Dana-Farber/Harvard Cancer Center (DF/HCC) Sponsored Funding
A. David Mazzone Research Awards Program
Project Development Award

Sponsor: Non-federal (DFCI)
Award Amount: Up to $50,000 per year for two years for direct costs only ($100,000 total).

One page Letter of Intent due by February 28, 2013. Submit letter online: Application Form Web Page
Application deadline: 04:59:59 PM EST, Friday, April 5, 2013
Funding decisions will be made through peer review by June 15, 2013
Anticipated award date: August 1, 2013
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SUBMISSION INFORMATION

Submission requirements: Applications must be submitted online: Application Form Web Page
Applications submitted using other means will not be reviewed or considered for this award. Applicants should notify their grant administrator/office and follow their institution’s policies and procedures for approval to submit applications. Applications will not be accepted after 04:59:59 PM EST, Friday, April 5, 2013.

Please direct questions to:
Juan Carlos Hincapie
Tel: (617) 632-6155
Email: mazzoneawards@partners.org

OVERVIEW
The A. David Mazzone Research Awards Program will fund a series of collaborative and innovative cancer research, career development, community outreach, and training projects to address a range of needs in prostate cancer and Lupron-treatable diseases.

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 INFORMATION

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.

ELIGIBILITY CRITERIA

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 Program’s Scientific Advisory Board (SAB) are ineligible to apply.

PROPOSAL SUBMISSION INFORMATION
Required items (4):

• Application Form: To be completed online by the Principal Investigator when submitting your proposal at Application Form Web Page. Provide a 250-word abstract description of the project in laymen’s terms.
• Research Proposal: The proposal should describe the research to which this award would be applied if funded. Maximum of 3 pages of text including figures. References and budget pages are not included in this page limit. Appendix material will be accepted with the following restrictions: a two-page limit of relevant supporting text or figures, and only manuscripts that have been accepted for publication with the journal acceptance letter.
• Biosketches: Current NIH Biosketch for each participating PI, including all funding sources.
• Budget: Budget requests (direct costs only) and budget justifications should be submitted as NIH 398 form with major divisions of funds (personnel, equipment, supplies, other, etc.; with adequate rationale). Separate budget pages must be submitted for each individual institution requesting funds. Funds will be distributed directly from DFCI to sub-recipients. A composite budget that includes the total costs of the project should also be included when multiple institutions are involved in the project. PIs may include a level of effort (minimum 5% total) and salary support commensurate with their efforts on the project. Support and effort may be split between the collaborating PIs. Funds may be used for direct research expenses only, which may include salary and benefits of PIs, postdoctoral or clinical research fellows and/or research assistants, research/laboratory supplies, and equipment.
• IRB approval if applicable will be required prior to funding.

Format: Items 2 – 4 (above) must be compiled and submitted as a single PDF file. Please include the PI’s name, project title, and page number at the top of each page.

Submit Proposal Online: Application Form Web Page
Application Deadline: 04:59:59 PM EST, Friday, April 5, 2013.
IN FAIRNESS TO ALL THERE WILL BE NO EXCEPTIONS TO THIS DEADLINE

REVIEW CRITERIA
Applications will be reviewed by members of the Program’s Scientific Review Board. Grants will be awarded on the basis of the following review criteria (in order of importance):

• Significance. The project should address an important problem or a critical barrier to progress in the field. The aims of the project should advance scientific knowledge, technical capability, and/or clinical practice and have near-term patient impact.
• Inter-institutional Links. Proposals that foster inter-institutional research will be favored in decisions between equally ranked applications.
• Investigators. The PIs, collaborators, and other researchers should have the necessary experience and expertise and proven track records of accomplishment. The investigators should have complementary and integrated expertise.
• Innovation. The application should challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions.
• Approach. The overall strategy, methodology, and analyses should be well-reasoned and appropriate to accomplish the specific aims of the project.
• Environment. The scientific environment in which the work will be done should contribute to the probability of success.
• Potential to gain independent funding. There should be a high likelihood that project will lead to NCI or other cancer research foundation funding.

PROGRESS REPORTS
Grantees must submit annual progress reports to DF/HCC including detailed narrative updates, accrual reports (if applicable), and expenditure reports. Progress will be measured through the review of progress reports. Generally, progress that approximately meets benchmarks, timelines, or specific aims that are set forth within corresponding proposals will be funded on a per-year basis through the completion of the grant term.

2012 Project Development Mazzone Awards Recipients

Castration-Resistant Luminal Cells in the Prostate
PI: Zhe Li (BWH)
Collaborator: Stuart Orkin (Children’s Hospital Boston)

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
PI: Massimo Loda (DFCI)
Collaborators: Kathryn Penney (Brigham and Women's Hospital), Svitlana Tyekucheva (Harvard School of Public Health)

Gleason score is currently the best clinical predictor of lethal prostate cancer. Many men diagnosed with low-grade prostate cancer are treated with radical prostatectomy (RP), despite evidence that the majority would never have died of their disease even without treatment. Those not treated initially with surgery undergo active surveillance with repeat PSA measurements and biopsies to track the progression of the cancer. The concern is the cancer itself may be transforming into a more aggressive disease with a higher Gleason score or that there is more aggressive cancer present not detected by the initial biopsy. Additional non-invasive tools for monitoring patients who choose active surveillance could provide more confidence in treatment decisions. Our prior work developed an mRNA signature for Gleason score in prostate tumor tissue; genes differentially expressed between high and low Gleason scores included those in metabolic pathways. We will now explore if metabolites themselves are present in differing amounts in blood from patients with high and low Gleason. However, metabolites may be associated with other patient characteristics that differ between men with high-grade and low-grade disease. We therefore propose to perform metabolic profiling on blood collected before and after RP; comparisons between these samples can help confirm that significant metabolites are truly influenced by the tumor (or the prostate) and not other characteristics. Metabolites in blood associated with Gleason score may detect the presence of higher-grade tumor not sampled at biopsy and may serve as a tool for monitoring patients in the context of active surveillance.

Nanoplatforms for Localized Chemo Radiation Therapy for Prostate Cancer
PI: Robert Cormack (DFCI)
Collaborators: Anthony D’Amico (Dana-Farber Cancer Institute), Alec Kimmelman (Dana-Farber Cancer Institute), Mike Makrigiorgos (Dana-Farber Cancer Institute), Srinivas Sridhar (Northeastern University)

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
PI: Myles Brown, MD. (Dana-Farber Cancer Institute)

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
PI: Nathanael Gray, PhD. (Dana-Farber Cancer Institute)
Collaborator: Steven Balk, MD, PhD (Beth Israel Deaconess Medical Center)

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
PI: Pier Paolo Pandolfi, MD., PhD (Beth Israel Deaconess Medical Center)

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.

DNase-seq for Cost-effective Identification of Functional Mutations in Prostate Cancers
PI: Xiaole Shirley Liu, PhD (Dana-Farber Cancer Institute)
Collaborators: Myles Brown, MD (Dana-Farber Cancer Institute) Levi Garraway, MD, PhD (Dana-Farber Cancer Institute) Soumya Raychaudhuri, MD, PhD (Harvard Medical School)

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.