Porter v. Tap Pharmaceutical, et al

Filing 592

Judge Richard G. Stearns: ORDER entered granting Dana-Farber's request to extend the end date of the DF/HCC - Prostate Cancer Foundation Mazzone Program to September 30, 2019, to enable the Program to use unspent funding for further activities to support Prostate Cancer research. (Zierk, Marsha)

A. David Mazzone
Research Awards Program
Request for No Cost Extension
To Extend the Program End Date
From September 30, 2017 to September 30, 2019
Principal Investigator: Myles Brown, MD
Dana-Farber/Harvard Cancer Center
Co-Principal Investigator: Jonathan Simons, MD
Prostate Cancer Foundation
Respectfully Submitted to
U.S. District Court for the District of Massachusetts
Boston, Massachusetts, April 30, 2018

Beth Israel Deaconess Medical Center
Brigham and Women's Hospital
Boston Children’s Hospital
Dana-Farber Cancer Institute
Harvard Medical School
Harvard School of Public Health
Massachusetts General Hospital

Table of Contents
I.

Proposed No Cost Extension Activities................................................................................... 2

II. Background of the Mazzone Program ..................................................................................... 5
III. Program Guidelines ................................................................................................................. 7
Appendix 1. Career Enhancement Program (CEP) of the DF/HCC Prostate Cancer SPORE:
program description, guidelines, and research highlights ............................................................... 9
Appendix 2. Sample Mazzone Program Career Development Proposal Submission Instructions
and Template ................................................................................................................................. 25
Appendix 3. Continuing Umbrella of Research Experiences (CURE) Program Proposed Funding
Request.......................................................................................................................................... 29
Appendix 4. Grant Funding Plan and Accounting Report by Dana-Farber Cancer Institute ....... 30
Appendix 5. Original Plan for Program Reporting to the Court ................................................... 32

1

I.

Proposed No Cost Extension Activities

Request to Extend the Program End Date from September 30, 2017 to September
30, 2019
As reported in the 2017 Sixth Annual Report of Research Progress and Accounting,
Report # 013 of the Mazzone Program by Dana-Farber/Harvard Cancer Center
(DF/HCC) and the Prostate Cancer Foundation (PCF), all originally approved research
activities of the Mazzone Program concluded leaving unspent funds.
As of the period of the 2017 report, all projects submitted accounting and progress
reports of successful completion of their activities, including three DF/HCC projects
which received extensions through July 2017 and the DFCI CURE Student Training
Program. As in prior years, Highlights of the research supported by the Mazzone
Program evidenced a significant impact in the field of Prostate Cancer research and a
number of promising findings that will transform treatment and will bring researchers
and the medical community closer to finding effective cures for Prostate Cancer.
After careful review and accounting reconciliation of all Program awards, we
ascertained that the DF/HCC component of the Program ended with a cash received
unspent balance of $48,041 as stated in the signed accounting report. This balance
does not include the final payment, which is pending disbursement from the Court for
approximately $101,000. Therefore, DF/HCC has an unspent balance of approximately
$149,000. The unspent balance is the result of various projects which concluded their
research and submitted final progress and accounting reports leaving unspent funds
balances primarily by two of the DF/HCC projects funded in the period of 2014 to 2017.
Given the availability of funding at DF/HCC, we hereby request from the Mazzone
Program sponsor, the Massachusetts District Court an extension of the end date of the
program with no additional cost from September 30, 2017 to September 30, 2019. This
extension will allow the Program to invest the remaining funds in new worthwhile
research projects, which will add value and strengthen the Program’s overall impact.
The Mazzone Program hereby requests the Court’s approval for the following proposed
activities to be supported by remaining funds. At the end of the Extension Period, the
Mazzone Program will submit to the Court a final progress and accounting report by
September 30, 2019 to document the outcomes of the activities proposed.

Proposed Activities:
$106,000 funding for two Career Development awards through the DanaFarber/Harvard Cancer Center’s Prostate Cancer SPORE Program
We propose offering two grants for Career Development in Prostate Cancer research
through the DF/HCC Prostate Cancer SPORE Program’s Career Enhancement
Program (CEP). The two grants continue in the spirit and guidelines of the original
Mazzone Program Career Development awards. The Prostate Cancer SPORE

2

Program’s CEP is a distinguished and highly successful research enterprise led by
Principal investigators Drs. Massimo Loda and Steven Balk. Appendix 1 provides a full
description of the SPORE CEP and highlights of successful award recipients of the
Program.
Using established and transparent methodology for evaluating applicants for the CEP,
Drs. Loda and Balk will nominate two highly promising and deserving candidates to
apply for these awards. Each award will run for one year for the period of July 1, 2018 to
June 30, 2019 and each project will receive funding for $53,000 for direct costs only.
Each candidate will submit a proposal to the SPORE program using the original
Mazzone Program Career Development application template and instructions –see
Appendix 2 for the sample of Mazzone Career Development proposal submission
instructions and template. They will benefit the CEP resources and guidance and they
will be required to submit a progress and accounting report at the end of the project
year. Drs. Loda and Balk will review the proposals submitted by the candidates using
the criteria of the Mazzone Program’s Career Development Awards and the CEP
guidelines and requirements. The DF/HCC Mazzone Program Principal Investigator, Dr.
Myles Brown will provide final review and approval for funding.
$20,000 funding for Student Training Awards
Given the success and significant contribution by the Mazzone Program funding to the
field of cancer research opportunities for minorities underrepresented in the sciences.
We request funding to be administered through the DF/HCC Continuing Umbrella of
Research Experiences (CURE) program. Funding will support tree stipends of $5000 for
students participating in an 8-12-week summer research experience. $3000 to plan and
support professional development activities including college readiness and student
travel to attend and present at conferences. $2000 to supplement the cost of offering a
networking event with other summer research programs related to career opportunities
beyond academia. This proposal is detailed in Appendix 3
$23,041 funding for a Mazzone Program Retreat and Program Closing Celebration
in May of 2019
We propose using the remainder of available funds to support the cost of a retreat and
closing celebration for the Mazzone Program. This event will provide an opportunity for
Program alumni to come together and share updates and accomplishments resulting
from their research supported by the Mazzone Program. This will also be an opportunity
to celebrate the tremendous accomplishments, success and advances in Prostate
Cancer research supported by the Program. The event will take place in Boston,
Massachusetts in a date to be determined in coordination with relevant Program
stakeholders.

3

Summary of Proposed Use of Funding
Unspent Funding (cash balance) as of Report Period Ending 12/31/17:
Estimated Funding Allocation Pending Disbursement by the Court:
Available Funding for Additional Program Activities:

48,041
101,000
149,041

Proposed Activities During No Cost Extension Period
Two awards for DF/HCC Prostate Cancer SPORE Program’s Career Enhancement Program (CEP)
Grant Period: July 1, 2018 to June 30, 2019, two awards $53,000 each
Dana-Farber/Harvard Cancer CURE Program for Cancer Education (proposal enclosed)
Mazzone Program Retreat and Closing Celebration, May 2019
Total Cost of Estimated Activities During No Cost Extension Period

106,000
20,000
23,041
149,041

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II. Background of the Mazzone Program
The Program is named in memory of the 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 derived 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. The Program is
administered jointly through Dana-Farber/Harvard Cancer Center (DF/HCC) and the
Prostate Cancer Foundation (PCF).
Program Goals: The overarching goal of the program is to leverage the existing
institutional infrastructure, funding mechanisms and relationships of DF/HCC and PCF
to distribute locally and nationally settlement funds annually on a competitive basis, to
support large-scale research collaborations in prostate cancer research; such as
cutting-edge pilot projects, development of promising junior investigators, and training
talented students.
Specific Program goals:
• To direct leftover Settlement Pool funds from Lupron litigation to research
initiatives of merit in prostate cancer and other Lupron-treatable diseases.
• To distribute Settlement Pool funds to researchers in prostate cancer and other
Lupron-treatable diseases at the national and local level, and to spur
collaborative research between prostate cancer and Lupron-treatable diseases.
• To distribute Settlement Pool funds through existing organizational channels that
have an established record of successful grant distributions (i.e., those that have
advanced the state of knowledge in the grants’ stated areas of research).
• To increase the power and breadth of research in prostate cancer and other
Lupron-related diseases, by (i) the strategic administration of new and existing
funding mechanisms; (ii) expanding current avenues of investigation; (iii)
recruiting new talent into the field; and (iv) ensuring that research is relevant to
the primary goals of advancing diagnostic, treatment and quality of life options for
patients with prostate cancer and other Lupron-treatable diseases.
Program Mechanism: Grant applications were solicited annually by DF/HCC and PCF
throughout the duration of the program. DF/HCC solicits several categories of grant
applications from the faculty of Harvard University and its affiliated hospitals
encouraging extramural collaborations. PCF solicited grant applications from interested
applicants on a national and international level.

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Governance: DF/HCC and PCF convened a high-level scientific advisory board (the
"Oversight SAB") to participate in the application review process, and to ensure that
Settlement Funds are distributed fairly, and in accordance with Requests for Proposals
guidelines and any other principles that are associated with such funds.
SAB Members:
• Donald Tindall, PhD, Director and Vice Chair of Urologic Research, Mayo Clinic
College of Medicine.
• Howard Soule, PhD, Executive Vice-President and Chief Science Officer at PCF.
• Jonathan Simons, MD, Co-Principal Investigator of the Mazzone Awards
Program, President and Chief Executive Officer at PCF.
• Ken Pienta, MD, Director of the Prostate SPORE at the University of Michigan.
• Peter Carroll, MD, Chief of Urology, Director of the Prostate SPORE at University
of California, San Francisco.
• Peter Nelson, MD, Director of the Prostate SPORE at the University of
Washington.
• Peter Scardino, MD, Chairman of Surgery and Chief of Urology, Director of the
Prostate SPORE at Memorial Sloan Kettering Cancer Center.
• William Nelson, MD, PhD, Director of the Cancer Center, Director of the Prostate
SPORE at Johns Hopkins University.
• Philip Kantoff, MD, Principal Investigator of the Mazzone Awards Program,
Director of the Lank Center for Genitourinary Oncology at DFCI through October
2015.
• Myles Brown, MD, Principal Investigator of the Mazzone Awards Program,
effective as of October 2015.
Court Appointed Members:
• Jonathan Tilly, PhD, Director, Vincent Center for Reproductive Biology,
Massachusetts General Hospital. –through December 2011.
• Gary Wente, JD, Circuit Executive at United States Courts; US District Court for
the District of Massachusetts, Patient Advocate for the Mazzone Awards Program.
–through July 2014.
The Court appointed board members and, upon request, Judge Richard G. Stearns, will
be included in all governance committee and scientific review board correspondence,
and will be invited to any face-to-face meetings or conferences that involve award
governance and/or grantee presentations.
Award Categories: Through the Mazzone Awards mechanism, DF/HCC offers funding
opportunities in High Impact research grants, High Impact Clinical Trials, LupronTreatable Diseases and Conditions research grants, Community Outreach grants, and
Student Education grants, as well as Career Development grants, Project Development
grants and Disparity Research grants. PCF will add to the number of Challenge grants
that it awards on an annual basis.

6

The following table provides a description of each category of award that will be made
possible through the Program.

Grant Awards Mechanisms (Revised list approved by the Court in 2012)
Award Category
Career Development
Community Outreach
Disparities Research
High Impact Award
Lupron-treatable
Project Development
Student Training
High Impact Trials
Seed Fund Community Outreach

Amount
100,000
100,000
100,000
500,000
100,000
100,000
20,000
500,000
10,000

Duration
2 years
2 years
2 years
2 years
2 years
2 years
2 years
2 years

PCF Challenge Award

1,000,000

2 years

Number of
Awards
6
4
5
4
3
9
8
1
1
5

Notes of modifications to the original distribution of funding mechanisms above:
In 2012, the Court authorized the DF/HCC contingent of the Mazzone Program to create
a new award category for “High Impact Clinical Trials” by reallocating one of the five
grants originally approved for “High Impact Awards”. This new award was advertised in
2012 and 2013 and an award was issued in 2013.
Per recommendation of the peer review panel and approval by the Court, a $10,000 one-time seed funding grant was awarded to Dr. Glenn Bubley in 2012.
In 2013, two out of four $100K Community Outreach grants remained unfunded. $200K
was reallocated to fund a partial High Impact Project
In 2013, the Court authorized the Prostate Cancer Foundation to fund a Mazzone
Program at $500,000 (half of the normal funding amount), which allowed the Foundation
to advertise and grant a final Mazzone Challenge Award in 2014.
In 2014, the Court authorized DF/HCC to use previously unallocated funds ($160,000)
from the original Lupron grant to support a special RFA on Community Outreach and
Disparities Research and additional funding for the Student Training program. Funding in
the amount of $140,000 was issued to two grant recipients selected in 2014 for two-year
Disparities Research grants. The remainder $20,000 was allocated as additional funding
to the DF/HCC CURE Program increasing the total Student Training grant to $180,000.

III. Program Guidelines
At DF/HCC, applications are reviewed by members of the DF/HCC Prostate Cancer
Program and SPORE Governance Committee, and by at least two non-DF/HCC
members of the Oversight SAB, who will likely serve in this capacity on a rotating basis.
The DF/HCC Prostate Cancer Program and SPORE Governance Committee is
comprised of approximately ten Harvard faculty members representing Harvard Medical
School and its affiliated institutions. The faculty members were chosen based on their
accomplishments, broad vision, impartiality, and diverse expertise. They have expertise

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and training in one or more of the following disciplines: medical oncology, urologic
oncology, radiation oncology, population science, and basic science.
Yearly reports on Settlement Pool Account financial activity will be submitted to the
Court designees and to Judge Stearns. The maximum grant period for grant recipients
will be two years; however, grant-making will be staggered over five years. A final
accounting will thus be achievable within seven years from the start of the distribution of
Settlement Pool funds.
Grant Disbursements and Program Accounting: All grant funds will be paid to
grantees according to contractual obligations; grantees are required to submit quarterly
invoices against actual expenditures. Progress and financial reports will be required
from grantees at the end of year one and will include detailed narrative updates and
expenditure reports. The issuance of the second year’s funding installment will be
contingent upon satisfactory progress by grantees. These payments will be made with
the approval of the respective board chairs and the Oversight SAB. Final progress and
financial expenditure reports will be expected at the end of the award term.
Both DF/HCC and PCF require that no award funds be directed to overhead expenses
at grantee institutions. Therefore, the Settlement Pool funds are subject to IDC at only
one point in the overall award process, i.e., upon receipt of funds by DF/HCC. Appendix
4 provides the grant Disbursement Structure and Institutional Financial Reports by
Dana-Farber/Harvard Cancer Center and the Prostate Cancer Foundation for the Period
of This Report
Program Reporting Schedule: The Program’s effective start date was October 1,
2010. The Program issued and sustained grants for five years and the reporting period
will run from October 1, 2010 through September 30, 2017 (seven years). Appendix 5
provides the full reporting schedule as approved by the Court.

8

Appendix 1. Career Enhancement Program (CEP) of the DF/HCC
Prostate Cancer SPORE: program description, guidelines, and
research highlights

9

DF/HCC Prostate Cancer SPORE Career Enhancement Program (CEP)
Principal Investigators:
Massimo Loda, MD
DANA-FARBER CANCER INSTITUTE
EDUCATIONAL TITLES
Professor, Pathology, Harvard Medical School
Principal Investigator, Pathology,
Dana-Farber Cancer Institute
Senior Pathologist, Pathology, Brigham And Women's Hospital

Dr. Loda received his M.D. summa cum laude at the University of Milan, Italy. He is a physician-scientist,
Professor of Pathology at Harvard Medical School, Chair of the Department of Oncologic Pathology at
Dana Farber Cancer Institute, Associate Member of the Broad Institute and senior surgical pathologist at
the Brigham & Women’s Hospital in Boston. Dr. Loda conceived, built and directs a state of the art
Molecular Pathology Core Laboratory at the Dana Faber Cancer Institute. Dr. Loda is one of the pioneer
molecular pathologists in the world and has discovered, and explored the mechanism of function of several
important cancer biomarkers. His laboratory has been focused for several years on metabolic alterations
in prostate tumorigenesis, with a specific interest in lipid metabolism and its regulation. Our approach is
multidisciplinary, utilizing cell lines, orthotopic tumor xenograft, genetically engineered murine models and
human tumors. They have also been at the forefront in the invention and application of novel molecular
pathology techniques such as ex vivo organotypic cultures, multiplexed immunohistochemistry and in situ
hybridization, advances in image analysis and applying molecular techniques such as metabolic profiling
to formalin-fixed, paraffin-embedded tissue.

Steven P. Balk, md, PhD
BETH ISRAEL DEACONESS MEDICAL CENTER
EDUCATIONAL TITLES
Professor, Medicine, Harvard Medical School
Staff Physician, Hematology/Oncology, Beth Israel Deaconess Medical Center

Dr. Steven Balk's lab developed methods to analyze advanced metastatic PCa through the use of bone
marrow biopsies and showed that one mechanism for disease progression after androgen deprivation
therapy was through mutations in the androgen receptor (AR). These mutations occur specifically in
patients treated with an AR antagonist, flutamide, and are the result of strong selective pressure exerted
by this drug. In subsequent studies his lab has further established a critical role for AR in PCa that relapses
after androgen deprivation therapy, and identified mechanisms that mediate AR reactivation (including
enhanced androgen synthesis by tumor cells). These results have led directly to successful clinical trials
with translational as well as clinical endpoints. An additional current focus is mechanisms of progression
from low grade to high grade prostate cancer, which will have an impact on management of low grade
disease. In conjunction with these research efforts, he has directed the establishment of a prostate cancer
tissue bank and correlative clinical database.

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PROJECT SUMMARY/ABSTRACT:
The investigators assembled in the DF/HCC Prostate Cancer SPORE have a substantial record
in mentorship and development of junior faculty working in the prostate cancer field. The goal of
the Career Enhancement Program of our SPORE is to build upon this record and continue a
formal process for the identification, selection, funding, and mentoring of individuals pursuing
careers in the study of the basic, translational, and clinical aspects of prostate cancer that will
lead to improved patient care.
PROJECT NARRATIVE (Public Relevance Statement):
The Career Enhancement Program aims to attract and develop the next generation of
translational investigators in prostate cancer.
SPECIFIC AIMS:
The Career Enhancement Program (CEP) of the Dana-Farber Harvard Cancer Center Prostate
Cancer SPORE has been very successful at developing the next generation of translational
researchers in prostate cancer over the last 15 years. It will continue to accomplish this goal by
pursuing the following aims:
1. Soliciting applications for CEP awards
2. Selecting Awardees
3. Mentoring the recipients of CEP awards
4. Monitoring the progress of CEP awardees careers
5. Evaluating the success of the CEP on an ongoing basis
RESEARCH STRATEGY:
The investigators assembled in the Dana-Farber Harvard Cancer Center (DF/HCC) SPORE in
Prostate Cancer have a substantial record in mentorship and development of junior faculty
working in the prostate cancer field (detailed below). The goal of the Career Enhancement
Program (CEP) of our SPORE is to build upon this record and continue a formal process for the
identification, selection, funding and mentoring of individuals pursuing careers in the study of the
basic, translational and clinical aspects of prostate cancer.
POLICIES, CRITERIA, AND PROCESSES FOR SELECTING CANDIDATES:
To succeed, the CEP requires: A) Effective candidate selection and evaluation, and B)
Mentorship. The steps taken by our SPORE for sustaining research and career progression are
summarized below.
The SPORE guidelines indicate that the CEP should “describe the process for selecting
candidates.” This Program will rely on the infrastructure created by Core A-The Administrative
Core to: Solicit applications and identify candidates, Evaluate applications to select CEP
recipients, Disburse Funds, Review recipient progress and evaluate the CEP.
Details of these processes for selecting candidates and facilitating their progress toward SPORE
goals follow.

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Solicitation of CEP Award
Applications
We have used two principal
mechanisms
for
the
solicitation of CEP award
candidates. One is a
Harvard Medical Schoolwide
Request
for
Applications (RFA). The
other
mechanism
for
solicitation is less formal.
Part of the responsibility of
the SPORE Directors and
the senior leadership of the
SPORE
(Co-PIs
and
Governance Committee) is
to seek out talented
investigators
at
the
different performance sites
and
solicit
their
participation in the SPORE.
Recruitment of qualified
women, individuals from
underrepresented
racial
and ethnic groups, and
individuals with disabilities
We have strived to recruit
women into the field and
have been fortunate to
have a strong candidate
pool, with about half of the
awards going to women. It
is also a high a priority of
the CEP and of the
Governance Committee to recruit qualified minority investigators to our program. Our efforts along
these lines include: 1) regular inclusion of the topic on the agenda of the Governance Committee,
2) working with DF/HCC and its minority recruitment program, and 3) working with the Dean’s
office at HMS and its office for Faculty Diversity and Development.
Instrument for Campus-Wide Solicitation. Figure 1 is an example of the RFAs used through the
DF/HCC Intranet and by mail to the Department Heads at HMS to solicit CEP award candidates.
The applications consist of the following components:
1)
A brief summary of the research plan (not to exceed 5 pages excluding references)
including an Abstract, Specific Aims, Background and Relevance, Preliminary Data, Experimental
Methods/Research Plan, Translational Goals, and anticipated time line.
2)
Budget (NIH 398 Form Page 4)
3)
For institution’s other than DFCI, institutional signature on a Statement of Intent is
4)
Applicant’s Biosketch (NIH Format – 5-page limit)

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5)
Reference letter from applicant’s primary mentor. The letter should outline the research
and career plan for the candidate.
6)
Letter of institutional support from the applicant’s department chair or division chief
providing evidence of institutional support and a guarantee of protected time, research space,
and office space.
Selection of Candidates:
The Governance Committee of the SPORE (Table 1),
with advice from additional internal reviewers in cases
where additional expertise is needed, chooses the CEA
recipients. Over the past funding cycle, Drs. Feldman and
D’Amico chaired the CEP with SPORE Directors, Drs.
Loda and Balk. We now propose that Dr. Feldman be the
sole Director of the CEP. Dr. D’Amico will now Chair the
Developmental Research Projects Program. The criteria
for judging the applicants are shown below in the “Criteria
for CEA Recipient Selection” section. Each application
has at least two assigned reviewers with expertise in the
relevant area (if these latter reviewers cannot attend the
review meeting, they are asked to provide a brief
summary to the Co-Chairs and the SPORE Directors,
which in turn is conveyed to the rest of the reviewers). At
each review meeting, each application is presented
briefly, and then scored. Each evaluation criterion is
scored using the standard NIH scoring system (Table 2).
Scores are submitted to the SPORE Administrator for
tally, and CEP applications are prioritized based on their
score. A consensus is quickly reached as to which ones
are potentially fundable. Proposals felt to be fundable are
then re-discussed and are given final rankings.
The SPORE Directors with the Co-Chairs resolves disagreements among committee members or
reviewers on CEA applications deemed of equal quality,
in cases where only one can be funded. In the event that
a Governance Committee member, an individual in his or
her group, or anyone with whom a conflict of interest
might be perceived submits a CEA application, the
Governance Committee member recuses him/herself
from the discussion and voting. It is the responsibility of
the SPORE Directors to make fair and equitable decisions
while giving a high priority to the quality of the candidate
and science, potential for translation, and the impact of
the CEP awards on the overall progress of the SPORE.
Criteria for CEP Award Recipient Selection. The
application and review process as outlined above is
implemented by the SPORE Directors and CEP Director, with the assistance of SPORE
Administrative staff to see that the RFA is sent out. The administrative office of DF/HCC, under
the direction of the Senior Vice President for Research, routinely facilitates such solicitations on
a DF/HCC-wide basis. In addition, SPORE administrative staff has mail and email access to HMS

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Department Chairpersons and administrative staff. The DF/HCC Prostate Cancer Program
leadership will also actively encourage applications from those individuals working within the
Program research labs and clinical research groups (with a special emphasis on women and
minorities, and those with disabilities). We have a very talented pool of trainees from which to pick
some of our CEP awardees.
A robust response to the University-wide solicitation is anticipated in the future, similar to the
robust pool of responders in the previous cycles of our SPORE CEP. As mentioned, the criteria
used to select the candidate includes: the track record of the individual and his/her potential to
contribute to the field as an independent investigator, the translational potential of the proposed
work, its programmatic relevance, the quality and commitment of the mentor, and the overall
quality of the science proposed. In some cases the Governance Committee may recommend a
co-Mentor to provide additional expertise and guidance with respect to basic science aspects or
translational potential of a project. CEA recipients will be expected to participate in the activities
of the SPORE, including attending monthly meetings, research retreats and presenting their
research accomplishments at appropriate times.
FUNDING:
The funding of the program will come from the SPORE as well as through institutional
commitment. The funding schema is shown below. (The distribution of funds is the responsibility
of the Administrative Core under the SPORE Directors.)
Table 3: Funding
Year 1
SPORE
$100,000
Institutional
$100,000
Commitment
Total
$200,000

Year2
$100,000
$100,000

Year 3
$100,000
$100,000

Year 4
$100,000
$100,000

Year 5
$100,000
$100,000

$200,000

$200,000

$200,000

$200,000

We will set aside $100,000 Direct Costs per year for the CEP. This will be supplemented with an
additional $100,000 per year in the form of institutional support. The award will facilitate the
research and development of basic, translational, and clinical investigators within our SPORE.
Thus, candidates will be fellows, senior postdoctoral fellows, and junior faculty within the various
training programs across the Harvard campus. It is our goal to attract, mentor and assure the
success of CEP award recipients. Success herein is defined as the development of
physician/scientists, or PhD scientists with a translational focus, into independent prostate cancer
investigators
CEP EVALUATION AND REVIEW:
The overall goal of the CEP is to nurture the success of talented new researchers in prostate
cancer. Young investigators are expected to become financially independent early in their
careers. This has particularly impacted clinical investigators who are increasingly pressured by
hospitals to increase their patient care volume as clinical reimbursement has diminished. This
SPORE CEP strives to protect young investigators from such forces and to attract minority and
female investigators to the field of prostate cancer. Award recipients participate in monthly
SPORE meetings and our annual retreat where they present any work accomplished during the
preceding year. Further, we encourage the recipient to maintain a long-term relationship with the
SPORE and with his or her mentor.

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Ongoing Review/Evaluation of the Overall Program. The CEP will be reviewed on an annual basis
by the Internal and External Advisory Boards (IAB and EAB). The review will consist of feedback
solicited from both awardees and mentors as to problems in the CEA process. In addition, the
entire program is on display at each annual SPORE retreat. Here, the IAB and EAB members
have a chance not only to meet the CEP awardees, but to also measure the progress of the entire
program. Each CEP candidate summarizes his or her work at the retreat meeting. Any problems
identified by either committee will be brought to the attention of the SPORE Directors. These will
be documented, as will any corrective action that is taken.
Evaulation of Individual CEP Award Recipients. One of the principal functions of the SPORE is
oversight and monitoring of the quality of the science and the progress of the projects and
program. CEP recipients provide annual progress reports during their funding period. SPORE
CEP awards are discussed at the monthly Governance Committee meetings, and their Principal
Investigators present the progress of the developmental projects on a rotating basis. In addition,
they are presented at the yearly Retreat. The progress that CEP recipients make is judged not
solely on the attainment of the objectives outlined in the proposal, but also on the
ability of the award recipient to make progress in becoming established as an independent
investigator focused
on prostate cancer translational research. Thus, in contrast to Developmental Awards (which are
more narrowly focused), CEP awardees can revise their scientific aims if their initially proposed
work meets insurmountable obstacles, provided that the adjusted aims remain committed to
scientifically sound efforts in translational prostate cancer research. As a whole, we feel that the
CEP recipients have made excellent progress in the last cycle of our SPORE, and such
modifications of CEP projects have not been necessary.
Managing Progress toward Stated Aims. When progress is made, several scenarios that lead to
a variety of outcomes are possible. These scenarios include: 1) the need for additional seed
money, 2) transition into SPORE Principal Investigator status, 3) requirement for additional
independent funding, and 4) completion of stated Aims without requirement of continued
investigation of the initial hypothesis. In the first scenario, the SPORE Directors with advisement
from the CEP Director and Governance Committee, possesses the option to renew funding
through the CEP or possibly DRP mechanism. In any scenario, the CEP recipient will be
encouraged to seek funding (e.g. NIH R01 or DOD) to expand or continue the breadth or depth
of his/her translational prostate cancer research studies.
MENTORSHIP:
Mentor Responsibility
A key component of the CEP process is provision of appropriate and effective mentoring to
facilitate the CEA awardee’s ability to make progress in his or her project and career alike. The
DF/HCC Prostate Cancer SPORE is dedicated to the mentorship and development of the CEP
awardees. The Prostate Cancer Program and SPORE have had a strong track record in
mentorship and training and conversion of junior faculty to successful independent researchers.
Mentors in this program have attracted and trained numerous junior faculty at several levels who
have come through the ranks as residents, post-docs or fellows. As mentioned previously,
selection of the appropriate mentor for awardees is a key aspect of the evaluation process, and
in almost all cases the candidate will have selected (and generally will already be working with) a
highly qualified mentor. However, the Governance Committee may in some cases make further
recomemndations with respect to mentors. Particularly, in some cases it is valuable to have a comentor when the research interests of the trainee go beyond the expertise of one individual. As
previously mentioned, this strategy has worked in the past. It is the mentor’s responsibility to guide
the awardee in his/her research activities and to encourage and critique manuscripts, etc. The

15

mentor also facilitates and encourages the acquisition of peer-reviewed funding and ensures the
appropriate protection time for research of clinical faculty.
Monitoring Success of Trainee and Mentor/Trainee Relationship
The second important component of the mentorship process is oversight of the mentorship/trainee
process and monitoring the ongoing success of the trainee. This responsibility has traditionally
been that of the various Cancer Center Program Leaders, Department Leaders and Division
Chiefs. While this will still occur, we have further formalized a structure for oversight and
monitoring. In so doing, we have ensured that the mentor is fulfilling the mentorship role, providing
the trainee with advice both scientifically and from a career advancement perspective, and acting
as an advocate for the trainee’s potential conversion to faculty. As such, an ad hoc mentorship
committee composed of two to three SPORE individuals appropriate to the awardee’s work is in
some cases created. When issues arise, the awardee and/or the mentor can seek guidance or
help from the ad hoc mentorship group, the Governance Committee, and/or the SPORE Directors.
Monthly SPORE
meetings have and will continue to provide more frequent, informal opportunities for the awardee
to discuss potential issues. The success of this program will be measured by the progress of
awardees to productive, independently funded investigators who become contributing members
to the field of prostate cancer research
and to our SPORE, or other institutions.
SUCCESS STORIES:
The CEP is one example of the success of our SPORE. We view it as a continuum of candidate
selection, mentorship and Career Enhancement through independent investigator and beyond.
Below are examples of success stories of past CEP awardees from the DF/HCC Prostate SPORE.
Zhe Li, MD, PhD, is currently an Assistant Professor of Medicine at Harvard Medical School and
Brigham and Women’s Hospital, and is in the process of being promoted to Associate
Professor. His lab studies stem cells and cancer using mouse models. In particular, the lab is
interested in elucidating how genetic, epigenetic, environmental, and stochastic factors
contribute to the cancer phenotype, and what are the underlying molecular and cellular
mechanisms. Dr. Li’s lab studies these by applying concepts and tools from stem cell biology
and developmental biology, and by using a combination of mouse genetics, biochemistry, and
genomic approaches. Under the support of the SPORE funding, they generated and
characterized several novel Tmprss2-ETS knockin mouse models recapitulating TMPRSS2ERG or TMPRSS2-ETV1 gene fusions that are present in ~50% of human prostate cancer
cases. They have continued to use these knockin mouse models to study how TMPRSS2-ETS
fusions, including the intrachromosomal region between the TMPRSS2 and ERG loci that is
deleted in some TMPRSS2-ERG fusions, contribute to prostate cancer development and what
are the additional oncogenic events that cooperate with TMPRSS2-ETS fusions.
Currently, Dr. Li and his lab are studying the role of Wnt signaling-responsive cells in
prostate cancer, particularly in castration-resistant prostate cancer; they are also studying
potential contribution of aging to the development of prostate cancer with TMPRSS2-ETS gene
fusions. The funding from the SPORE program provided a vital financial support during Dr. Li’s
transition to independence and contributed to funded grants from his group in the last several
years, including two grants from the Department of Defense, a DF/HCC sponsored Project
Development Award, and an NIH UH2 grant, as well as several publications.
Changmeng Cai, PhD, received the SPORE career enhancement award in 2009 when he was a
postdoc in Dr. Steven P. Balk’s lab. With the support from this award, he initiated the studies on
understanding abiraterone resistance in xenograft models (aim 1) and determining the

16

mechanisms mediating transcriptional repression function of AR (aim 2). These studies were the
foundations of his future research career and he has published a number of papers that were
related to the support from this award. Particularly, the study of AR transcriptional repression
function lead to a major publication in Cancer Cell (2011) and a K99/R00 grant (2012) from the
NCI/NIH. With the support from K99/R00 grant, Dr. Cai was able to successfully establish his
independent research lab at University of Massachusetts Boston in 2015. Directly related to his
CEP award, Dr. Cai received the Pathway to Independence award from the NCI/NIH, as well as
multiple publications.
Dr. Cai is currently in a position of Assistant Professor at Center for Personalized Cancer
Therapy (CPCT), a joint program of University of Massachusetts Boston and DFCI. His research
is focusing on understanding the biology and function of androgens and its receptor in prostate
cancer cells and targeting androgen receptor for treatment of castration resistant prostate
cancer. He has been in prostate cancer research field for more than 15 years and published
numerous papers for basic and translational studies. Currently, research in his lab focuses on
three aspects of prostate cancer biology (1. To understand the mechanisms that determine the
AR transcriptional repression activity and develop strategies to enhance the efficacy of high
androgen treatment for CRPC patients, 2. To study the function and activity of lysine-specific
demethylase 1 and its epigenetic regulation on AR activity, 3. To understand the mechanisms
that contribute for the resistance to abiraterone and enzalutamide) and all these projects were
initially related to the specific aims of the 2009 CEP award. Since Dr. Cai joined the CPCT, he
was continuously supported by DF/HCC prostate cancer SPORE through the joint program and
even received a Developmental Project Award in 2015. Additionally, he has recently been the
recipient of two awards from the U.S. Army: The Prostate Cancer Research ExplorationHypothesis Development Award, and the Research Idea Development Award.
Svitlana Tyekucheva, PhD, received a CEP award from the Prostate SPORE in 2012 when she
was a Research Associate. This award helped generate preliminary data for the NCI funded
R21 grant in 2014. Two publications resulting from this work are in preparation, one about batch
effect correction and preprocessing of the FFPE transcriptomic data, and the other about
differential gene expression and its association with lethality in prostate cancer subtypes defined
by ERG fusion, PTEN loss and their combinations. In 2013, Dr. Tyekucheva was promoted to a
Research Scientist position.
Dr. Tyekucheva actively collaborates with current SPORE investigators: Dr. Loda, Dr.
Mucci and Dr. Penney. She is interested in developing reproducible diagnostic and prognostic
signatures in prostate cancer using high-dimensional ‘omic’ data, which includes preprocessing
methods for the high-throughput assays, application of machine learning technics and designing
discovery and validation studies to ensure best reproducibility of the results. As a part of the
Biostatistics Core, Dr. Tyekucheva gained extended expertise in metabolomics data analysis,
and was invited as a guest lecturer at the AACR Methods Workshop “Complex measurements
of tumor metabolism” in 2016. She also co-authored a chapter entitled “Bioinformatic Analysis of
Epidemiological and Pathological Data” in the book “Pathology and Epidemiology of Cancer”
edited by Drs. Mucci and Loda et al. Dr.Tyekucheva is Co-PI of proposed Core B.
Jennifer R. Rider, ScD, MPH, is currently Assistant Professor in the Department of
Epidemiology at the Boston University School of Public Health and Adjunct Assistant Professor
in the Department of Epidemiology at the Harvard T.H. Chan School of Public Health. As a
cancer epidemiologist focusing almost exclusively on prostate cancer, she uses epidemiologic
methods to identify patient and tumor characteristics that could prevent lethal disease, improve
risk prediction, or reduce overtreatment. She has utilized data from large Swedish populationbased studies and a Swedish randomized trial (SPCG-4), Swedish clinical cohorts, as well as
the Harvard-based Physicians’ Health Study and the Health Professionals Follow-up Study. Dr.

17

Rider’s current research involves uncovering contributors to prostate cancer disparities by
utilizing the diverse prostate cancer patient population at Boston Medical Center, the largest
safety net hospital in New England.
Following the completion of her DF/HCC Prostate SPORE Career Development Award,
Dr. Rider was selected for a Prostate Cancer Foundation Young Investigator Award and an
Eleanor and Miles Shore 50th Anniversary Fellowship for Scholars in Medicine from Harvard
Medical School. In 2016 she was awarded an Early Career Catalyst Award from the Boston
University School of Public Health. Dr. Rider currently has 73 published original research
articles, 66 in the area of prostate cancer. One of her first-authored papers was selected as the
Best Clinical Research Paper of 2012 by European Urology (Popiolek and Rider et al, Eur Urol
2013), and in 2016 her first-authored paper was among European Urology’s Top 5 most
downloaded papers of the year (Rider et al, Eur Urol 2016). Dr. Rider has also served on
multiple grant review panels for the Department of Defense Prostate Cancer Research Program
and the National Cancer Institute.
Mark Pomerantz, MD, specializes in genitourinary oncology with a scientific interest is the
genetics of disease. A focus of his work has been prostate cancer epigenetics. Much of his
effort, including his preliminary experiments, have been supported by the DFCI/HCC Prostate
Cancer SPORE. His team has developed the methods for performing chromatin
immunoprecipitation followed by high throughput sequencing (ChIP-seq) in primary human
prostate tissue. They have, for the first time, annotated androgen receptor (AR) binding
genome-wide in a cohort of primary prostate tumor and matched normal prostate tissue. They
demonstrated that the pattern of AR binding shifts consistently from normal to tumor tissue
across all subjects. The tumor-only and normal-only AR sites are highly informative. The tumoronly sites are co-occupied with two transcription factors, FOXA1 and HOXB13. Dr. Pomerantz
and his team further demonstrated that introduction of these transcription factors into a normal
prostate cell line model causes a shift in AR binding from a normal to tumor pattern (Pomerantz
et al, Nature Genetics, 2015). The findings provide new insight into the factors involved in
prostate tumorigenesis and identify particular genetic loci and genes that warrant further
investigation. This work is ongoing and has attracted substantial funding, including an NIH/NCI
R01 (R01CA193910-01) and a Prostate Cancer Foundation Challenge Award. Dr. Pomerantz
is the clinical co-PI of Project 3 in the current application.
Akash Patnaik, MD, PhD, is currently an Assistant Professor of Medicine within the Section of
Hematology/Oncology, Director of the Laboratory for Developmental Therapeutics and
Attending Physician within the Genitourinary Oncology Program at the University of Chicago
Comprehensive Cancer Center. Dr. Patnaik and his translational laboratory research team focus
on targeting PI3K signaling and DNA repair pathways to convert PTEN-deficient cancers from
immunologically “cold” to “hot” tumors. He has recently published a groundbreaking paper in
Cancer Discovery that represents a paradigm shift in our understanding of how tyrosine kinase
inhibitors such as cabozantinib may activate anti-tumor innate immunity resulting in
eradication of refractory murine PTEN/p53 deficient cancers. This discovery opens the door to
investigating combination trials of tyrosine kinase inhibitors with adaptive immunotherapy, such
as T-cell checkpoint blockade or vaccine-based approaches. In addition to his laboratory focus,
Dr. Patnaik is a Principal Investigator on several early-phase prostate cancer clinical trials
(investigator-initiated and industry-sponsored), and serves as a national correlative science
chair for an Alliance Foundation clinical trial in prostate cancer. In the clinic, he focuses on the
treatment of patients with genitourinary cancers, which include prostate, kidney, bladder and
testicular cancers.
Following his SPORE Career Development Award, Dr. Patnaik has been a Principal
Investigator recipient of numerous grants/awards in recognition for his recent work, which

18

include the DOD Prostate Cancer Research Program Physician-Researcher Award, BristolMyers Squibb/International ImmunoOncology Network Award, Cancer Research Foundation
Young Investigator Award, American Cancer Society Research Grant and Phi Beta Psi
Research Organization Award. Most notably, Dr. Patnaik and his research team won the
prestigious Prostate Cancer Foundation Challenge Award, given to 8 teams internationally,
chosen from a global competition of 100 applications from 67 cancer research centers in 14
countries.
TRACK RECORD OF CAREER ENHANCEMENT RECIPIENTS FROM THE CURRENT
FUNDING CYCLE AND THEIR ACCOMPLISHMENTS
Awardees from previous funding cycle (2013-2018):
Over the course of the last funding cycle we funded 9/37 (24%) CEP applicants who applied. With
a commitment of further institutional resources in the ciurrent application, we anticipate being able
to increase the number of awards. The following investigators were recipients of CEP awards in
our third cycle of funding (2013-2018) and are listed in Table 4.

19

Table 4. Career Enhancement Program Projects, 2013-2018
2013-2014 Awards
RFA not distributed; 2nd year of funding awarded to the 2012 Projects
PI(s)
Institution
Project Title
Svitlana
DFCI
RNA-Seq profiling of formalin fixed paraffin
Tyekucheva, Ph.D
embedded prostate cancer samples
2014-2015 Awards
5 Applications Received; 2 NEW Projects Funded
PI(s)
Institution
Project Title
Atish Choudhury,
DFCI
Genomic profiling of circulating tumor cells
M.D., Ph.D.
in a trial of combined crizotinib and
enzalutamide
Adam G.
BIDMC
Molecular basis for progression to Gleason
Sowalsky, Ph.D.
4 Prostate Cancer
2015-2016 Awards
9 Applications Received; 2 NEW Projects Funded
PI(s)
Institution
Project Title
Laura Cato, Ph.D
DFCI
Cochaperone Control of Androgen
Receptor Action: Implications for Prostate
Cancer Therapy
Lauren Harshman,
DFCI
Collection of Specimens and Clinical Data
MD
for Patients with Prostate Cancer or at High
Risk for
Prostate Cancer
2016-2017 Awards
6 Applications Received; 2 NEW Projects Funded
PI(s)
Institution
Project Title
Sen Chen, Ph.D.
BIDMC
Targeting Apoptopic Pathways in Advanced
Prostate Cancer
DFCI
Combinational therapy study with PI3K
Xueliang (Gary)
specific
inhibition in prostate cancer
Gao, Ph.D.
2017-2018 Awards
17 Applications Received; 3 NEW Projects Funded
PI(s)
Institution
Project Title
Sarah Markt
HSPH
Circadian rhythm disruption and advanced
prostate cancer
Kent Mouw
DFCI
Developing Tools to Study DNA Repair
Deficiency in Prostate Cancer
Daniel Schmidt
BIDMC
Investigating PKM2/targeted Therapy for
the Treatment of Prostate Cancer

Total Cost
$87,464

Total Cost
$80,697

$80,696

Total Cost
$77,400

$77,400

Total Cost
$83,540
$83,541

Total Cost
$85,935
$89,000
$85,935

We list below the specific aims of each project and then in a table list how these projects have
enhanced the research environment (grants and further funding obtained). Publications

20

consequent to their SPORE participation that are relevant to progress in translational cancer
research are listed directly after this narrative.
Svitlana Tyekucheva, Ph.D.
“Methods for RNA-Seq profiling of formalin fixed paraffin embedded prostate cancer
samples”
Specific Aims:
The goal of this project is to determine feasibility of RNA-Seq approach to the gene expression
profiling of the formalin-fixed paraffin embedded (FFPE) prostate tissues and to identify
peculiarities/patterns in the data related to the FFPE-specific RNA fragmentation and
degradation that require development of novel bioinformatical approaches.
Atish Choudhury, M.D., Ph.D.
Genomic profiling of circulating tumor cells in a trial of combined crizotinib and
enzalutamide
Specific Aims:
Aim 1: Whole-exome sequencing of CTCs before treatment and at progression to assess for
genetic determinants of response and resistance to crizotinib and enzalutamide
Aim 2: RNASeq of CTCs on treatment with crizotinib and enzalutamide to assess
pharmacodynamic response, and at progression to assess resistance pathways
Aim 3: Generation of comparator gene expression profiles from spiked cells for interpretation of
resistance pathways
Adam G. Sowalsky, Ph.D.
Molecular basis for progression to Gleason 4 Prostate Cancer
Specific Aims:
Aim 1: Identify mechanisms that drive progression to higher-grade prostate cancers.
Aim 2: Identify the spectrum of genomic lesions predictive of Gp3 cancers coincident with Gp4.
Laura Cato, Ph.D.
Cochaperone Control of Androgen Receptor Action: Implications for Prostate Cancer
Therapy
Specific Aims:
The overreaching goal of the project was to characterize the mechanism by which the
cochaperone Bag-1L modulates androgen receptor (AR) activity in hormone-dependent
and castration-resistant prostate cancer (CRPC), and to generate knowledge on the
potential of this protein for the therapeutic intervention in prostate cancer. The three specific
aims to address this were:
1. Examination of the relevance of Bag-1L in prostate cancer and in CRPC
2. Characterization of the Bag-1L/AR interactors in prostate cancer and in CRPC
3. Investigation of Bag-1L/AR inhibitors and analysis of their potency in prostate cancer.
Lauren Harshman, M.D.
The impact of SLCO genes and common medications such as statins on abiraterone
acetate efficacy in prostate cancer.
Specific Aims:
The primary objective of the study was to assess whether statins impact the efficacy of
abiraterone acetate (AA) in patients with advanced castration-resistant prostate cancer (CRPC).
Statins may compete with AA for influx by the membrane transporter SLCO2B1, which could
negatively impact its efficacy.

21

Sen Chen Ph.D.
Targeting Apoptosis Pathways in Prostate Cancer: RTK Inhibitors Synergize with
Navitoclax Through Downregulation of MCL1
Specific Aims:
Aim 1. Assess the effect of multiple kinase inhibitors on MCL1 expression in LNCaP xenografts
Aim 2. Assess the response to therapy with Navitoclax in combination with kinase inhibitors that
reduce MCL1 in LNCaP xenografts
Gao, Xueliang (Gary) Ph.D.
Project Title: Combinational therapy study with PI3K specific inhibition in prostate
cancer

Specific Aims:
Aim 1. To evaluate potential combination partners for p110β inhibitors in PCa.
Aim 2. To study p110β inhibition in primary human prostate tumor explants and
organoid cultures in vitro.
Enhancement of Research Environment:
These SPORE projects enhanced the ability to develop other funded grant applications for
members of the study team, including new independent research awards as well as career
development awards for research fellows and junior faculty (Table 5). This Table does not include
leadership positions in clinical trials. Clinical trials led by Lauren Harshman and by Atish
Choudhury, are important elements of the current proposal.

22

Publication list by awardee:
Below is a summary of publications directly related to the SPORE Career Enhancement
Program Award.
Atish Choudhury, M.D., Ph.D.
Genomic profiling of circulating tumor cells in a trial of combined crizotinib and
enzalutamide
Adalsteinsson VA, Ha G, Freeman SS, Choudhury AD, Stover DG, Parsons H, Gydush G, Reed
S, Loginov D, Livitz D, Rosebrock D, Leshchiner I, Kim J, Stewart C, Rosenberg M, Francis
J, Zhang CZ, Cohen O, Oh C, Ding H, Lloyd M, Mahmud S, Helvie K, Merrill MS,
Santiago RA, O’Connor E, Jeong SH, Leeson R, Barry R, Kramkowski J, Zhang Z, Polacek
L, Lohr JG, Oliver N, Marini L, Harshman L, Tolaney S, Van Allen E, Winer EP, Lin NU,
Nakabayashi M, Taplin ME, Johannessen CM, Garraway L, Golub TR, Boehm JS, Wagle
N, Getz G, Love JC, Meyerson M. “Reproducible and scalable approach for whole-exome
sequencing of cell-free DNA from patients with metastatic cancer.” Manuscript in review.
Adam G. Sowalsky, Ph.D.
Molecular basis for progression to Gleason 4 Prostate Cancer
Sowalsky, A., Kissick, H., Gerrin, S., Schaefer, R., Xia, Z., Russo, J., Arredouani, M., Bubley,
G., Sanda, M., Li, W., Ye, H., and Balk, S.: Gleason score 7 prostate cancers emerge
through branched evolution of clonal Gleason pattern 3 and 4, Clinical Cancer Research, In
press.
*Gerrin, S., *Sowalsky, A., Balk, S., and Ye, H.: Mutation profiling indicates high grade Prostatic
intraepithelial neoplasia as distant precursors of adjacent invasive prostatic
adenocarcinoma, The Prostate. 2016: 76: 1227-1236.
Laura Cato, Ph.D.
Cochaperone Control of Androgen Receptor Action: Implications for Prostate Cancer
Therapy
Cato L, Neeb A, Sharp A, Buzon V, Ficarro S, Yang L, Muhle-Goll C, Kuznik N, Figueiredo
I, Riisnaes R, Armant O, Gourain V, Ntim EA, Rodrigues DN, Rescigno P, Adelmant G,
Westerling T, Fauser F, Wu J, Shatkina L, Ester C, Luy B, Puchta H, Stahle U, Marto
JA, Nienhaus GU, Al-Lazikani B, Salvatella X, de Bono JS, Cato ACB, Brown M (2017)
Transactivation by the intrinsically disordered androgen receptor N-terminal domain is
enabled by the cochaperone Bag-1L. (Submitted)
Cato L, Neeb A, Brown M, Cato ACB (2014) Control of nuclear receptor dynamics and
function by genomic action of molecular chaperones. Nucl Recept Signal 12: e005
Jehle K*, Cato L*, Neeb A, Muhle-Goll C, Jung N, Smith EW, Buzon V, Carbó LR,
Estébanez- Perpiñá E, Schmitz K, Fruk L, Luy B, Chen Y, Cox MB, Bräse S, Brown M,
Cato ACB (2014) Coregulator control of androgen receptor action by a novel nuclear
receptor-binding motif. J Biol Chem 289: 8839-8851

*authors contributed equally to this work
Lauren Harshman, M.D.
The impact of statin use on the efficacy of abiraterone acetate in patients with
castration-resistant prostate cancer.
Wang X, Harshman LC, Xie W, Nakabayashi M, Qu F, Pomerantz MM, Lee GS, Kantoff
PW. Association of SLCO2B1 Genotypes With Time to Progression and Overall
Survival in Patients Receiving Androgen-Deprivation Therapy for Prostate Cancer. J
Clin Oncol. 2016 Feb 1;34(4):352-9.
23

Harshman LC, Werner L, Tripathi A, Wang X, Maughan BL, Antonarakis ES,
Nakabayashi M, McKay R, Pomerantz M, Mucci LA, Taplin ME, Sweeney CJ, Lee
GM, Kantoff PW. The impact of statin use on the efficacy of abiraterone acetate in
patients with castration-resistant prostate cancer. Prostate. 2017 May;77(13):13031311
Sen Chen, Ph.D
Targeting Apoptosis Pathways in Prostate Cancer: RTK Inhibitors Synergize with
Navitoclax Through Downregulation of MCL1
Arai S*, Chen S*, and Balk SP, Kinase Inhibitors Increase MCL1 Degradation
Independent of GSK3 and Synergize with Navitoclax to Drive Prostate Cancer
Apoptosis, submitted for publication *co-1st authors
Xueliang (Gary) Gao
Combinational therapy study with PI3K specific inhibition in prostate cancer

Xueliang Gao, Shidong Jia, Onur Cizmecioglu, Manav Korpal, Joshua M. Korn, Charles
Z. Wang, Fabienne Schmit, Thanh Von, Lan Jiang, Raymond Pagliarini, Yi Yang,
Sabina Signoretti, Jean J Zhao, Guo-Cheng Yuan, Massimo Loda, Thomas M.
Roberts. Novel combination therapies for invasive castration resistant prostate
cancer based on the critical role of PI3K p110β. (submitted)
Jing Zhang, Xueliang Gao, Fabienne Schmit, Guillaume Adelmant, Michael J. Eck,
Jarrod A. Marto, Jean J. Zhao, and Thomas M. Roberts CRKL mediates p110βdependent PI3K signaling in PTEN-deficient cancer cells. Cell Reports, in press.
EXAMPLES OF POTENTIAL CANDIDATES FOR NEXT FUNDING CYCLE:
We list as examples of potential candidates (Table 6) for the next funding cycle the candiates
who applied most recently who we were not able to fund this year due to an overwhelming
amount of applications in response to our CEP RFA.

24

Appendix 2. Sample Mazzone Program Career Development Proposal
Submission Instructions and Template
OVERVIEW
The A. David Mazzone Research Awards Program funds 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.
Funding Agency: The funding agency for the Program is a grant from the U.S. District
Court for the District of Massachusetts of 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. The program is
administered jointly through DF/HCC and the Prostate Cancer Foundation.
Career Development Awards will support junior investigators transitioning from
training to independent investigators. Research may focus on any aspect of prostate
cancer prevention (health promotion, modifiable risk factors, new animal models and
extrapolation of these models to human cancer, genetic predisposition to prostate
cancer, detection of precursor lesions, chemoprevention, trials in human populations,
behavioral research and behavioral intervention trials); epidemiology (classic, genetic,
molecular); biostatistics; human cancer genetics; human nutrition; health services and
health policy research; and medical decision analysis. Research may also focus on
survivorship and quality of life as they relate to prostate cancer; basic and applied
research in the behavioral sciences that independently or in combination with
biomedical approaches reduces prostate cancer risk, incidence, morbidity, and mortality
over the lifespan and across the entire process of carcinogenesis from primary
behavioral prevention in youth, to screening, treatment, and survivorship.
AWARD INFORMATION
Award is for $53,000 for one year for direct costs only. The projected award period is
July 1, 2018 to June 30, 2019. Two awards in total are available in this category.
ELIGIBILITY AND REQUIREMENTS
Two applicants for this award will be recommended by the Principal Investigators of the
DF/HCC SPORE in Prostate Cancer Developmental Research Project based on the
following criteria:
Significance. The scientific merit/quality of the proposal (coherent presentation,
candidate's own work, prostate cancer focus, translational nature)
Candidate. Quality of prior mentored period of cancer research training;
demonstrated interest in problems relevant to prostate cancer, and potential
ability to successfully manage an independent research project.
Mentor(s): Mentor's statement describing the potential and capability of the
candidate to become a successful independent investigator.

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Research Plan. Appropriateness of the proposed research project for the
candidate’s stage of research development; proposed research relevance to
stated career objectives.
Career Development Plan. Appropriateness of the career development plan
and the likelihood that the award will contribute substantially to the scientific
development of the candidate and consistency of the career development plan
with the candidates prior research experiences and current research career
goals.
Environment and Institutional Commitment to the Candidate. The quality of
the research environment (mentor support, resources available) and institutional
commitment to fostering the career development of the candidate.

APPLICATION COVER PAGE AND ABSTRACT
Principal Investigator
Name:
Degrees:
Appointment/title:
Institution:
Department:
Address:
Telephone Number:
Email Address:
DF/HCC Member (yes/no):
Collaborators/Mentors:
Name:
Degrees:
Appointment/title:
Institution:
Department:
Address:
Telephone Number:
Email Address:
DF/HCC Member (yes/no):
Add persons as needed
Abstract:
Description of the project in Laymen’s Terms ($250 words max)

26

PROPOSAL SUBMISSION INFORMATION
Required items (8):
1. Application Cover Page and Abstract (see above)
2. 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.
3. Applicant’s Career goals
4. Mentor’s letter of support
5. Applicant’s NIH Biosketch
6. Mentor’s NIH Biosketch
7. Budget: Budget requests and budget justifications should be submitted as NIH 398
form with major divisions of funds (personnel, travel, supplies, other, etc.; with
adequate rationale). Funds may be used for up to $53,000 for one year for salary
and fringe for PIs, up to $3,000 per year for their scientific meetings expenses, and
materials as needed.
8. IRB approval documents and Human Subject Training if applicable (IRB
approval will be required prior to funding)
Format: Items 2 – 7 (above) must be compiled and submitted as a single PDF file. The
3 page research proposal should include an introduction, specific aims, and research
strategy (significance, innovation, and approach). Use standard size paper (8 ½” x 11”),
Arial or Helvetica font, 11 points or larger with margins ½ inch or larger (top, bottom,
left, and right). Figures and legends must be of legible size and legible when printed in
black and white.
Submit Proposal via email to [e-mail]
Application Deadline: 11:59:59 PM EST, Thursday, May 31, 2018.
PROGRESS REPORTS
Grantees will be required to submit a progress report to the Mazzone Program including
detailed narrative, and expenditure reports (a report form and instructions will be
provided to the PI before the end of the award period). Funding will be disbursed based
on quarterly invoicing and final funding disbursement will be contingent upon
satisfactory receipt of progress and accounting.
Mazzone Program Contact:
Juan Carlos Hincapie
Mazzone Program Administrator
Tel: [phone]
Email: [e-mail]

27

Program Director/Principal Investigator (Last, First, Middle):
FROM

DETAILED BUDGET FOR INITIAL BUDGET PERIOD
DIRECT COSTS ONLY

THROUGH

List PERSONNEL (Applicant organization only)
Use Cal, Acad, or Summer to Enter Months Devoted to Project
Enter Dollar Amounts Requested (omit cents) for Salary Requested and Fringe Benefits
NAME

ROLE ON
PROJECT

Cal.
Mnths

Acad.
Mnths

Summer INST.BASE
Mnths
SALARY

SALARY
REQUESTED

FRINGE
BENEFITS

TOTAL

PD/PI

SUBTOTALS
CONSULTANT COSTS
EQUIPMENT (Itemize)

SUPPLIES (Itemize by category)

TRAVEL
INPATIENT CARE COSTS
OUTPATIENT CARE COSTS
ALTERATIONS AND RENOVATIONS (Itemize by category)

OTHER EXPENSES (Itemize by category)

CONSORTIUM/CONTRACTUAL COSTS

DIRECT COSTS

SUBTOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD (Item 7a, Face Page)

$

FACILITIES AND ADMINISTRATIVE COSTS

CONSORTIUM/CONTRACTUAL COSTS

TOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD

$

PHS 398 (Rev. 01/18 Approved Through
03/31/2020)
OMB No. 0925-0001

Page

28

Form Page 4

Appendix 3. Continuing Umbrella of Research Experiences (CURE)
Program Proposed Funding Request
July 2018 – June 2019
Program Description:
Established by Dana-Farber/Harvard Cancer Center (DF/HCC) in 2002, the Continuing
Umbrella of Research Experiences (CURE) program provides talented young minority high
school and undergraduate with the training and skills they need to pursue careers in STEMrelated fields. Since CURE’s inception, the program has trained 365 promising students from
backgrounds that have been traditionally underrepresented across the medical community.
Many of these students were the first in their families – and among the first in their communities
– to attend college.
Program Goals:
Identify, coach, and nurture talented and highly motivated underrepresented high school and
college students for potential careers in biomedical cancer research and other STEM fields.
Enhance students’ skills in best research practices, analytical thinking, oral and written
presentations, and ethics.
Expose students to real-time laboratory/research and clinic settings while simultaneously
giving practical meaning to academic course work through novel professional and personal
development.
Proposed Program Expenses:
Total Amount Requested $20,000
Three stipends of $5000 for students participating in an 8-12-week summer research
experience. $3000 to plan and support professional development activities including college
readiness and student travel to attend and present at conferences. $2000 to supplement the
cost of offering a networking event with other summer research programs related to career
opportunities beyond academia.

Expense
Stipends
Summer salaries of three trainees at
$5,000 per student
Stipends Subtotal

Cost
$15,000
$15,000

Professional Development (PD)
PD activities including college
readiness, travel scholarships for
three students to attend national
conferences
Networking event for current CURE
students and other similar research
programs program alumni
Professional Development Subtotal

$3,000

$2,000

$5,000

Total

$20,000

29

Appendix 4. Grant Funding Plan and Accounting Report by DanaFarber Cancer Institute

30

31

Appendix 5. Original Plan for Program Reporting to the Court

Note:
As per later agreement with the Court, Research Progress and Accounting
reports are for annual research activities covering the period August 1 to
July 31 each year, as opposed to the period July 1 to June 30.

32