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DF/HCC A. David Mazzone Program awards over $3.5 Million for Prostate Cancer Research

The A. David Mazzone Research Awards Program funds a series of innovative cancer research projects administered jointly through Dana-Farber/Harvard Cancer Center (DF/HCC) and the Prostate Cancer Foundation (PCF). The Program leverages these institutions’ infrastructure and funding mechanisms to distribute funds locally and nationally through annual RFAs.

The Program is named in memory of Honorable Judge A. David Mazzone, who provided an indelible contribution to the United States legal system. For nineteen years, Judge Mazzone presided over the federal legal case to clean up the Boston Harbor, a legacy that lives on for generations to enjoy. He demonstrated a life-long commitment to environmental causes and contributed to the organization of local efforts to fundraise for cancer research. Judge Mazzone himself succumbed to Prostate Cancer at a premature age.

The funding agency for the Program is a grant from the U.S. District Court for the District of Massachusetts from a pool of unclaimed funds from the 2004 class action suit settlement by TAP Pharmaceuticals. The class action suit was related to marketing and sales practices for the prostate cancer drug Lupron.

This summer, DF/HCC granted eleven Mazzone awards in the following five research categories: High Impact, Career Development, Disparities Research, Lupron-Treatable Diseases and Conditions, and Project Development. Additionally, the Program funded three student summer awards through the DF/HCC CURE Program. The two-year High Impact award is for $500,000; the ten two-year grants in the other research categories are for $100,000 each. Furthermore, PCF Challenge Awards funded two $1,000,000 projects from a pool of outstanding proposals. All winning 2011 proposals are listed below.

Research Category: High Impact
Functional Annotation of Prostate Cancer Risk Loci Discovered through Genome Wide Association Studies
PI: Matthew Freedman, MD (DFCI)
Collaborator: Gerhard Coetzee, PhD (USC/Norris Cancer Center - Keck School of Medicine)

The understanding of genetic predisposition to complex diseases such as prostate cancer has undergone a revolution during the past five years, mainly due to the utilization of high-throughput genomic technologies and large cohorts. Numerous genome-wide association studies (GWAS) were published during this time in high-impact journals. In these studies genetic variation known as single nucleotide polymorphisms (SNPs) are commonly used to capture genome-wide variation and allele-frequency changes in numerous diseases including prostate cancer cases versus controls. A primary goal of such genetic association studies has been (and still is) to identify genes and associated novel biological pathways/mechanisms involved in the risk for the particular disease. To date prostate cancer-associated SNPs that mark more than 50 genetic regions (loci) have been identified in this way. Remarkably, the risk-associated SNPs in many of these regions are in DNA outside of known protein coding regions. Their biological significance is therefore not immediately obvious. This project’s overall hypothesis is that some of these non-coding genomic regions encompass regulatory DNA, which are affected by risk-SNPs and thus modify the expression of genes and pathways involved in disease predisposition and/or progression. This project intends to identify and study such risk regions. The results will yield novel predisposition genes as well as the biological mechanisms of prostate carcinogenesis, and more broadly solidify critical post-GWAS approaches applicable to a multitude of complex human diseases where risk SNPs are commonly identified far from coding sequences.

Research Category: Career Development
Probing androgen receptor signaling in circulating tumor cells in prostate cancer
PI: David Miyamoto, MD, PhD (MGH)
Collaborator: Daniel Haber, MD, PhD (MGH)

Prostate cancer progression critically depends on a molecular signaling pathway called the androgen receptor (AR) pathway. The first-line treatment for metastatic prostate cancer is hormonal therapy, which works by turning off the AR pathway in cancer cells and preventing their growth. Several promising new prostate cancer drugs also target the AR pathway, but with even greater effectiveness. However, at the present time, there are no reliable assays to determine whether or not these drugs are working effectively during treatment. This project proposes to use a new technology called the “CTC-chip,” which isolates cancer cells circulating in the bloodstream of patients (circulating tumor cells, or CTCs), to perform molecular tests to determine whether cancer drugs are properly hitting their target. Specifically, the project will use the CTC-chip to isolate CTCs from patients with advanced prostate cancer before and after hormonal therapy, and perform tests on these CTCs to determine whether the AR pathway has been effectively turned off. In addition, the project will examine AR signaling activity at the single cell level using a combination of high resolution imaging and sophisticated molecular analyses. If successful, these studies may provide a blood test that can show whether hormonal therapy is effectively attacking a patient’s prostate cancer, and will yield new scientific insights into the AR signaling pathway that may provide clues to new approaches to prostate cancer treatment.

Research Category: Career Development
Prostate cancer genetic variants, molecular alterations and mRNA expression
PI: Kathryn Penney, ScD, BA (BWH)
Collaborator: Massimo Loda, MD (BWH)

Prostate cancer is known to be highly heritable; numerous germline genetic variants have been identified through genome-wide association studies that are significantly associated with PCa risk. However, the function of these genetic variants and their biological mechanisms are generally unknown. mRNA expression levels can offer clues to these mechanisms, providing insight into opportunities for prevention. Additionally, men with specific genetic risk variants may be more likely to develop particular molecular subtypes of Prostate Cancer. This prospective study of 413 men with Prostate Cancer will assess the association of each confirmed Prostate Cancer germline risk variant with the mRNA expression of 29,000 gene targets in prostate tumor and adjacent normal tissue to identify possible genes and pathways involved. The study will also examine the association of the risk variants with the most common and relevant Prostate Cancer molecular alterations, TMPRSS2:ERG fusion, loss of PTEN, and MYC amplification. This comprehensive study will ascertain biological pathways that explain the link between genetic risk variants and Prostate Cancer; identifying these genes and pathways is a necessary step in developing targeted therapies. If a man’s genetic risk variant profile makes him more susceptible to developing specific molecular subtypes of Prostate Cancer, this new information could influence treatment choices among men carrying these particular risk variants.

Research Category: Career Development
Phosphorus and calcium intake, tumor microenvironment and prostate cancer progression
PI: Kathryn Wilson, Sc.D. (HSPH)
Collaborators: Lorelei Mucci, MPH, ScD (BWH); Edward Giovannucci, MD, ScD (HSPH); Michelangelo Fiorentino, MD, PhD (HSPH)

Prostate cancer mortality is often due to bone metastasis, which occurs frequently in Prostate Cancer. Factors that increase the affinity of tumor cells for bone are likely to be related to prostate cancer progression and mortality. Previous findings have suggested that bone-related nutrients (calcium, vitamin D, phosphorus) may be risk factors for prostate cancer. The Health Professionals Follow-up Study found that higher dietary intakes of calcium and phosphorus are associated with increased risk of prostate cancer, particularly with more aggressive forms of the disease. This project hypothesizes that calcium and phosphorus intakes may influence tumor cell expression of bone metabolism-related proteins: osteopontin, calcium-sensing receptor, PTH-related protein, and its receptor, all of which have been linked to bone metastasis and cancer progression. This project proposes to study this hypothesis using the Health Professionals Follow-up Study, which has a unique combination of data on dietary habits of men before and after prostate cancer diagnosis, prostate cancer tissue specimens, and long-term follow up of patients. This will allow a study of the relationship between dietary phosphorus and calcium intakes and tumor expression of bone-related proteins, and how these factors relate to long-term survival in prostate cancer patients. By combining diet, tumor tissue, and survival information, this unique patho-epidemiology investigation will help to clarify previous results on the role of diet in prostate cancer, support public health efforts to improve prostate cancer survival, and shed light on underlying disease mechanisms.

Research Category: Disparities Research
Enhancing Usability of the Personal Patient Profile-Prostate (P3P) for Black and Hispanic Men
PI: Donna Berry, PhD, RN (DFCI)
Collaborators: Julia Hayes, MD (DFCI); Martin Sanda, MD (BIDMC); Seth Wolpin, PhD, MPH, RN (University of Washington)

Selecting treatment is a daunting task for men with newly diagnosed localized prostate cancer (LPC). No single treatment option is clearly superior in terms of efficacy and morbidity. There is a growing body of evidence that men with a recent diagnosis of LPC engage in the treatment decision making process by strongly considering their personal factors along with medical factors. The research team has developed and tested the Personal Patient Profile-Prostate (P3P), the first automated, tailored and efficacious intervention to support men with LPC. The team has evidence that P3P significantly decreases decisional conflict over 6 months after diagnosis; yet found higher decisional conflict in minority men. While the randomized trial included a diverse sample, the earlier pilot work was conducted in a predominantly White sample. Intensive usability evaluations in minority men, conducted parallel to the trial, suggested additional development needs for both the English and Spanish versions of P3P. Therefore, the team’s aim is to improve the a) linguistic and contextual appropriateness of P3P content; and b) technical usability for Black and Hispanic men. We will refine the P3P user interface to enhance usability and acceptability while being careful to not change the nature of the intervention. To address these issues, the team will employ an established iterative development process with a sample of 20 Black and 20 Hispanic men with a recent diagnosis of LPC. The goal is to measure: a) program content reading level; b) health literacy; c) navigation of the program; d) usability and e) acceptability.

Research Category: Disparities Research
Understanding Racial Differences in Prostate Cancer Mortality
PI: Nancy Keating, MD, MPH (HMS)
Collaborators: Glen Taksler, PhD (New York University); David Cutler PhD (Harvard University School of Economics)

This study seeks to explain the black-white racial gap in prostate cancer mortality and identify clinical and social opportunities to reduce those disparities. Racial gaps in prostate cancer mortality are among the largest in any disease, yet remain incompletely explained. In year 1, the study will decompose the racial gap in prostate cancer mortality into differential incidence and stage-specific survival using SEER-Medicare data for prostate cancer patients and controls. The study can then attribute the racial gap in stage-specific incidence to disparities in PSA testing, comorbidities, and income. Then, the study will analyze how tumor characteristics, differential receipt of tests and treatments, access to different physicians, and socioeconomic differences impact the racial gap in survival. In year 2, the study will consider how differential vitamin intake may affect racial differences in prostate cancer incidence.
Individuals with darker skin pigmentation absorb less Vitamin D, and Vitamin D may lessen cancer risk. The possible link between sun exposure and racial differences in prostate cancer mortality has not been investigated. The study will assess whether the racial disparity in prostate cancer mortality is greater in U.S. regions with greater sunshine, where white males may benefit disproportionately from Vitamin D absorption. Such findings would suggest closer monitoring of Vitamin D levels in black men. The study’s quantitative approach to decomposing the racial gap is novel and it applies advanced econometric techniques to address potential confounding, a challenge of observational studies.

Research Category: Lupron-Treatable Diseases and Conditions
Cancer and Endometriosis
PI: Stacey Missmer, MS, ScD (BWH)
Collaborators: Rulla Tamimi, MS, ScD (BWH); Jiali Han, PhD (BWH)

Endometriosis is a prevalent gynecologic disease, for which Lupron is a primary treatment, which is marked by unclear etiology and signs and symptoms that can be physically debilitating and correlated with infertility. Emerging hospital discharge and case-control data suggest that women with endometriosis may be at greater risk of hormonal and inflammatory-related cancers, with breast cancer, ovarian cancer, and melanoma risk most consistently observed. However, data have not been available to address these relations with a time-dependent approach and accounting for the potential correlation of risk factors and impact of treatment. This project will utilize the more than 20 years of prospectively collected data from the Nurses' Health Study II that began in 1989 when nearly 120,000 women were enrolled -- among whom 8000 laparoscopically-confirmed endometriosis cases have been incidentally diagnosed. Successful completion of these aims may advance our understanding of the etiologies of endometriosis and these cancers and form the basis for public health interventions that can promote earlier detection in these women at greater risk. This study will further collaborative work on the genetic basis of endometriosis at Oxford University as well as inform additional collaborative ongoing investigations of cytoskeletal protein mutations associated with breast cancer and endometriosis at MIT.

Research Category: Project Development
Epigenetic Reprogramming of AR Function in CRPC
PI: Myles Brown, MD (DFCI)

Epigenetic alterations have been hypothesized to play important roles in carcinogenesis and tumor progression, including the development of castration-resistant prostate cancer (CRPC). Work from several groups demonstrates a continued critical role for the androgen receptor (AR) in CRPC. In addition, recent work from this lab defining the AR cistromes in a model of androgen-dependent prostate cancer and CRPC has shown that AR is recruited to distinct genomic sites in CRPC where it executes a distinct transcriptional program. These CRPC selective AR binding sites harbor epigenetic chromatin marks characteristic of active transcriptional enhancers and regulate a set of cell cycle regulatory genes that are over-expressed in authentic cases of CRPC. EZH2, a SET domain histone methyltransferase known to play a role in gene silencing through H3K27 methylation is up-regulated in CRPC. In preliminary studies the lab found that EZH2 can be recruited to the cis-regulatory elements of CRPC selective AR target genes such as CDK1 and UBE2C, forming a complex with AR in prostate cancer cells. Surprisingly, EZH2 directly up-regulates these AR targets in CRPC cells but not in androgen-dependent prostate cancer cells. In addition EZH2 is required for the growth of CRPC cells. Thus the overall hypothesis that will be tested in this study is that the epigenetic regulator EZH2 reprograms AR function in CRPC to stimulate the induction of a set of cell cycle regulatory genes required for the AR-dependent growth of CRPC.

Research Category: Project Development
Pharmacological validation of Etk/BMX as a target for the treatment of prostate cancer
PI: Nathanael Gray, PhD (DFCI)
Collaborator: Steven Balk, MD, PhD (BIDMC)

Prostate cancer is the third most common cause of death from cancers in men of all ages and is the most common cause of death from cancer in men over 75 years old in the Western world. In the United States in 2009 it was estimated that 218,890 new cases were diagnosed and 27,050 men died from this disease. 1 The high mortality and shortage of effective treatment for prostate cancer underscore the urgent need for the identification and development of a new generation of targeted therapeutics. Drugs targeting kinases such as Bcr-Abl, EGFR, PDGFR, b-raf, EML4-ALK have now demonstrated remarkable efficacy and tolerability in a number of diverse tumor types. Recent evidence indicates that deregulation of the non-receptor tyrosine kinase Etk/BMX (Bone Marrow X kinase) may be critically linked to the PCa cell survival and growth.2 In order to elucidate the functions of BMX in prostate cancer and to pharmacologically validate it as an effective anti-PCa target, this project proposes to synthesize and characterize the first highly potent, selective, irreversible BMX inhibitors.

Research Category: Project Development
Cancer Stem Cells Targeting in Castration Resistant Prostate Cancer
PI: Pier Paolo Pandolfi, MD, PhD (BIDMC)

The mainstay of systemic therapy for prostate cancer for the past 70 years has been Androgen Depletion Therapy (ADT). This therapy is generally effective with an initial success rate of almost 90%, however cancer almost invariably becomes resistant. Interestingly, an extremely wide variability in the durability of ADT is well documented. Given the genetic variability of prostate cancer, it is likely that the genetic forces driving the progression of disease will also affect the response to ADT. Accordingly, preliminary data generated by this lab demonstrate that this is indeed the case, as we observe differential response to castration in different genetically engineered mouse models (GEMMs) of prostate cancer. Emerging evidence suggests the existence of pools of quiescent cells in tumors that share many similarities with normal stem cells. These cells entitled Cancer Stem Cell (CSC) represent a vitally important concern for current therapies as most of these are targeted at the highly proliferative bulk of the tumor, leaving the CSCs unscathed. Since relatively little is known about the role of human prostate CSCs in androgen independent tumor growth, this study proposes to utilize faithful GEMMs of human CaP to identify the castration resistant prostate CSCs and define new strategies to eradicate them. Impact: Data obtained in this study will be fundamental to develop new effective “personalized” strategies towards the eradication of the prostate CSCs compartment in genetically stratified human prostate cancer.

Research Category: Project Development
DNase-seq for Cost-effective Identification of Functional Mutations in Prostate Cancers
PI: Xiaole Shirley Liu, PhD (DFCI)
Collaborators: Myles Brown, MD (DFCI); Levi Garraway, MD, PhD (DFCI); Soumya Raychaudhuri, MD, PhD (HMS)

Prostate cancers are often associated with somatic mutations in the non-coding regions of the genome, which are traditionally detected by SNP arrays and more recently by whole genome sequencing. This study hypothesizes that DNase-seq coupled with computational analysis could be a cost-effective alternative approach to identify functional mutations in the non-coding regions of prostate cancer genomes. Since DNase-seq is enriched in approximately 3% of the genome which marks gene bodies of highly expressed genes, functional promoters and regulatory sequences, a single lane of Illumina paired-end sequencing provides sufficient coverage to detect SNPs, CNVs, indels, and genome arrangement within these regions. In addition, the functional relevance of these mutations could be directly evaluated by their level of differential DNase-hypersensitivity. The major bottleneck to DNase-seq profile of prostate tumor samples is the amount of cells required for DNase-seq experiment and the lack of good analysis algorithms. Therefore, this study proposes a prove-of-principle study to: 1) optimize the protocol for DNase-seq with low cell count; 2) develop effective analysis pipeline to detect mutations from DNase-seq data; 3) apply DNase-seq on several prostate tumor samples with their paired normal control that have whole genome sequenced, evaluate the mutations DNase-seq could accurately detect, and use DNase data to provide functional insights on GWAS-detected prostate cancer risk loci. If the pilot study is successful, DNase-seq could be applied to many prostate tumor samples to identify functional mutations in the genome, reveal important mechanism underlying prostate cancer development, and provide insight on prostate cancer risk, diagnosis, and prognosis.

Research Category: PCF Challenge Award
Imaging Biomarkers of Treatment Response Using NaF PET/CT Imaging: a Prostate Cancer Clinical Trials Consortium (PCCTC) Effort
PI: Glenn Liu, MD – (UW Carbone Cancer Center)
Co-investigators: Michael Morris, MD (Memorial Sloan-Kettering Cancer Center); William Dahut, MD (National Cancer Institute); Steven Larson, MD (Memorial Sloan-Kettering Cancer Center); Peter Choyke, MD (National Cancer Institute); Robert Jeraj, PhD (University of Wisconsin Carbone Cancer Center).

As prostate cancer advances and spreads, it homes in on the bones. Monitoring the establishment and spread of cancerous tumors in the bone poses a major challenge. It is also crucial for the evaluation of anti-cancer therapies in patients for tracking both individual lesions and total disease progression in the bone. The PI, with his team of notable experts in prostate cancer drug development, nuclear medicine and quantitative molecular imaging, is evaluating a novel tool for tracking the spread of prostate cancer and treatment response using 18F-Sodium fluoride (NaF), which is highly specific for cancerous bone lesions. Imaging NaF in the bone with periodic PET/CT scans will help study both the spread of prostate cancer to the bone and the effectiveness of medications that target prostate cancer bone metastases. The research team will also evaluate different Imaging Biomarkers of Clinical Response (IBCR) that can confidently report the effectiveness of treatment and select the strongest biomarker demonstrating the highest detection rate.
Potential patient benefit: The work of this research team has the potential to deliver greater confidence to patients and their physicians through enhanced diagnostic and treatment response tools.

Research Category: PCF Challenge Award
Induction of Synthetic Lethality with Epigenetic therapy (ISLET) for Systemic Treatment of Prostate Cancer
PI: William Nelson, MD, PhD (Johns Hopkins Medicine)
Co-investigators: Srinivasan Yegnasubramanian, MD, PhD (Johns Hopkins Medicine); Jun Liu, PhD (Johns Hopkins Medicine); Stephen Baylin, MD (Johns Hopkins Medicine); Michael Carducci, MD (Johns Hopkins Medicine); Martin Aryee, PhD (Johns Hopkins Medicine).

One of the causes for the initiation of cancer is the switching off or complete shutdown of certain critical genes (gene silencing) that should remain active. Tumor cells also use this mechanism as the cancer spreads and becomes resistant to treatment. Cancer cells adapt to currently available drugs by switching off the targets of these medications and rendering them ineffective. The PI and his team of scientists plan to discover innovative new medicines that will turn switched-off genes back on so that currently available medications can effect tumor regression. The reversal of gene-silencing by new medications will have a two-pronged effect; one, switching on the ‘good’ genes that cancer switches ‘off’ and two, switching on the ‘bad’ genes so that currently available medications can more effectively identify and target them.
Potential patient benefit: New medications discovered by this research team could attack tumors in new ways. Combined with currently available treatments, these new therapies for metastatic prostate cancer have the potential to improve patient outcomes.