PCF selected the 9 2012 Challenge Awards out of 96 proposals from highly-qualified research teams at 70 prestigious cancer centers spanning 10 countries across the globe. Following an extensive peer review, consisting of an external advisory board, PCF selected the top research proposals for funding. These projects represent a range of focus and expertise and will address the most challenging problems in basic or translational research in prostate cancer. These Challenge Awards include two Judge A. David Mazzone-PCF Challenge Awards and three Movember-PCF Challenge Awards. The Challenge Award Class of 2012 represents a $9 Million investment in advanced prostate cancer research.
The 2012 Movember-PCF Challenge Awards
Karen Knudsen, PhD
Thomas Jefferson University
Interrogation of Aberrant DNA Repair in Sporadic Prostate Cancer
Co-investigators: Johann De Bono, MD, PhD, Royal Marsden Hospital; Felix Feng, MD, University of Michigan; Mark Rubin, MD, Weill Cornell Medical College.
What this means to patients: Understanding the extent and impact of alterations in DNA Damage Response pathways in prostate cancer patients will target specific DNA repair problems and allow effective Precision Medicine (tailored treatment regimens) based on molecular subtyping of patient DDR alterations matched to drug therapy.
Synopsis: DNA Damage Response (DDR) pathway alterations are changes in DNA repair mechanisms that promote genomic instability and have been associated with local and advanced prostate cancer. Dr. Knudsen and team will identify and comprehensively determine the frequency of abiraterone in DDR pathways at different stages of prostate cancer progression. They will determine the clinical relevance of these DNA repair defects in prostate cancer patients and their role in the development and progression of treatment-resistant prostate cancer. Previous studies showed that the DNA repair protein PARP1 is elevated in tumors of advanced prostate cancer patients. PARP1 is recruited to sites of androgen receptor function and is required for AR activity in both hormone-dependent and treatment refractory disease. PARP inhibition therefore has dual effects on cancerous cells; 1) impairs DNA repair in tumors and, 2) suppresses AR signaling—halting cancer progression. Dr. Knudsen and colleagues will evaluate effects of combination therapy with PARP inhibitors and next generation anti-androgens in treatment-resistant prostate cancer patients.
In addition, this team will determine the best positioning for PARP1-inhibitors in the clinical setting. Samples from prostate cancer patients undergoing clinical trials with PARP-inhibitors (NCI 9012 and TO-PARP trials) will be comprehensively examined for genomic biomarkers that indicate which patients will respond.These biomarkers will then be validated and developed into clinical-grade assays that will allow physicians to assign patients to receive these promising therapies.
John Isaacs, PhD
Johns Hopkins Medicine
First-in-Man Clinical Studies of Mesenchymal Stem Cell Based Therapy for Prostate Cancer
Co-investigators: Neil Bhowmick, PhD (Cedars-Sinai Medical Center); Jeffrey Karp, PhD (Harvard University); Samuel Denmeade, MD, PhD (Johns Hopkins Medicine); Alan Partin, MD, PhD (Johns Hopkins Medicine).
What this means to patients: This proposal could potentially lead to a novel system to deliver therapeutic agents—like slipping commandos in behind enemy lines—to metastatic sites of castration resistant prostate cancer while sparing toxicity to normal cells.
Synopsis: It is known that a type of stem cell derived from human bone marrow called mesenchymal stem cells (MSCs) homes to sites of prostate cancer after IV administration. Dr. Isaacs and team plan to use MSCs as a cell-based “Trojan Horse” to selectively deliver therapeutic agents to metastatic prostate cancer sites. The research team proposes a first-in-man clinical study to assess the ability of MSCs to home in sites of prostate cancer by infusing these cells into men with localized prostate cancer prior to prostatectomy. By evaluating prostate tissue, researchers will quantify the amount of MSCs in micro dissected sites of prostate cancer and normal prostate tissue. The investigators plan to generate modified MSC loaded with cytotoxic compounds and characterize their efficacy against human prostate cancer animal models.
Rob Reiter, MD
University of California, Los Angeles
Preventing Treatment Resistance by Co-Targeting Androgen Receptor and SRC/MEK1-Dependent Epithelial to Mesenchymal Transition
Co-investigators: Hong Wu, MD, PhD; Owen Witte, MD; Jiaoti Huang, MD, PhD; Matthew Rettig, MD; Steve Horvath, PhD, University of California, Los Angeles
What this means to patients: The successful development of a combination drug treatment strategy (inhibition of AR and EMT) should prevent metastasis and the development of treatment resistance.
Synopsis: Epithelial to mesenchymal transition (EMT) is a process by which cancer cells become migratory and invasive, resulting in cancer metastasis and treatment resistance. Dr. Reiter and colleagues hypothesize that interrupting the adaptive EMT response induced by treatment resistance will prolong disease free survival. The research team proposes a randomized Phase II, three-armed neoadjuvant (treatment prior to prostatectomy) clinical study comparing the inhibition of two upstream mediators of EMT with maximal androgen blockade in a population of high-risk patients. Data from the clinical trial and preclinical models will help to identify alternative drivers of EMT, new targets and new combinations to optimally inhibit metastasis.
The 2012 A. David Mazzone-PCF Challenge Awards
Martin Pomper, MD, PhD
Johns Hopkins Medicine
Promoter-Driven Molecular Radiotherapy for Prostate Cancer
Co-investigators: George Sgouros, PhD (Johns Hopkins Medicine); Paul Fisher, PhD (Virginia Commonwealth University).
What this means to patients: Relying upon recent advances in nanomedicine, in particular nanoparticle delivery, this project may provide a new prostate-cancer specific therapy in which a therapeutic transgene is delivered systemically to address both local and metastatic disease.
Synopsis: Dr. Pomper and colleagues propose a new method for treating both primary and metastatic prostate cancer using a nanoparticle harboring a gene promoter that is selectively active within prostate cancer cells. The promoter, known as the progression elevated gene-3 promoter (PEG-Prom), discovered by Dr. Pomper’s co-investigator, Dr. Paul Fisher, will be used to drive production of toxic proteins or proteins capable of concentrating therapeutic radionuclides within transfected cells. Additional studies will attempt to place proteins on the prostate tumor cell surface that can further be leveraged as therapeutic targets.
Bert O’Malley, MD
Baylor College of Medicine
Targeting the p160 Steroid Receptor Coactivators (SRCs) as a Novel Approach for the Treatment of Castration-Resistant Prostate Cancer
Co-investigators: Nancy Weigel, PhD; Ming-Jer Tsai, PhD; Francesco DeMayo, PhD; Michael Ittmann, MD, PhD; Nicholas Mitsiades, MD, PhD; Sean McGuire, MD, PhD, Baylor College of Medicine
What this means to patients: This study holds potential to identify a new class of potent inhibitors of CRPC development and treatment resistance to new drugs such as Zytiga (abiraterone) and Enzalutamide (MDV3100).
Synopsis: Androgen receptor (AR) signaling remains a key driver of prostate cancer growth and treatment resistance—highlighting the need for additional approaches to blocking AR signaling after complete androgen depletion with current medications. Dr. O’Malley and colleagues have identified a group of proteins called p160 SRCs (Steroid Receptor Cofactors) that are essential for AR activity and are associated with shorter time to disease recurrence and promote more aggressive disease. Investigators have screened roughly 400,000 compounds and identified a series of small molecule inhibitors of SRCs. They will test these compounds in prostate cancer cell lines and animal models to identify a panel of novel, first-in-class therapeutic SRC-targeting approaches to inhibit AR activity and treatment-resistant prostate cancer growth.
The 2012 PCF Challenge Awards
Massimo Loda, MD, PhD
Harvard Medical School
Shedding Light on Stromal-Epithelial Interaction in Prostate Cancer carcinogenesis and Mortality
Co-investigators: Lorelei Mucci, ScD (Harvard School of Public Health); Giovanni Parmigiani, PhD (Harvard University); William Watson, PhD (University College Dublin); Stephen Finn, MD, PhD (Trinity College Dublin); Meir Stampfer, MD, PhD (Harvard School of Public Health); Ove Andren, MD, PhD (University of Orebro).
What this means to patients: Studying the interaction of tumor cells with normal cells in their vicinity will shed light on mechanisms of cancer progression and treatment resistance. These studies will help in the identification of aggressive disease-specific markers for better patient stratification and potential new drug targets.
Synopsis: Cancer cells, their neighboring stromal cells (non-tumor, connective tissue cells) and interactions between the two compartments form the tumor microenvironment. Crosstalk between cancer (epithelial) and stromal cells is implicated in carcinogenesis and disease progression, but is not well understood. Dr. Loda and his team of researchers propose to study the role of the stroma in the initiation and progression of prostate cancer. They will identify critical cellular pathways in the stromal-epithelial microenvironment associated with the progression to invasive disease, based on gene expression and regulatory RNA expression in patient tissues. Using these aggressive disease-specific signatures and statistical approaches, they propose to identify stromal markers of prostate cancer progression targetable by currently available drugs.
Richard Mithen, PhD
Quadram Institute Bioscience
Sulforaphane and Prostate Cancer Interception
Co-investigators: Colin Cooper, PhD, University of East Anglia and Maria Traka, PhD, Quadram Institute Bioscience
What this means to patients: Consumption of sulforaphane in broccoli may provide validated intervention to prevent progression of prostate cancer in active surveillance patients, alleviating overtreatment.
Synopsis: Cellular oxidative stress can result from an imbalance in cellular processes and its inability to readily eliminate toxic intermediates of normal cellular reactions, and may cause disruptive mutations, leading to metabolic transformation and cancer. Certain dietary factors, such as red meat and dairy products, can enhance oxidative stress. Other dietary factors, such as sulforaphane obtained from broccoli, can reduce oxidative stress and prevent or reverse metabolic deregulation. Dr. Mithen and his team propose to undertake a human intervention study to test the hypothesis that sulforaphane can alter the metabolism and gene expression of at-risk, non-cancerous tissues in active surveillance patients in a manner that would reduce the probability of the emergence of aggressive clones.
The study will examine global gene expression and metabolite profile from prostate biopsies before and after a 12-month intervention, combined with analyses of metabolites in plasma and urine from active surveillance patients. The study will provide evidence for the role of sulforaphane in metabolic transformation and will identify the underlying mechanisms by which sulforaphane can reduce the risk of aggressive prostate cancer.
Shaomeng Wang, PhD
University of Michigan
Development of Small Molecule Inhibitors of the ERG Transcription Factor in Prostate Cancer
Co-investigators: Arul Chinnaiyan, MD, PhD; Jeanne Stuckey, PhD; George Wang, PhD; Chao-Yie Yang, PhD; Bushra Ateeq, PhD, University of Michigan
What this means to patients: These promising inhibitors of an important prostate cancer driver protein, once considered undruggable, will provide a new therapeutic agent for Lupron-resistant prostate cancer, both in early and late disease progression.
Synopsis: The transcription factor ERG, a protein that binds DNA and initiates gene expression, is an oncogenic driver in both hormone-sensitive and treatment-resistant prostate cancer. ERG has so far been considered undruggable. Dr. Wang and colleagues have designed small, cell-penetrating synthetic peptide molecules that function as potent inhibitors of ERG both in vitro and in vivo. The peptides specifically disrupt ERG-DNA interaction, prevent DNA damage and cell invasion and suppress tumor growth and metastasis in animal models of prostate cancer. Researchers propose to generate three-dimensional crystal structures of ERG in complex with these peptides, which will allow optimization of the ERG inhibitors by improving the pharmacology of these drug candidates.
Charles Swanton, MD, PhD
University College London
Defining the Clinical Relevance of Intratumor Heterogeneity and Subclonal Evolution in Prostate Cancer
Co-investigators: Johann De Bono, MD, PhD (Royal Marsden Hospital); Mark Emberton, MD, MBBS (University College London); Marco Gerlinger, MD (CRUK London Research Institute); Hashim Ahmed, MD, MBBS (University College London); Gerhardt Attard, PhD (Royal Marsden Hospital).
What this means to patients: Understanding intratumoral heterogeneity will better inform precision medicine regimens for the treatment of prostate cancer patients.
Synopsis: Recent groundbreaking research on renal cell carcinoma by Dr. Swanton’s group showed that individual tumors demonstrate extensive genetic heterogeneity. This diversity among multifocal tumors within an organ can make personalized treatment more complex. Dr. Swanton and his team of investigators propose to investigate the role of intratumor heterogeneity (ITH) in the progression to metastatic disease and treatment-resistance in prostate cancer patients. They will perform deep genome sequencing on multiple biopsies representing individualized foci of primary and metastatic tumors from patient cohorts with high-grade, localized metastatic and intermediate tumors to determine ITH in prostate cancer and its possible role in governing metastatic potential. This project could lead to the discovery of ITH-based markers of disease progression and prioritize drivers of heterogeneity and metastatic disease for drug discovery.