Funding Support Center
DF/HCC Sponsored Funding
Dana-Farber/Harvard Cancer Center (DF/HCC) Sponsored Funding
Sponsor: Non-federal (DFCI)
One page Letter of Intent due by February 28, 2013. Submit letter online: Application Form Web Page
Submission requirements: Applications must be submitted online: Application Form Web Page
Please direct questions to:
Project Development Awards will support investigators conducting innovative pilot projects in prostate cancer translational research spanning the disciplines of basic biology, population studies, outcomes, or social science. The emphasis of this RFA is on translational research. Projects should be designed to test the relevance of a biological discovery in prostate cancer risk, prevention, diagnosis, prognosis or treatment and/or to determine the biological and molecular basis of disease. Special consideration will be given to studies focused on prevention and treatment with a high probability of near-term patient benefit and impact on future research and treatment. Projects should develop preliminary data necessary to prepare and submit a competitive research grant application to a major funding agency.
Award is for $50,000 per year for up to two years ($100,000 total in direct costs). The next projected award period is August 1, 2013 to July 31, 2015. Two awards remain in this category to be awarded over a two-year period.
Funding Agency: The funding agency for the program is a grant from the U.S. District Court for the District of Massachusetts. Funding was derived from a pool of unclaimed funds from the settlement in 2004 of a class action suit against TAP Pharmaceuticals. The class action suit was related to marketing and sales practices for the prostate cancer drug Lupron.
The Mazzone Awards Program is a DFCI sponsored award, administered jointly through DF/HCC and the Prostate Cancer Foundation.
Applications will be accepted from two or more independent investigators, at least one of whom holds a full-time Harvard faculty appointment at the level of Instructor or higher. Awardees will be encouraged to apply for DF/HCC membership and will be invited to attend program activities (meetings, retreats, research presentations). Applicants from institutions throughout the country are encouraged to apply as long as they have a collaborator in one of the DF/HCC institutions. Applicants may apply for multiple grants; however, individuals may only be awarded one A. David Mazzone Research Award at a time.
Employees or subcontractors of a government entity or for-profit private industry are not eligible. Exceptions include applicants holding full-time positions at a veterans' hospital or national laboratory (e.g., Lawrence Berkeley National Laboratory) in the United States. Members of the Programís Scientific Advisory Board (SAB) are ineligible to apply.
PROPOSAL SUBMISSION INFORMATION
Format: Items 2 Ė 4 (above) must be compiled and submitted as a single PDF file. Please include the PIís name, project title, and page number at the top of each page.
Submit Proposal Online: Application Form Web Page
2012 Project Development Mazzone Awards Recipients
Understanding the molecular programs leading to castration-resistant prostate cancer (CRPC) is critical for designing novel approaches to treat and to prevent CRPC. Such programs can be acquired by cancer cells after they acquire additional mutations; they can also be pre-existing in cancer cells that inherit the castration-resistant capacity from normal prostate cells from which they are derived (i.e., cells of origin). There are two major epithelial cell types in the prostate, luminal cells and basal cells. Studies in mice suggest basal cells contain prostate stem cells and are castration-resistant. However, human prostate cancers are luminal in nature and are characterized by loss of basal cells. Interestingly, recently it was demonstrated that the prostate luminal lineage also contains self-sustained stem cells, and that luminal cells can indeed serve as cells of origin for prostate cancer much more effectively, and more importantly, some luminal cells are intrinsically castration-resistant. Thus, it is of great importance to identify and characterize such castration-resistant luminal cells, as they may contribute to the more aggressive clinical behavior of CRPC directly. Signaling pathways essential to these cells may be identified as potential therapeutic targets for preventing and treating CRPC. To identify this unique subset of luminal cells, we will use a novel single cell profiling approach to identify cell surface markers specifically expressed in surviving prostate luminal cells, following castration. We will use these markers to purify such luminal cells by flow cytometry and to define their unique molecular programs (e.g., unique metabolic program) by microarray analysis.
Developing a Blood-based Metabolomic Signature of Gleason Score
Nanoplatforms for Localized Chemo Radiation Therapy for Prostate Cancer
The goal of this pilot project is to develop a new modality for chemo-radiation therapy (CRT), termed Biological In-Situ Image Guided Radiation Therapy (BIS-IGRT), which aims to locally radio-sensitize the prostate to enable prostate cancer (PCa) cure with the use of lower radiation doses, thereby leading to less rectal toxicity. BIS-IGRT involves the coating of spacers routinely used in prostate brachytherapy with radiosensitizing drugs. This approach provides localized in-situ delivery, without introducing additional patient discomfort, of the sensitizer to the tumor and avoids the toxicity associated with current CRT using systemic delivery which does not provide the sustained delivery or the local concentration and spatial uniformity needed for efficient radiosensitization. Recent work has shown that Olaparib, a PARP inhibitor, is a potent radiosensitizer in PCa animal models. We hypothesize that local, sustained delivery using nanocoated brachytherapy spacers which elute Olaparib over 6 weeks will be far more efficient for radiosensitization than systemic, intermittent administration, and will lead to minimal systemic toxicity. This project will test this hypothesis in cell and animal chemo-radiation studies.
If successful, this pilot project will be the first to deliver a biological agent locally to the prostate in a sustained manner over long periods, and will provide preliminary results for a large grant. Translated to the clinic, BIS-IGRT would proffer PCa clinicians with a new treatment option with immediate crucial benefit for patients (~50%) with localized ETS fusion-positive prostate cancers.
2011 Project Development Mazzone Awards Recipients
Epigenetic Reprogramming of AR Function in CRPC
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.
Pharmacological validation of Etk/BMX as a target for the treatment of prostate cancer
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.
Cancer Stem Cells Targeting in Castration Resistant Prostate Cancer
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 ďpersonalizedĒ strategies towards the eradication of the prostate CSCs compartment in genetically stratified human prostate cancer.
DNase-seq for Cost-effective Identification of Functional Mutations in Prostate Cancers
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.