Prostate Cancer Research
Young Investigator Award Recipients 2011
The PCF Young Investigator Award-Class of 2011 recipients are:
The 2011 John F. Scarpa – PCF Young Investigator Award
In previous studies, Dr. Joshi Alumkal has shown that the LSD1 (Lysine-specific demethylase 1) protein is a driver of prostate cancer cell growth and survival and that LSD1 is upregulated in aggressive prostate cancers. Thus, LSD1 suppression might provide a unique opportunity to control prostate cancer progression. Dr. Alumkal’s work will clarify the LSD1 gene pathways that account for LSD1’s effects, and he will evaluate small molecule inhibitors of LSD1. His results will lead the way to Phase I clinical trials of LSD1 inhibitors in patients with metastatic castration-resistant prostate cancer-the lethal form of this disease.
Mentors: Joe Gray, PhD and Tomasz Beer, MD
The 2011 Emilio Bassini – PCF Young Investigator Award
Dr. Bajor, under the mentorship of Dr. June and Dr. Vonderheide will generate engineered T-cells directed to kill prostate tumors. He plans to express PSMA (Prostate-Specific Membrane Antigen)-recognizing molecules on the surface of patient T-cells. PSMA is abnormally overexpressed on prostate cancer cells in high grade and hormone-refractory, metastatic disease. It is an established target in advanced prostate cancer, being exploited for the development of direct immunotherapy and imaging for this disease. If successful, the findings from this proposal will lead to the development of a cellular therapy for malignant hormone refractory prostate cancer that will destroy recurrent tumor while conferring persistent protection against newly arising PSMA-expressing tumors in patients.
Mentors: Robert Vonderheide, MD, DPhil and Carl June, MD
The 2011 Peter and Laurie Grauer – PCF Young Investigator Award
Dr. Christopher Barbieri, under the mentorship of Dr. Mark Rubin has identified a unique subclass of prostate cancer. Recurrent mutations in the gene for SPOP define this unique subset of patients. SPOP mutations result in the loss of the critical functions leading to increased invasiveness of the tumor which facilitates metastatic spread. Dr. Barbieri’s research will further inform subtyping of prostate cancer patients. This classification, in time, will support personalized treatment for patients. Discovery of SPOP inhibitors holds potential for a new therapy for metastatic prostate cancer.
Mentor: Mark Rubin, MD
The 2011 Albert Fuss – PCF Young Investigator Award
The 2011 Cayre Family Foundation – PCF Young Investigator Award (second year)
The 2011 Robert Kraft – PCF Young Investigator Award (third year)
More than 50% of prostate cancers have a common underlying rearrangement of genes that leads to the abnormal fusion of two genes, TMPRSS2 and ERG and the overexpression of ERG. ERG belongs to a family of proteins called oncogenes that activate several genes to drive the progression of cancer. Therefore, inhibiting ERG activity has far-reaching implications for the discovery of new prostate cancer therapeutics. Unfortunately, oncogenes such as ERG are generally thought to be ‘undruggable’, being difficult to inhibit with medicinal compounds. Brenner’s work will add understanding of how TMPRSS2:ERG gene fusions promote prostate cancer which will form the basis of a new anti-neoplastic drug discovery program.
Mentor: Arul Chinnaiyan, MD, PhD
The 2011 David H. Koch – PCF Young Investigator Award
A subset of prostate cancer cases (~10%) overexpresses the protein SPINK1. SPINK1 overexpression is associated with a poor outcome for prostate cancer and is thought to be associated with a lethal variant of the disease. However, the mechanism of overexpression of this protein in this subgroup of aggressive prostate cancer remains unknown. Normally, SPINK1 is expressed only in gastroenteric organs such as the pancreas. The master regulator of SPINK1 expression in these organs is HNF4G (Hepatic Nuclear Factor 4 Gamma) which governs normal liver and colon development. Dr. Chen’s previous research has shown that SPINK1-positive prostate tumors also express abnormally excessive amounts of HFN4. Dr. Chen’s studies will potentially validate the protein HNF4G in the SPINK1-positive subset of prostate cancer as a prognostic biomarker for aggressive disease and as a target for therapeutic intervention.
Mentors: Howard Scher, MD and Charles Sawyers, MD
The 2011 Judy and Ronald Baron – PCF Young Investigator Award
The landscape of therapeutic options for men with advanced prostate cancer is evolving at an unprecedented rate. Multiple novel agents extend survival and quality of life via independent, non-overlapping mechanisms; but all are expensive, and many questions regarding their optimal use, timing, sequencing, and combination have not yet been answered. CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor) is a registry which since 1995 has accrued men with prostate cancer. This open cohort now including over 14,000 men with prostate cancer treated across the United States, mostly in community-based practices, has been the source of many invaluable studies in health services and outcomes research. The registry accrues men at time of diagnosis, and historically has focused for the most part on localized or locally-recurrent disease. Dr. Cooperberg proposes to expand the CaPSURE framework to include later stages of disease, in order to study rapidly emerging prostate cancer management trends, clinical practice patterns and outcomes for men with advanced prostate cancer.
Mentors: Peter Caroll, MD and Charles Ryan, MD
The 2011 Joe and Ali Torre – PCF Young Investigator Award (first year)
The 2011 Bonnie Pfeifer Evans – PCF Young Investigator Award (second year)
The 2011 Todd Boehly – PCF Young Investigator Award
The first medical treatment for metastatic prostate cancer is Androgen Deprivation Therapy (ADT). Unfortunately, nearly 100% of patients become refractory to this treatment and their cancer progresses to androgen-independent, castration-resistant stage (CRPC). Eliminating the CRPC-regenerating tumor cell population might inhibit disease recurrence; however, it is unclear if such a population exists. Dr. Andrew Goldstein has developed a direct transformation assay that can re-program normal human prostate cells to reconstitute human prostate cancer in immunodeficient mice. Ultimately, he proposes to use this model to investigate various genetic drivers to castration resistance and is studying the mechanisms that lead to the development of castration-resistant prostate cancer with a focus on treatment targets that will reverse lethality of the disease.
Mentor: Owen Witte, MD
The 2011 Richard and Ellen Sandler – PCF Young Investigator Award
Genomic rearrangements that lead to the juxtaposition of two non-neighbor genes such as TMPRSS2 and ERG are some of the most common alterations in prostate cancer. The origin of these rearrangements remains unclear. There is growing evidence to suggest a new model for the generation of these genomic rearrangements that requires stimulation of normal prostate cells with androgens resulting in the formation of breaks in the DNA to recruitment of the DNA break-repair machinery to imperfect DNA repair that allows two un-related genes to fuse together and promote cancer progression. Dr. Haffner is evaluating the roles of TOP2B and the DNA damage/repair pathways in cancer progression which may result in a new strategy for therapeutically targeting advanced prostate cancer. In the second part of his research, he will exploit AR-signaling associated DNA breaks for therapeutic targeting in the setting of advanced prostate cancer.
Mentor: Srinivasan Yegnasubramanian, MD, PhD
The 2011 Kovler Family Foundation – PCF Young Investigator Award
Dr. Joshu and colleagues previously observed that men who gained weight circa the time of prostatectomy were twice as likely to recur as compared with men who maintained their weight. The biological mechanism underlying this association remains unclear. To assess this association, Dr. Joshu, is evaluating two novel predictors of prostate cancer risk and prognosis: telomere length and inflammation. Dr. Joshu will evaluate whether weight gain and obesity are associated with 1) variable telomere length in cancer cells among patients surgically treated for clinically localized prostate cancer; and 2) the extent of inflammation present in benign and malignant prostate tissue among patients surgically treated for clinically localized PCa. This work may ultimately provide physicians and men with prostate cancer with a strategy to reduce risk of prostate cancer recurrence by avoiding or intervening on weight gain.
Mentors: Elizabeth Platz, ScD and Angelo DeMarzo, MD, PhD
The 2011 PCF-Hellenic Fund Young Investigator Award
To address the challenges of resistance to therapy and cancer progression in CRPC patients, it is important to study the underlying mechanisms. Dr. Maria Karlou proposes to address these challenges by studying cancer progression in mouse models and cell-based models of human prostate cancer. These studies will inform the design of better therapies for castration-resistant prostate cancer. Dr. Karlou is establishing a new Tissue Derivatives Laboratory at the University of Athens. She proposes to study mechanisms of resistance to therapy in castration-resistant prostate cancer patients which may improve treatment strategies for patients with advanced, castration-resistant prostate cancer.
Mentor: Christopher Logothetis, MD
The 2011 Ben Franklin – PCF Young Investigator Award
T-cells are a type of fighter blood cells that activate a ‘killing’ mechanism in response to exposure to a foreign material such as a pathogen or new proteins on the surface of a tumor cell. Dr. Carl June at the University of Pennsylvania will generate engineered T-cells directed to kill prostate tumors. He plans to express PSMA (Prostate-Specific Membrane Antigen)-recognizing molecules on the surface of patient T-cells. If successful, the findings from this proposal will lead to the development of a cellular therapy for malignant hormone refractory prostate cancer that will destroy recurrent tumor while conferring persistent protection against newly arising PSMA-expressing tumors in patients.
Mentor: Carl June, MD
The 2011 Steven A. and Alexandra M. Cohen – PCF Young Investigator Award
Circulating Tumor Cells (CTCs) detach from metastatic tumor sites and can be isolated from patient blood specimens. CTCs are good predictors of metastatic tumor biology. Dr. Lee proposes to study CTCs from the blood of castration-resistant prostate cancer (CRPC) patients to identify features that can predict response/resistance to specific treatments. RANKL and AR signaling pathways are two critical systems that drive prostate cancer progression and metastases to bone. Denosumab is an inhibitor of RANKL signaling and Abiraterone targets androgen receptor (AR) signaling. Both agents are FDA-approved. Dr. Lee proposes to study RANKL and AR signaling in CTCs from PCa patients and will study tumor response by assessing PSA and/or measurable disease responses. This work is a step forward in personalizing Denosumab and Abiraterone therapy for advanced CRPC patients. CTC analysis of drug sensitivity will inform better use of these two new and very promising treatments.
Mentor: Matthew R. Smith, MD, PhD
The 2011 Elaine Wynn – PCF Young Investigator Award
PTEN (phosphatase and tensin homologue on chromosome 10) is a tumor suppressor that is commonly lost in several cancers. Loss of PTEN is one of the most common molecular aberrations in prostate cancer and is frequently associated with high risk disease. Routine and accurate identification PTEN inactivation may potentially serve as a prognostic biomarker in prostate cancer and might also help select appropriate treatment for patients. Dr. Lotan has developed a sensitive assay to detect PTEN loss in prostate cancer. This test will assist pathologists in identifying early, potentially aggressive prostate cancer, the results of which will inform decisions on personalizing therapy.
Mentors: Angelo DeMarzo, MD, PhD and Elizabeth Platz, ScD
The 2011 Joel Pashcow – PCF Young Investigator Award
The Gleason score (derived from the microscopic appearance of prostate tumor tissue) is currently the only reliable predictor for prostate cancer prognosis and treatment. Dr. Penney has previously identified a signature of 157 genes associated with lethal disease, which can help distinguish high from low Gleason grade prostate tumor tissue. Her previous research has also identified pathways differentially enriched in high and low grade disease, generating hypotheses for biological mechanisms that may underlie disease progression. Dr. Penney proposes to advance this molecular Gleason signature into clinical validation and will investigate the biological pathways that underlie tumor aggressiveness. If validated in biopsy tissue, Dr. Penney’s 157-gene signature will improve outcome prediction and clinical decision making for PCa patients at the time of diagnosis. Studies on the metabolic pathways associated with Gleason grade may lead to discovery of new targets for drug development and may serve as tools for monitoring patients in the context of active surveillance.
Mentors: Massimo Loda, MD and Meir J. Stampfer, MD, DrPH
The 2011 Richard B. Handler – PCF Young Investigator Award
A critical unmet need for prostate cancer research is the identification of aggressive tumors at an early stage while potentially curable and distinguishing them from indolent tumors to avoid over-treatment of clinically insignificant disease. The study of chemical modifications to DNA is called epigenetics. Prostate cancer is driven by several epigenetic alterations and genetic abnormalities. Epigenetic alterations can be detected non-invasively with high sensitivity in peripheral blood and urine. Therefore, detecting prostate cancer-specific epigenetic alterations holds potential for both improved prostate cancer diagnostics and patient risk-stratification. Dr. Perry is developing blood and urine biomarkers for the non-invasive detection of aggressive prostate cancer. Dr. Perry’s results will potentially help discern aggressive, high-risk prostate cancer from indolent disease. The identification of an epigenetic pattern of DNA alterations that is specifically associated with aggressive prostate cancer holds promise for alleviating the burden of over-treatment of indolent disease.
Mentors: William Watson, PhD and Donal Hollywood, MD PhD
The 2011 Lori Milken – PCF Young Investigator Award
The success of next-generation androgen receptor (AR) inhibitors for treatment of castration-resistant prostate cancer validates the critical role played by AR in advanced disease. Unfortunately, patients develop resistance to AR-targeted therapy. One proposed mechanism of resistance to AR inhibition is through dysregulation of a central cellular signaling pathway known as PI3K. Research from Dr. Neal Rosen’s group and other laboratories has shown that PI3K and AR are the two most frequently activated signaling pathways in prostate cancer. These signaling pathways regulate each other through reciprocal feedback such that inhibition of one activates the other, leading to treatment-resistance and cancer progression. Dr. Rathkopf is conducting preclinical and initial clinical investigation of combination therapies for metastatic castration-resistant prostate cancer, a significant unmet medical need.
Mentors: Howard Scher and MD Neal Rosen, MD, PhD
The 2011 Foundation 14 – PCF Young Investigator Award
Dr. Roychowdhury works to underline and identify genetic alterations, which is a major step forward in personalizing cancer treatments. This work will provide a greater understanding of the totality of genetic alterations in patient tumors. Comprehensive genetic analysis of all cancer patients’ tumors, presented at the University of Michigan Comprehensive Cancer Center, will allow matching specific patients with specific genetic alterations with currently available FDA-approved or experimental treatments.
Mentors: Arul Chinnaiyan, MD, PhD and Ken Pienta, MD
The 2011 Todd Boehly – PCF Young Investigator Award
It is unclear why prostate cancer selectively metastasizes to and proliferates in bone. Although multiple factors are thought to be involved in the dissemination process of disseminated tumor cells (DTCs) to the marrow, growing evidence suggest that DTCs gain access to the bone marrow using similar ‘homing’ mechanisms of hematopoietic stem cells (HSCs). HSCs are the stem cells that give rise to all types of blood cells in the bone. Recent studies have shown that many of the same molecules that play critical roles in homing of HSCs to the bone marrow are also used by tumor cells to metastasize and establish footholds in the marrow. Dr. Shiozawa is studying the process of prostate cancer metastasis to bone. If successful, the proposed studies will provide a mechanism to explain why prostate cancer cells target bone during metastases and the process of the secondary spread of cancer. These studies may enable the design of new therapeutics targeting prostate cancer bone metastases.
Mentor: Russell Taichman, DMD
The 2011 Ben Franklin – PCF Young Investigator Award
For prostate cancer patients at higher risk of recurrence after radical prostatectomy (RP), early adjuvant radiation therapy (RT) has been shown in randomized trials to improve PSA-relapse free survival, metastasis-free survival and overall survival. Despite evidence to support adjuvant RT, less than 20% of qualifying patients in the U.S. actually receive this treatment. A national survey conducted by Dr. Showalter and colleagues has previously shown that urologist recommendations for adjuvant RT are influenced by perceptions of RT-related toxicity. The evidence to inform these toxicity estimates is lacking. Therefore, it is essential to bridge this difference by elucidating the real-world complication rates of post-prostatectomy RT, and to critically evaluate the significance of RT timing on the risk of complications. Dr. Showalter’s findings will improve management of high-risk prostate cancer, including the influence of timing after surgery, improve cure rates for these patients, and limit complications for lower risk patients.
Mentors: Adam Dicker, MD, PhD and Theresa Hyslop, PhD
The 2011 LeFrak Family – PCF Young Investigator Award
Dr. Srivastava is studying malignant cells from different regions of the prostate to analyze their genetic relationships with the aim to answer the following questions.
Is one patient’s prostate cancer made up of a single type that evolves into multiple genetic types or do multiple genetic changes exist in primary prostate cancer?
Does highly malignant disease originate in the prostate or does it evolve during the metastatic process?
Is there a specific cell lineage in a tumor that correlates to aggressive disease?
Dr. Srivastava’s research will provide insight into the evolution of prostate cancer from the single cancerous cell to aggressive, malignant disease. These studies will inform prostate cancer diagnostics, prognostics and improved treatment.
Mentor: Ashutosh Tewari, MD, PhD
The 2011 Reggie Jackson Team – PCF Young Investigator Award
One of the challenges in prostate cancer care is distinguishing men with high-risk disease requiring aggressive therapy from those who can be managed with active surveillance. The work’s proposal is based on findings from his recent prostate oncogenome project. Dr. Taylor and colleagues at MSKCC found certain global patterns of DNA alterations in primary tumors, called Copy Number Alterations (CNAs). CNAs are alterations of the DNA that result in the cell having an abnormal number of copies of one or more sections of the DNA. Dr. Taylor’s results showed that CNAs are associated with disease recurrence after radical prostatectomy. His preliminary studies showed that patients with these DNA alterations in their tumors were highly likely to develop castration-resistant disease. This study of the clinical importance and pathogenicity of DNA copy number alterations will, if successful, deliver a clinical diagnostic test that could impact treatment decisions in men diagnosed with prostate cancer.
Mentors: Charles Sawyers, MD and Chris Sander, PhD
The 2011 John Tyson – PCF Young Investigator Award
Understanding the molecules and mechanisms that contribute to prostate cancer progression and resistance to therapies will help researchers to design better treatments for patients. Dr. Andreas Varkaris is studying how prostate cancer cells are able to activate the oncogenic growth factor receptor, MET, to develop resistance to drugs that inhibit MET or other targets. Prostate tumor cells that have developed resistance to the MET inhibitor cabozantinib, will be studied to determine how MET becomes reactivated and escapes inhibition by cabozantinib. MET can be activated by a number of alternative pathways against which drugs are currently being tested in clinical trials for prostate and other cancers. These pathways will be studied to determine how MET is activated by them and whether cabozantinib-resistance mechanisms of MET-reactivation could cause resistance to these other drugs. If successful, this project will lead to the development of combination treatment strategies that override or bypass MET-mediated drug resistance mechanisms.
Mentors: Gary Gallick, PhD and Christopher Logothetis, MD
The 2011 Progenics Dr. Stephen Morris – PCF Young Investigator Award
The first medical treatment for metastatic prostate cancer is Androgen Deprivation Therapy (ADT). Unfortunately, nearly 100% of patients become refractory to this treatment and their cancer progresses to androgen-independent of castration-resistant stage (CRPC). A critical understanding of the biochemical mechanisms underlying castration resistance is important and may lead to the discovery and delivery of new treatments for patients with this potentially lethal form of prostate cancer. Dr. Kexin Xu is assessing the function of one protein, EZH2 that has been implicated in previous studies to play a critical role in the development of castration-resistant prostate cancer. Findings from the research will provide information on mechanisms underlying progression of prostate cancer to a state of castration resistance. This knowledge will guide the discovery of more effective and targeted therapies for advanced, metastatic prostate cancer.
Mentor: Myles Brown, MD
The 2011 Scott Minerd – PCF young Investigator Award (first year)
The 2011 Earle I. Mack – PCF young Investigator Award (second year)
2011 Rebecca and Nathan Milikowsky – PCF young Investigator Award (third year)
Technical advances have led to the identification and isolation of CTCs (Circulating Tumor Cells) from prostate cancer patients’ blood. Recent data have suggested that it is possible to use CTC counts and their molecular characteristics to monitor patients’ response to therapy and to guide their management; this may expedite the administration of active drugs, decrease toxicity and optimize resource utilization, without adversely impacting the survival of patients. Dr. Yap plans to conduct a clinical trial in castration-resistant, chemotherapy-naive prostate cancer patients, in which individual patient management is guided by CTCs. He plans to molecularly characterize and sequence genes of individual CTCs and circulating plasma nucleic acids from these patients to study the association of certain subtypes of prostate cancer with drug sensitivity and resistance. If successful, this has the potential to impact patient benefit by individualizing therapy and to accelerate antitumor drug development.
Mentor: Johann De Bono, MD, PhD