RICHARD G. STEARNS, District Judge.
On November 2, 2015, Dr. Philip Kantoff of the Dana-Farber/Harvard Cancer Center (DF/HCC), the principal investigator for the A. David Mazzone Research Awards Program (Program),
Prior to the previous 2014 reporting period, the court allocated an additional $140,000 of Program monies to fund two Disparities Research grants of $90,000 and $50,000 each, and another $20,000 to support student training through the DF/HCC Cure Program. PCF also awarded its final $500,000 matching grant.
As of July 2015, year 2012 DF/HCC and PCF research award recipients had completed the maximum three year funding cycle; year 2013 grantees had completed the second year; and year 2014 grantees the first. Each award recipient has submitted annual scientific progress and financial reports for review and approval by Dr. Kantoff and Dr. Simon, where appropriate members of the Scientific Advisory Board (SAB).
The cumulative reports paint a picture of solid progress in achieving the Program's goal of finding a cure for prostate cancer and related diseases. Some highlights portrayed in Dr. Kantoff's and Dr. Simon's Report include:
In completing this high impact grant, researchers:
Dr. Garraway's team plans to continue intensive mechanistic studies of INPP5A-silencing-driven resistance to castration. Members will also initiate the CRISPRA-gain-of-function pooled screen in LNCaP cells to study resistance to CSS +/- enzalutamide or ARN-509. Dr. Garraway reports that the results achieved through the shRNA screening supported by a Mazzone Award have enabled him and members of his team, including Ginevra Botta, the postdoctoral fellow engaged in the project, to obtain the funding necessary to continue their investigative work.
The Cormack team successfully demonstrated a robust nanoparticle formulation NanoOlaparib of the PARP inhibitor Olaparib. The researchers found that NanoOlaparib has a tumor-sensitive drug release profile, is a better radiosensitizer than Olaparib in prostate cancer cells, and has 10 fold higher accumulation than Olaparib in mouse prostate tumors.
The results show great promise for NanoOlaparib as a monothearapeutic and as a radiation sensitizer in combination therapy of prostate cancer in mice. The team is in the midst of invivo animal studies in PC3, VCaP models to study the effect of NanoOlaparib on radiation when delivered intravenously and locally through brachytherapy spacers. The team's nanoformulation will provide a safe vehicle for intravenous delivery that permits doses to be delivered to the local tumor area, thereby increasing bioavailability and tumor accumulation. The team's discovery offers a superior substitute for oral administration, the currently used mode of olaparib delivery in both preclinical in vivo studies and in clinical practice.
In Aim 1, the researchers developed a novel analytic approach to quantify the population attributable fraction (PAF) to make possible a determination of differences by race in the prevalence of risk factors for lethal prostate cancer. The team's findings were replicated in both the Health Professionals Follow-Up Study (HPFS) and National Health and Nutrition Examination Study III (NHANES III) cohorts. The preliminary data show that, on average, black men are 24% more likely to smoke, 20% less likely to be taking statin medication, 11% more likely to have low vitamin D (<40ng/ml), 6% less likely to be high consumers of coffee (>4 cups/day), and 2% more likely to be diabetic when compared to white men. Moreover, the prevalence of several known potential genetic risk loci appears to differ between racial groups. These discrepancies in the prevalence of risk factors are thought likely to contribute to the racial gap in prostate-cancer specific mortality, as each factor has been shown to be significantly associated with increased risk (diabetes, low vitamin D, smoking) or decreased risk (coffee, statin use) in previous HPFS studies that used fatal prostate cancer as an endpoint. The research team also found that if black men had the same frequence of identified risk factors as white men, they would experience significant reductions in the risk of developing lethal prostate cancer: 18% for Vitamin D, 7% for obesity, 4% for coffee, 4% for current smoking, and 1% for tomato sauce (a rich source of cancer-inhibiting lycopene). In Aim 2, with the additional support of thirdparty funding, the team completed whole genome gene expression profiling for 425 men with prostate cancer in the PHS and HPFS, including 10 African-American men, gaining added valuable data.
The manuscript for Aim 1 is currently being readied for publication with data from a new, more comprehensive combined attributable fraction model designed by the team that incorporates additional linked mortality data from the NHANES III. This model will allow the researchers to more precisely estimate the racial burden of prostate cancer mortality that is attributable to dietary and lifestyle factors. To further Aim 2, the group accessed the TCGA prostate cancer data (in preparation) and are undertaking analyses to compare the mutational landscape of alterations comparing white, Asian and black men.
The Nelson team reports significant accomplishments and new avenues of research opened by work sponsored by this Mazzone Award grant. First, researchers identified several key signaling programs capable of sustaining PC growth in the absence of AR activity, the most promising of which, from a clinical perspective, is the FGF/FGFR axis. The team plans to conduct clinical tests of FGFR antagonists in men with ARlow/AR-null PC. Second, the team identified new cell surface proteins expressed in AR-null/low tumors, including members of the CEA family (CEACAM4-6), that will be useful in identifying circulating tumor cells that no longer express canonical epithelial markers or AR-regulated genes (e.g., PSMA). Third, the group identified a cohort of genes that are repressed by AR signaling and consequently de-repressed by either short-term AR inhibition or long-term AR ablation (e.g., APIPC). The team's hypothesis is that these de-repressed genes, including cMET and NFkB, activate prosurvival pathways that are critical for maintaining prostate cancer cell viability until AR signaling is reconstituted. The immediate goal is to develop a strategy for inhibiting these de-repressed genes. In the meantime, the team is preparing to publish the FGF/FGFR APIPC results with an acknowledgement of the support provided by the Mazzone Program.
The team will pursue the screening approaches it undertook with Mazzone Program support, complemented by additional transcript and mutation profiling studies, with the ultimate goal of developing an integrated assessment of cell signaling operative in AR-null cells. It will continue its collaborative work with Marc Vidal, Ph.D.'s laboratory at DFCI, in the endeavor to identify networks and pathways underlying APIPC growth and its vulnerability to targeting. Support for the further studies has been provided by the PCF and an additional grant application has been made to the Department of Defense Prostate Cancer Program.
This team worked with the Southern Community Cohort Study to gather the necessary data for the study. The data pool is derived from a cohort of 32,804 men, of whom 22,175 are African American. Within this cohort, the researchers have identified 637 cases of prostate cancer. The researchers have also acquired neighborhood crime statistics (a residential/environmental stressor) from ESRI (a geographic information systems software) and have successfully linked patterns of criminal activity to the geographical coordinates of each study participant. Once the matrix of chronic stress measures is perfected, the team intends to use Cox proportional hazards modeling to determine: (a) whether increased stress increases the subsequent risk of prostate cancer; (b) whether the association, if any, is modified by beta-blocker use or tumor grade; and (c) whether any of the racial disparity in prostate cancer occurrence can be attributed to racial differences in exposure to chronic stress.
The p160 steroid receptor coactivators (SRCs): SRC-1, SRC-2 (also known as TIF2, GRIP1, or NCOA2), and SRC-3 (also known as AIB1, ACTR, or NCOA3) are "master regulators" of the transcription factor activity that promotes cancer cell proliferation, survival, metabolism, and metastasis. SRC overexpression and overactivation occur in human cancers because of a variety of genomic, transcriptional and post-translational mechanisms. SRCs are associated with poor clinical outcomes and resistance to therapy, and are thus important therapeutic targets. In prostate cancer, the p160 SRCs play critical roles in AR transcriptional activity, cell proliferation, migration, and resistance to androgen deprivation therapy. Depletion of p160 SRCs in hormone-dependent prostate cancer, and in castrationresistant prostate cancer cell lines impedes cell proliferation and AR transcriptional activity, including that of the AR-dependent induction of TMPRSS2-ERG. Elevated expression of all three p160 SRCs occurs in prostate cancer and is associated with a shorter time to recurrence and overall more aggressive disease. Gene amplification, point mutations, and widespread overexpression of SRC-2 (NCOA2) are associated with increased AR transcriptional activity and poor clinical outcomes.
The major findings of Dr. O'Malley's study include: (1) the discovery of tool compounds that interrupt SRC-AR interaction, thus creating a pathway to a new class of experimental medications for the treatment of advanced prostate cancer; (2) discovery of an SRC-driven metabolic reprogramming to a lipid profile that activates known drivers of prostate cancer survival and progression; and (3) means of measuring new SRCrelated metabolic molecules with the goal of developing a biomarker profile with prognostic power for aggressive prostate cancer.
Dr. Pomper's study has focused on the optimization of polymer/DNA nanoparticle (NP) carriers to improve in vivo delivery efficiency to metastatic prostate cancer, while reducing toxicity compared to linearpolyethylenimine (l-PEI), a gold standard polymer. New science indicates that l-PEI/DNA NPs aggregate in serum and are sequestered by macrophages, promoting toxicity. The rapid aggregation of l-PEI/DNA complexes often leads to entrapment in lung capillaries, limiting gene expression. Polyethylene glycol (peg) conjugation improves the colloidal stability of such particles and can increase circulation time. However, reported results are inconsistent because of variations in the physical properties of the NPs in biological media. Dr. Pomper's group has observed that pegylation of polycationic gene carriers can lead to the formation of NPs with different shapes, including spherical, rod-like, and worm-like, which may influence their transport properties in vivo. The investigation demonstrated that micelle shape dramatically influences transgene delivery efficiency, when delivered to the liver by bile duct infusion.
These optimized NPs have been used to deliver genes to prostate cancer cells with the goal of expressing a new cell surface molecule. Molecules that bind to the new surface molecules have been armed with a lethal isotope that has been shown, in early preclinical studies, to reduce tumor burden in animal models. The breakthrough results made possible by Mazzone Program financing have attracted additional public and private funds to support the continued development of this encouraging new therapy for metastatic prostate cancer.
Dysfunction of immune system defenses leads to high risk of developing cancer. White blood cells are essential to the ability of the human body to recognize and directly destroy cancer cells. In collaboration with investigators led by Dr. David Norris at the University of Washington, Dr. Wu's research team has identified the mechanisms by which prostate cancer cells disarm white blood cells and progress to metastasis. Following on this discovery, the team has developed a cancer-specific therapeutic antibody to restore and enhance a patient's immune system.
During the funded period of this Mazzone Challenge award, the researchers completed the in vivo validation of the therapeutic effect of this antibody. They demonstrated that this cancer-specific antibody restored the host's immune system to fight primary and metastatic prostate cancer (without castration) in a "human-like" prostate cancer mouse model, with no toxicity.
The group then joined with Dr. Norris, who developed a compound drug (LCL521) to perturb cancer cell lipid, to further demonstrate that coadministration of antibody B10G5 and LCL521 could synergize to eliminate both primary and metastatic prostate cancer in "human-like" pre-clinical animal models. With the support of Dr. Norris and his team, the researchers were able to show that monotherapy of B10G5 results in shrinkage of primary prostate tumors and elimination of metastasis through revamping endogenous innate and adoptive anti-tumor immune responses. They then demonstrated that LCL521 augments the therapeutic effect of B10G5 by inducing tumor cell death, while simultaneously inhibiting tumor cell proliferation. A curative effect of the combined therapy was observed in an advanced spontaneous mouse prostate tumor model. The study results have been featured in the Journal of Clinical Investigation (2013), Clinical Cancer Research (2015), and the Journal of Hematology and Oncology (2015). Other peer-reviewed journal articles reporting study results are anticipated in the near future.
In the coming year, the researchers' goal is to determine whether this combination therapy can have a long-term curative effect for symptomatic recurrent metastatic prostate cancer. They will also compare the therapy to the effectiveness of castration. The team is currently working with a commercial partner to prepare the antibody and the small molecule drug candidate for human investigation.
During the Program year 2015-2016, the Mazzone Program will continue to monitor the eight projects which received a no cost extension, and the two recently funded projects that were approved to continue into project year two. The submission of final progress and accounting reports on these projects in September of 2016 will end the active research phase of the Mazzone Program. However, the court is confident that, thanks to the efforts of the many Award recipients and the consistent leadership of Dr. Kantoff and Dr. Simon, the effects of the Program will reverberate in the annals of the search for a cure for prostate cancer.
The court approves the progress and accounting reports submitted for the period 2014-2015. The Court ORDERS that the Court Registry Investment System issue a check — as its next to last disbursement of the fund in this case — in the amount of $1,585,000.00 (the entire amount of the fund less $100,000). DF/HCC and the PCF will submit the final progress report (including a final report for those projects that received extensions, and the two community outreach projects issued in 2014) in September of 2016. The court will disburse the final $100,000, plus any interest earned, on certification by DF/HCC and the PCF of the final accounting.
SO ORDERED.