proposal Title: Investigation of Molecular Mechanisms and Biomarkers of Treatment Resistance in a Randomized, Phase 2 Neoadjuvant Intense Androgen Deprivation Trial in Patients with Localized, Intermediate to High Risk Prostate Cancer






There is no curative treatment available for high-risk, primary prostate cancer patients. Most of these tumors will initially respond to androgen deprivation therapy (ADT) but inevitably recur as a lethal form of castrate-resistant prostate cancer (CRPC).

Dr. Huihui Ye will identify molecular mechanisms and biomarkers of treatment resistance in patients from a phase 2 neoadjuvant intense ADT clinical trial – a combinatorial regimen of conventional ADT (Lupron) plus abiraterone acetate (AA).

Resistance mechanisms that will be explored include altered activation of the androgen receptor (AR), the primary prostate cancer oncogene and target of these therapies, and activation of a novel oncogene, Sox9.

If successful, this study will identify mechanisms of resistance to intense ADT and will help to develop combination therapies to increase response and cure rates.

What this means for patients: Many patients diagnosed with primary high risk prostate cancer who are treated with androgen deprivation therapy (ADT) will eventually develop recurrent, lethal, ADT-resistant disease. This study will identify mechanisms and biomarkers of ADT resistance to inform optimal treatment of patients with potentially lethal disease.