Porter v. Tap Pharmaceutical, et al

Filing 586

Judge Richard G. Stearns: ORDER entered. MEMORANDUM Acknowledging Mazzone Awards Program Report #7.(Zierk, Marsha)

UNITED STATES DISTRICT COURT
DISTRICT OF MASSACHUSETTS
M.D.L. NO. 1430
CIVIL ACTION NO. 01-10861
IN RE LUPRON® MARKETING AND
SALES PRACTICES LITIGATION
MEMORANDUM ACKNOWLEDGING THE RECEIPT AND
REVIEW OF THE A. DAVID MAZZONE THIRD ANNUAL RESEARCH
AWARDS PROGRESS and ACCOUNTING REPORT #7
December 22, 2014
STEARNS, DJ.
The A. David Mazzone Research Awards Program is reaching the end
of a fourth year of medical investigation dedicated to finding a cure for
prostate cancer.1 The Mazzone Awards Program was made possible by a cy
pres distribution of funds remaining after the satisfaction of individual
claims arising from the settlement of a national class action involving
overpricing of the prostate cancer treatment drug marketed as Lupron®.
See In re Lupron Mktg. and Sales Practices Litig., 677 F.3d 21 (1st Cir.
2012). The Mazzone Awards Program presently supports the work of 137
The Program was established in the memory of A. David Mazzone,
who served for twenty-six years as a Judge of the United States District
Court of Massachusetts. Judge Mazzone died prematurely of complications
of prostate cancer. The Program is also intended to honor the other victims
of prostate cancer, many of whom were members of the plaintiff class in the
underlying Lupron® litigation.
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investigators worldwide who are involved in thirty-eight separate research
projects.2
On November 10, 2014, Dr. Philip Kantoff of the DanaFarber/Harvard Cancer Center (DF/HCC), the principal investigator, and
Dr. Jonathan Simon, President of the Prostate Cancer Foundation (PCF),
and the co-principal investigator, submitted the seventh in a scheduled
series of Progress and Accounting Reports for the court’s review.3 The
Report covers the period from August 1, 2013, to July 31, 2014. The Report
summarizes the research progress and accountings of the current grantees,
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The specified goals of the Program are as follows:

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 which 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.
Of the current thirty-eight research initiatives, thirty-three are
funded by DF/HCC and five by PCF Challenge Awards.
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as well as and the highlights of the A. David Mazzone Awards Program
Retreat held on May 6, 2014, at the Dana-Farber Cancer Institute. The
court had the pleasure of attending the Retreat along with members of the
prostate cancer research community.
Table 1 of Report No. 7 lists each of the current Mazzone Awards.
They are as follows:
DF/HCC Roster I (August 2011-July 2013)
High Impact
Matthew Freedman (Dana Farber Cancer Institute (DFCI)) Functional annotation of prostate cancer risk loci discovered through
GWAS
Career Development
Kathryn Wilson (Harvard School of Public Health (HSPH)) Phosphorus and calcium intake, tumor microenvironment and prostate
cancer progression
Disparities Research
Donna Berry (DFCI) - Enhancing usability of the Personal Patient
Profile-Prostate (P3P) for black and Hispanic men
Nancy Keating (Harvard Medical School (HMS)) - Understanding
racial differences in prostate cancer mortality
DF/HCC Roster II (August 2012 – July 2014)
High Impact
Levi Garraway (DFCI) - Defining the spectrum of resistance to
androgen ablation therapy in prostate cancer
3

Steven Balk (Beth Israel Deaconess Medical Center (BIDMC)) Molecular characterization of Gleason 3 tumors that progress to Gleason
4
Zhe Li (Brigham & Women’s Hospital (BWH)) - Castration-resistant
luminal cells in the prostate
Massimo Loda (DFCI) - Developing a blood-based metabolomic
signature of Gleason score
Robert Cormack (DFCI) - Nanoplatforms for localized chemo
radiation therapy for prostate cancer
Lupron-Treatable Diseases and Conditions
Aaron Styer for Jose Teixeira (Massachusetts General Hospital
(MGH)) - Pre-clinical in vivo studies investigating the efficacy of mTOR
inhibitors for uterine fibroids
Elizabeth Henske (BWH) - Targeting
mechanisms in lymphangioleiomyomatosis LAM

estrogen-dependent

Career Development
Julie Batista/nee Kasperzyk (BWH) - Within-person molecular
differences in primary versus metastatic prostate cancer
Jennifer Rider (HSPH) - Inflammation and tissue microenvironment
as predictors of prostate cancer risk, mortality and therapy response
among men with an initially benign TURP
Disparities Research
Lorelei Mucci (HSPH) - Estimating the prostate cancer burden
attributed to lifestyle and genetic factors among African-American and
white men

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Christopher Lathan for Karen Emmons (DFCI) - Factors influencing
willingness to participate in biobanking among Black men with and atrisk for prostate cancer
Community Outreach
Jennifer Allen (DFCI) - Engaging
communities in prostate cancer education

African

American

faith

DF/HCC Roster III (August 2013 – July 2015)
High Impact
Karen E. Knudsen (Thomas Jefferson University) - Co-Targeting AR
and ERG to treat advanced prostate cancer
Mark Pomerantz (DFCI) - Genome-wide analysis of response to
androgen deprivation therapy
Peter Nelson (University of Washington) - Targeting androgen
receptor bypass pathways
High Impact Trials
Mary-Ellen Taplin & Elahe A. Mostaghel (DFCI) Clinical trials
assessing mechanisms mediating sensitivity and resistance to
enzalutamide
Project Development
Gregory Verdine (Harvard University) - Targeting the co-activator of
the androgen receptor
Karen Cichowski (BWH) - Developing novel targeted therapies for
advanced prostate cancer
Career Development
Jennifer Sinnott (HSPH) - Impact on prognosis of inter- and
intratumor heterogeneity in prostate cancer
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Disparities Research
Jennifer Rider for Lisa Signorello (HSPH) - Chronic stress and racial
disparities in prostate cancer
Community Outreach
Larissa Nekhlyudov, M.D. (Harvard Vanguard Medical Associates) Shared medical appointments: An innovative approach to prostate cancer
survivorship care
PCF Challenge Awards – Roster II (August 2012 – July 2014)
Bert O’Malley, M.D. (Baylor College of Medicine) - Targeting the p160
steroid receptor coactivators (SRCs) in castration resistant prostate
cancer
Martin Pomper, M.D. (Johns Hopkins University) - Promoter-driven
molecular radiotherapy for prostate cancer
PFC Challenge Awards – Roster III (August 2013 – July 2015)
Jennifer Wu, Ph.D. (Medical University of South Carolina) - Synergistic
immune and lipid metabolism targeting for metastatic prostate cancer
The court is satisfied with the financial accounting of the Mazzone
Program to date and is pleased with the solid scientific advances made by
the individual investigators.
Special insight into the accomplishments of the Mazzone Program
investigators was provided by the presentations given by the 2011 and 2012
grantees at the Retreat sponsored by DFCI on May 6, 2014. The Retreat
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was hosted by Dr. Edward J. Benz, Jr., the President of the Dana-Farber
Cancer Institute, and by Dr. Kantoff. I have attempted to summarize below
some of the highlights of the showcased presentations.
Session I: High Impact Awards
1. Charting the androgen receptor cistrome in human prostate tissue,
Matthew Freedman M.D., Dana-Farber Cancer Institute
Dr. Freedman’s clinical interest involves a shift of the traditional focus on
genetic to epigenetic molecular studies. The goal of his research is to use
ChIP-sequencing technique to learn define how the androgen receptor (AR)
functionally interacts with genetic sites across the human genome.
Dr. Freedman evaluated primary prostate tumors and matched normal
samples from prostatectomy specimens with more than 70,000 AR binding
site. Some were exclusively from tumor tissue, others exclusively from
normal tissue, and some expressed in both. The analysis of these AR
binding sites identified two different motifs (HOXB13 and FOXA1), which
co-localize with AR only in tumors. Dr. Freedman’s work revealed
remarkable plasticity of the AR program during tumorigenesis, dependent
on FOXA1 and HOXB13. Interestingly, mutations in HOXB13 were shown
to be related to prostate cancer risk.
2. Molecular characterization of Gleason 3 tumors that progress to
Gleason 4, Steven Balk M.D., Ph.D., Beth Israel Deaconess Medical
Center
Dr. Balk concentrates on the study of early stage localized prostate cancer,
with the goal of identifying those tumors with low grade features that are
more likely to progress to aggressive stages of the disease. For that purpose,
microdissection of the Gleason 3 and Gleason 4 areas is performed within
the same tumor and analyzed using exome sequencing (DNA analysis
looking at the occurrence of mutations in the protein-coding area of the
genome). Additional in-depth analysis of selected relevant oncogenes as
well as distinct expression of genes between the two patterns is also
performed. To date, several tumors have been identified as confirming
clonal mutations in both Gleason 3 and Gleason 4 areas (meaning the
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evolution from a low grade to a higher grade tumor). Distinct molecular
alterations between low grade and high grade such as loss of PTEN allele
and some new mutations have also been observed, as well as biological
pathways that have been associated with higher grade tumors.
3. Characterizing resistance to androgen deprivation in prostate
cancer, Levi Garraway M.D., Ph.D., Dana-Farber Cancer Institute
Prostate cancer is an androgen-dependent disease. Several therapeutic
agents targeting the androgen receptor (AR) pathway have been developed
to treat the disease. However, different mechanisms of resistance to these
agents have also been identified. The goal of Dr. Garraway’s research is to
identify molecular pathways driving resistance to androgen deprivation
therapy through AR-dependent and AR-independent mechanisms.
Dr. Garaway identified several new genes of interest using loss of function
RNAi screens as drivers of androgen resistance in prostate cancer cell lines.
Among them, loss of inositol phosphatase INPP5A, a potential tumor
suppressor gene, and loss of PLZF, a known tumor suppressor gene, were
able to sustain growth even in the absence of androgens. The
understanding of these mechanisms of resistance allows the development
of agents to attack both androgen receptors and mechanisms of resistance
in order to achieve durable responses in patients with advanced form of the
disease.
Session II: Student Training, Career Development, Disparities Research
1. Student Perspective: Prostate Cancer Research, Irene Wong,
Brandeis University, Dana-Farber/Harvard Cancer Center,
CURE Program
Inspired by current breast cancer research, Irene Wong has focused her
study on GRANULIN (GRN), a protein that promotes tumor growth by
converting normal fibroblast (cells of the microenvironment present in
normal and tumor tissues) to act as tumor fibroblast (providing a favorable
environment for tumor survival and proliferation). Specifically, this protein
has been identified to be present in the development of tumors in young
patients.

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Investigator Wong’s work has characterized the relationship between aging
and the ability of bone marrow cells to promote tumor growth. This ability
might be related to a lower expression of GRN in bone marrow cells, and
decreased amounts of GRN at the tumor site, and ultimately to a reduction
of fibroblast transformation to “tumor fibroblast.”
2. Analysis of AR signaling in circulating tumor cells in prostate
cancer, David Miyamoto MD, PhD, Massachusetts General
Hospital
Cells released by a tumor in the blood stream are rare. If isolated, however,
they can be used as a form of “liquid biopsy.” Based on a new technology
developed at the MGH (CTC-chip), scientists are able to measure AR
activity using PSA/PSMA expression ratio in the CTCs.
Castration sensitive tumor cells are characterized by high PSA and low
PSMA expression. On the other hand, castration resistant cells express low
PSA and high PSMA. PSA and PSMA levels in CTCs are used by Dr.
Miyamoto to measure AR signaling status in “real time” during therapy. Dr.
Miyamoto’s research suggests a potential role for the measurement of AR
activity in CTCs to be used as a predictor of patient response to endocrine
therapy.
3. Prostate cancer genetic variants, molecular alterations and
mRNA expression, Kathryn Penney ScD, Brigham and Women’s
Hospital
Dr. Kathryn Penney received the A. David Mazzone Career Development
Award for her work on prostate cancer risk variants analysis. Dr. Penney
compared tumor samples with normal tissue from the same organ in a large
number of patients to identify the genetic variants potentially involved in
cancer development. To determine the biological mechanism of these
variants entails three major potential outcomes: (1) the understanding of
the etiology of the disease; (2) finding an explanation of the mechanism
driving epidemiologic results; and (3) identifying new treatment and
prevention strategies.
The work presented by Dr. Penney correlated genetic variants with the risk
of developing prostate cancer. Interestingly, genetic variants are specifically
associated with two distinct molecular subtypes of prostate cancer (ERG+
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and ERG- tumors). These associations suggest that prostate carcinogenesis
may be different for men with different genetic predispositions.
4. Phosphorus and calcium intake, tumor microenvironment and
prostate cancer progression, Kathryn Wilson ScD, Harvard
School of Public Health
High calcium is a potential risk factor for prostate cancer. Dr. Kathryn
Wilson, a Harvard School of Public Health epidemiologist, presented data
from a health professional follow-up study involving more than 51,000
subjects. In this cohort, questionnaires were directed specifically to diet and
lifestyle. In addition, where available, specimens were obtained from
patients who developed prostate cancer.
An analysis of proteins related to the bone metastasis mechanism was
conducted with primary tumor specimens. This analysis suggested that two
proteins [osteopontin and calcium S receptor (CaSR)] are associated with
an increased risk of lethal prostate cancer. Questionnaire data was also
correlated with protein expressions associated with a high calcium intake.
The results support the hypothesis that diet and lifestyle may impact the
risk of prostate cancer and its behavior.
5. Estimating the prostate cancer burden attributed to lifestyle and
genetic factors among African-American and white men, Lorelei
Mucci ScD, Harvard School of Public Health
Dr. Lorelei Mucci’s work is built on observed disparities in prostate cancer
mortality by race and ethnicity. African-American men in the United States
have the highest risk of developing prostate cancer, a risk sixty times
greater than men in low risk countries (such as Japan and China).
Moreover, they are 1.6 times more likely to be diagnosed with and 2.4 times
more likely to die from prostate cancer than white men in the United
States. Even when adjustments for differences in access to treatment and
care are made, marked disparities remain.
The use of three large cohort studies’ datasets were used by Dr. Mucci to
assess the different risk factors associated with prostate cancer in AfricanAmerican men. Significantly, 7 out of 10 factors were more pronounced in
African-American than for white men, including obesity and low vitamin D
intake. Lifestyle and genetic risk factors associated with prostate cancer
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may explain a substantial portion of the differing incidence and mortality
or prostate cancer among white men. Dr. Mucci’s work raises additional
concerns about future patterns of prostate cancer mortality among
Hispanic men given trends of increasing obesity, vitamin D deficiency, and
lower levels of physical activity.
Session 3: Prostate Cancer Foundation Awards
1. Imaging biomarkers of treatment response using NaF PET/CT
imaging: a prostate cancer clinical trials consortium (PCCTC)
effort, Glenn Liu, M.D., Carbone Cancer Center
Dr. Liu presented the results of his innovative imaging research that can be
used to identify and characterize metastatic lesions, and may assist drug
development in the treatment of prostate cancer. Since the metastatic
disease is very heterogeneous, a quantitative total bone imaging using NaF
PET/CT is a promising new tool in evaluating treatment effects by
providing a biomarker for treatment responses. In addition, this technology
may allow for molecular image-directed biopsies leading to a better
understanding of the biology of the disease and its mechanism of
resistance.
2. Induction of synthetic lethality with epigenetic therapy (ISLET)
for systemic treatment of prostate cancer, William Nelson, M.D.,
Ph.D., Johns Hopkins Medicine
As previously discussed, epigenetic mechanisms that induce changes in
gene activity that are not caused by changes in the DNA sequence hold
promise not only for cancer biology discovery, but also for therapeutics.
This the focus of the research conducted by Dr. William Nelson at John
Hopkins.
The objective of Dr. Nelson’s work is to build a therapeutic combination
agent that would have the potential to better target prostate cancer cells.
The overall idea of this approach is that the modulation of epigenetic
mechanisms may enhance the sensibility of a therapeutic compound. This
phenomenon has been termed Induced Synthetic Lethality. To further that
purpose, Dr. Nelson has investigated the effects of decitabine, a well-known
agent used in hematology, and hypomethylates DNA, to inhibit DNA
methyltransferase (key enzymes involved in epigenetic regulation). When
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used at low dose, this agent may prove to be a promising epigenetic
therapy.
3. Promoter-driven molecular radiotherapy for prostate cancer,
Martin Pomper, M.D., Ph.D., Johns Hopkins Medicine
Targeted nanoparticles have the potential to overcome the toxicity and
efficacy limitations associated with traditional cytotoxic agents and
molecularly targeted drugs by releasing drug directly to cancer cells. Dr.
Pomper presented results of experiments with the next generation of
radiopharmaceutical compounds for detecting and guiding treatment in
prostate cancer.
4. Targeting the p160 steroid receptor coactivators (SRCs) as a
novel approach for the treatment of castration resistant prostate
cancer, Bert O’Malley, M.D., Baylor College of Medicine
The focus of the work presented by Dr. Bert O’Malley was the p160 steroid
receptor co-activator 2 (SRC2). SRC-2 is a key protein for metabolic
regulation of energy/lipids. SRC-2 also plays a role in cancer: it has been
previously demonstrated that its overexpression induces metastasis
proliferation, and on the contrary, its deletion inhibits PC metastasis in
mouse models. SRC-2 activity in cancer is related to its ability to enhance
lipid (energy) production in early metastatic cells by regulating glutaminedependent lipogenesis. The next step in Dr. O’Malley’s work is to
investigate SRC-2 as a potential target in cancer.
CONCLUSION
The court lauds the solid scientific and medical research work being
conducted under the oversight of Dr. Kantoff and Dr. Simons and the
stewardship they have exercised over the funds made available through the
Mazzone Awards Program. These have been distributed in innovative ways
that have reached out to the larger medical community. The court notes
that the next progress report is due March 30, 2015.
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/s/Richard G. Stearns___________
UNITED STATES DISTRICT JUDGE

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