Nearing a Goal of 100 Young Investigators, the Prostate Cancer Foundation Expands Global Research Enterprise
A Nearly $3.4 Million Investment Raises the Total of PCF Young Investigators to 89
February 22, 2012 -- Committed to funding the most innovative minds in the field of prostate cancer research, the Prostate Cancer Foundation (PCF) expanded its global knowledge exchange in 2012 and will be expanding its research efforts in new countries later this year. A total of 15 competitive research grants have been awarded to-date in 2012, bringing the total of Young Investigators awarded to 89.
Young Investigator awards are designed to promote long-term careers in the field of prostate cancer by providing three year grants for transformational research focused on prostate cancer treatments to improve patient outcomes. Since 2007, PCF has invested more than $20 million in Young Investigator grants.
“PCF-supported young investigators have changed the scope of prostate cancer research, advancing treatment sciences and improving the lives of patients worldwide,” said Howard Soule, PhD, chief science officer and executive vice president of PCF. “It is with great pride and appreciation that PCF can now announce our young investigator program spans across six countries and 42 research institutes.”
Each Young Investigator recipient is awarded $225,000 over a three-year period. Funding is also matched dollar-for-dollar by each recipient’s research institution, making the total award worth $450,000. A total of 148 applicants applied for 2012 PCF Young Investigator funding and over 74 global professionals reviewed these applications, which addressed 29 specialized scientific areas within prostate cancer research.
Buoyed by PCF support and the research it enables, many funded researchers go on to win additional government and privately funded grants to help advance the field of prostate cancer research.
The 15 new 2012 PCF Young Investigator Award recipients are:
The 2012 Robbins Family – PCF Young Investigator Award
Tarek Bismar, MD
University of Calgary
Mentor: Peter Forsyth, MD
The two most common genomic aberrations in prostate cancer are the ERG gene rearrangements and PTEN deletion. TMPRSS2-ERG represents the most common form of ERG rearrangements. It is an aberration in the genome of prostate cancer cells created when two distinct genes, TMPRSS2 and ERG (found in two different regions of DNA), are shuffled around and erroneously juxtaposed. PTEN is a tumor suppressor gene (a gene that protects against cancer) and is often deleted from the DNA code of prostate cancer cells. Dr. Bismar’s work centers on identifying the molecular differences between prostate cancer cells that harbor these genetic alterations and prostate cancer cells that do not. To understand how TMPRSS2-ERG and PTEN deletion change the behavior of prostate cancer cells, Dr. Bismar compared the molecular profile of tissue samples from patients who were either positive or negative for the two genetic alterations. In his comparative analysis he has identified a list of genes that are either elevated or depleted in prostate cancers with in relation to their TMPRSS2-ERG and PTEN status. So far, Dr. Bismar has discovered 5 novel, candidate prostate cancer biomarkers (a molecule that indicates a biological process or pathogenesis) that are discriminate benign tissue, from localized prostate cancer and lethal prostate cancer. Some of these genes may also represent new therapeutic targets for patients with prostate cancer. Dr. Bismar and his team are currently working on validating their findings in larger studies.
The 2012 Sternlicht Family Foundation – PCF Young Investigator Award
Dimple Chakravarty, PhD, DVM
Weill Cornell Medical College
Mentor: Mark Rubin, MD
Androgens and Androgen Receptor (AR) fuel prostate cancer. Therefore, androgen deprivation therapy (ADT) is usually the preferred treatment modality. However, prostate tumors employ multiple alternate mechanisms to bypass the need for androgens or AR, progressing on the path to castration-resistance. Several recent studies in Dr. Mark Rubin’s laboratory and others have shown that prostate tumors express the Estrogen Receptor a (ERa) at early onset of the disease. However, the role of ERa in prostate cancer still remains unclear. Dr. Dimple Chakravarthy proposes to study this ERa-lncRNA axis in prostate cancer. She will validate the relevance of ERa and ERa-regulated lncRNA as prognostic biomarkers of tumor progression and therapy response. Dr. Chakravarthy will also evaluate the therapeutic potential of knocking down lncRNAs using nanoparticles. She will test the combinatorial therapy with anti-androgens and anti-lncRNA medications to control prostate cancer growth and metastasis.
The 2012 John A. Moran – PCF Young Investigator Award
Junjie Feng, PhD
Wake Forest University
Mentor: Jiangfeng Xu, MD, PhD
Androgen Receptor (AR) mediates the action of the male hormones, androgens by binding to genomic DNA and regulating gene expression. The precise sites on the genome to which AR binds are called AR Response Elements (AREs) or AR binding sites. Recent reports have shown that approximately 1/3 of all known prostate cancer risk-associated genetic variants reside in these AR binding sites. Genetic variations that predispose a man to prostate cancer are usually found to be concentrated in the specific DNA regions to which AR binds. Other PCF-funded studies have shown that AR signaling is causally related to the formation and/or expression of recurrent oncogenic gene fusions (e.g. TMPRSS2-ERG), suggesting that altered AR signaling caused by inherited genetic changes may have a profound impact on the pathogenesis and progression of prostate cancer. To test this hypothesis, Dr. Junjie Feng proposes to 1) identify genome-wide AR binding sites and prostate cancer-specific fusion genes; 2) prostate cancer risk/aggressiveness-associated genetic variants that are located within AR binding sites, and 3) assess whether these genetic variants cause altered AR signaling and influence the formation and/or expression of fusion genes.
The 2012 Steve Wynn – PCF Young Investigator Award
Stephen Finn, MBBS, PhD
University of Dublin, Trinity College
Mentors: John O’Leary, MD, PhD and Lorelei Mucci, ScD, MPH
Genetic information flows from genes on DNA as follows: gene (DNA)→RNA→protein. RNAs, which are the products of DNA, either give rise to proteins (coding RNAs) or do not produce proteins (non-coding RNAs). However, these non-coding RNAs (ncRNAs) are functional molecules that perform specialized roles in the cell, such as regulation of gene expression. Recent reports have provided evidence for the role of small ncRNAs in the development and progression of prostate cancer. Dr. Stephen Finn proposes to identify the ncRNA repertoire associated with aggressive prostate cancer (defined by failure to respond to Androgen Deprivation Therapy (ADT); disease specific mortality etc.). Dr. Finn’s research will identify the role of ncRNAs in aggressive prostate cancer and correlate these to prostate cancer-specific outcome, laying the groundwork for the design of novel ncRNA-targeting therapeutics. These studies will also provide reliable biomarkers of aggressiveness which can help in patient stratification for therapy and more efficient disease monitoring.
The 2012 Lowell Milken – PCF Young Investigator Award
Terence Friedlander, MD
University of California, San Francisco
Mentors: Charles Ryan, MD and Pamela Paris, PhD
One of the medications used for androgen deprivation therapy (ADT) is the recently FDA-approved Abiraterone (Zytiga) which targets the biosynthesis of androgens in the adrenal glands and more importantly, in the tumor itself. Though patients respond well to Abiraterone and other ADT medications, almost all develop resistance to this therapy and their cancers progress. This stage of treatment resistance is termed castration resistant prostate cancer (CRPC). CRPC is hypothesized to develop due to either 1) the increased production of androgens by the tumor itself, or 2) mutations in the AR that make it independent of the presence/absence of androgens. Dr. Terence Friedlander proposes to investigate the specific genetic changes in prostate cancer cells that occur during the development and progression of castration resistance. During the course of these investigations, Dr. Friedlander will collect metastatic tumor biopsies and circulating tumor cells from patients to evaluate the precise mechanisms underlying Abiraterone resistance. A better understanding of the mechanisms that cause CRPC development will allow clinicians to optimize and sequence the new therapies available for the treatment of CRPC.
The 2012 Mortimer Sackler – PCF Young Investigator Award
Matthew Galsky, MD
Mount Sinai School of Medicine
Mentors: William Oh, MD and Michael Ohlmeyer, PhD
The protein FOXO1 regulates cellular growth and survival pathways in normal cells. To effect its function, FOXO1 has to move from its location outside the nucleus (the cellular compartment that harbors the genome (DNA)) to inside the nucleus. Prostate cancer (PCa) cells, however, redirect the cellular localization of FOXO1 and sequester it outside of the nucleus, in its inactive form. Scientific approaches to relocalize FOXO1 to the nucleus represent a novel strategy for the treatment of prostate cancer, especially treatment resistant PCa. A group of chemical compounds called the tricyclic neuroleptics have previously been shown to inhibit the transport of FOXO1 proteins from the nucleus.
Under this PCF-funded study, Dr. Galsky will explore the anti-cancer effects and mechanism of action of these novel compounds in preclinical prostate cancer models. He will also study circulating tumor cells from castration-resistant prostate cancer (CRPC) patients to identify suitable pharmacodynamic markers that can efficiently report the localization of FOXO1 in patient tumors. Dr. Galsky’s research will set the stage for early phase clinical trials of these experimental medications for the treatment of advanced prostate cancer.
The 2012 Leon and Debra Black – PCF Young Investigator Award
Kalpana Kannan, PhD
Baylor College of Medicine
Mentors: Laising Yen, PhD and Michael Ittman, MD, PhD
Chimeric RNAs are the fused products of two different genes. Recent studies have shown that chimeric RNAs are present in normal cells and their presence allows the limited number of human genes to encode a substantially larger number of RNAs and proteins, forming an additional layer of cellular complexity. Dr. Kalpana Kannan and her team recently identified 27 novel, highly recurrent chimeric RNAs in prostate cancer. Their results showed that these chimeric RNAs occurred at a higher frequency in cancer compared to normal cells. These preliminary findings show that chimeric RNAs form a potentially unique class of molecular alterations in prostate cancer. She will also evaluate the significance of these chimeric RNAs in prostate cancer diagnosis and prognosis. If validated, these chimeric RNAs will serve as useful biomarkers for the identification of prostate cancer subtypes. New therapeutic targets for advanced prostate cancer may also emerge from this work. Dr. Kannan proposes to study the biological significance and potential clinical applications of these recurrent RNAs in prostate cancer.
The 2012 Michael Milken – PCF Young Investigator Award
Stacey Kenfield, ScD
Brigham and Women's Hospital, Harvard University
Mentors: June Chan, ScD and Meir Stampfer, MD
Under the mentorship of Dr. Chan and Dr. Stampfer, Dr. Kenfield has evaluated whether diet and lifestyle factors after prostate cancer diagnosis are associated with disease progression in men with localized disease. This proposal is a natural extension of this work and will focus specifically on men with advanced and recurrent prostate cancer and whether diet and lifestyle factors can reduce risk of distant metastasis or prostate cancer-specific mortality. The ultimate goal of this work is to translate these results into cancer survivorship tools for the community. First, Dr. Kenfield will develop a prognostic score for prostate cancer mortality and other outcomes that will incorporate clinical, pathological, and lifestyle variables. The analyses will be performed in two large studies with extensive data available on lifestyle factors: the Health Professionals Follow-Up Study and CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor) and the findings could be important in guiding physician counseling of men with prostate cancer. Second, she will examine whether diet and other lifestyle factors may reduce progression in men with advanced or recurrent prostate cancer, which may elucidate strategies for reducing progression of disease. Third, she will build novel web-based cancer survivorship tools and use them in a clinical trial to determine if a web-based intervention program can help men with prostate cancer adopt healthier behaviors associated with reduced prostate cancer mortality. If successful, it could be administered efficiently in a variety of settings and scaled up to reach larger populations of men with prostate cancer.
The 2012 Steve Wynn – PCF Young Investigator Award
Hung-Ming Lam, PhD
University of Cincinnati
Mentor: Shuk-Mei Ho, PhD
The protein G-protein coupled receptor 30 (GPR30) regulates several signaling pathways governing cell growth, migration, etc. In previous studies, Dr. Hung-Ming Lam has shown that the chemical compound G1 tightly binds GPR30 in highly selective manner and this G1-GPR30 complex inhibits the growth of prostate cancer cells. In this study, Dr. Lam proposes to evaluate the efficacy of GPR30 inhibition by G1 for the treatment of castration-resistant prostate cancer (CRPC). Previous studies have shown that the expression of GPR30 in cells shows an inverse correlation with the levels of androgens. The recently FDA-approved medication Abiraterone acetate (Zytiga) inhibits androgen synthesis. Dr. Lam proposes to evaluate combinatorial therapy with G1 and Abiraterone to treat prostate cancer in a two-pronged fashion: 1) delaying cancer relapse and the emergence of metastatic CRPC and, 2) extending the time to chemotherapy in patients with advanced cancer. Dr. Lam also aims to determine the levels of GPR30 before and after ADT in human specimens with bone and lymph node metastases. Her studies will help define a group of patients most suitable for GPR30-targeted therapy.
The 2012 John A. Moran – PCF Young Investigator Award
Heather Montie, PhD
Thomas Jefferson University, Jefferson Medical College
Mentors: Diane Merry, PhD and Karen Knudsen, PhD
Prostate cancer is driven by the male hormones, androgens which mediate their activity through the androgen receptor (AR). Unfortunately most prostate cancerous tumors progressively become resistant to the preferred treatment modality, androgen deprivation therapy. One of the mechanisms proposed to enhance the activity of androgen receptors in castration-resistant prostate cancer, even in the absence of androgens, is the addition of a small chemical group/moiety to the AR protein. This modification of AR is termed ‘acetylation’ and is proposed to convert the protein to a ‘super AR.’ However, there is currently no experimental data to show that AR acetylation directly enhances AR-dependent prostate cancer cell viability. Dr. Heather Montie proposes to evaluate the role of AR acetylation in the enhanced AR functional activity central to CRPC. She will study the precise mechanisms by which this modification of AR enhances its cancer-promoting activity. Dr. Montie will also validate the potential of AR acetylation as a therapeutic target for castrate-resistant prostate cancer.
The 2012 Lori Milken – PCF Young Investigator Award
David Mulholland, PhD
University of California, Los Angeles
Mentor: Hong Wu, MD, PhD
The use of anti-androgens is standard treatment for prostate cancer patients in the management of PSA recurrence and metastatic disease. However, all men with metastatic prostate cancer become castrate resistant (CRPC) during which time conventional androgen deprivation therapy is no longer effective. This indicates that cancerous cells may become less reliant upon androgen or androgen receptor (AR) mediated signaling and more dependent upon alternative survival pathways either as a consequence of treatment or during the natural disease evolution.
Recent studies on stem cells in in vitro experimental systems have shown that the deletion of important housekeeping genes can give rise to castration-resistant prostate cancerous tumors. In an extension to these observations, Dr. Mulholland proposes to study whether stem/progenitor cells with tumorigenic capabilities may acquire independence from the androgen/AR signaling axis and whether such cells are a potential source of the initiation of prostate cancer or the progression of aggressive metastatic prostate cancer. The short term goal of this proposal is to ascertain whether cancer initiating cells with impaired AR function can reconstitute disease progression in a manner that is entirely autonomous from AR function. The long term goal is the identification of alternative survival pathways, and therefore relevant targets, for cancers that are non-responsive to anti-androgen therapy.
The 2012 Heritage Medical Research Institute – PCF Young Investigator Award
Paul Nguyen, MD
Dana-Farber Cancer Institute, Harvard University
Mentors: Anthony D’Amico, MD, PhD and Phillip Kantoff, MD
One of the most pressing dilemmas in the care of patients with prostate cancer is the ability to distinguish indolent from aggressive disease. However, considering the complexity of the disease, it is important to note that no single marker or diagnostic modality will likely account for all of the variability in prostate cancer outcome. In this proposal, Dr. Nguyen proposes to combine multiple markers of disease outcome into a single prognostic model to achieve maximum predictive accuracy. The overall goal of Dr. Nguyen’s efforts is to identify and integrate underlying genetic differences (polymorphisms), serum biomarkers, imaging characteristics and novel clinical factors to enhance the predictive ability of the current tools. He will study prostate cancer patient blood and tissue samples to identify biological and clinical predictors of outcome. Dr. Nguyen’s research will potentially provide a single unified system that integrates multiple types of prognostic information. These results will ultimately allow patients to understand their risk of cancer recurrence with greater certainty, and make better treatment choices.
The 2012 Foundation 14 – PCF Young Investigator Award
Luke Selth, PhD
University of Adelaide, Dame Roma Mitchell Cancer Research Laboratories
Mentor: Wayne Tilley, PhD
Androgen receptors mediate the action of the male sex hormone and fuel prostate cancer—which is why the primary treatment for prostate cancer is androgen deprivation therapy. Unfortunately, almost all patients develop resistance to ADT and their cancers resume growth despite hormone therapy. Recent research has revealed that highly active variants of AR rather than the normal AR protein may be the key drivers of CRPC and androgen receptor variants usually lack the ability to bind androgens. Therefore, androgen receptor variants (ARVs) can easily drive prostate cancer, even during ADT. Dr. Luke Selth proposes to study the molecular mechanisms by which AR variants initiate and drive CRPC. He will identify the precise genes activated by AR variants to promote CRPC. Dr. Selth will also determine the co-factors that regulate ARV-driven CRPC. Dr. Selth’s research will be a crucial next step in the development of strategies to counter the role of AR variants in CRPC development.
The 2012 Chris and Felicia Evensen – PCF Young Investigator Award
Karen Sfanos, PhD
Johns Hopkins University School of Medicine
Mentors: Angelo DeMarzo, MD, PhD and William Nelson, MD, PhD
The major risk factors for the development of prostate cancer are advanced age, family history, and African-American race; however, there is also a distinct geographic distribution to prostate cancer incidence, and an apparent increase in risk with the adoption of a “Westernized” lifestyle. Therefore, there is a high probability that prostate cancer development involves environmental factors in addition to hereditary factors. Two major environmental factors shown to have a strong linkage with prostate cancer are dietary carcinogens, and chronic infections that cause inflammation, which over time leads to the initiation of prostate cancer. Dr. Sfanos proposes to study the combined effects of dietary carcinogens and tumor-promoting inflammation in preliminary prostate cancer initiation and/or tumor progression.
The 2012 David H. Koch – PCF Young Investigator Award
Hans David Ulmert, MD, PhD
Memorial Sloan-Kettering Cancer Center
Mentor: Jason Lewis, PhD
The androgen receptor (AR) signaling pathway is a key component in the progression of prostate cancer to its lethal form, castration resistant prostate cancer (CRPC). Several, recently developed, potent inhibitors of AR-signaling have shown encouraging, though highly variable responses in patients. One of the reasons for this inconsistent response is the biological heterogeneity of different cancerous lesions in the same patient. Therefore, documenting the response of individual tumor lesions to therapy is important for prostate cancer clinical management (e.g. understanding the overall patient therapeutic response; decision-making for dose escalation or designing therapy combinations that more completely suppress AR-signaling etc.). Dr. Ulmert aims to evaluate the efficiency of 89Zr-5A10-PET for measuring tumor response to next-generation androgen-deprivation therapeutics such as MDV3100 and Abiraterone. Dr. Ulmert also proposes to conduct first-in-man studies to determine if 89Zr-5A10 can detect CRPC.
If successful, this radiotracer (89Zr-5A10) will potentially be an important molecular imaging tool to definitively measure AR inhibition in individual tumor lesions in response to AR pathway-directed therapies. Since the complexities of metastatic CRPC still remain unclear, understanding the biology of responsive and resistant lesions could provide a clear rationale for the individualization of patient care, impacting decisions for dose escalation and/or combination therapy to completely suppress AR signaling.
About the Prostate Cancer Foundation
The Prostate Cancer Foundation (PCF) is the world’s leading philanthropic organization funding and accelerating research. Founded in 1993, PCF has generated more than $475 million and provided funding to over 1,600 research projects at nearly 200 institutions in 15 countries around the world. PCF advocates for greater awareness of prostate cancer and more efficient investment of governmental research funds supporting transformational cancer research. Our efforts have helped produce a 20-fold increase in government funding for prostate cancer. More information about PCF can be found at pcf.org.