Peer Reviewed Medical Research Programs (PRMRP)

Action to Cure Kidney Cancer initiated, in 2004, its advocacy campaign to obtain federal funding for kidney cancer research as part of the Department of Defense’s Peer Reviewed Medical Research Programs (PRMRP), which comes under the DoD Congressionally Directed Medical Research Programs (CDMRP).

The initial co-sponsors of our effort were Sen. Charles Schumer (D-NY), Sen. Arlen Specter (R-PA), Rep. Peter King (R-NY), and Rep. Carolyn McCarthy (D-NY). In federal FY2006, we were successful in convincing Congress to fund kidney cancer as part of DoD’s CDMRP*. The first award winner, in FY2006, was Maria F. Czyzyk-Krzeska from the University of Cincinnati for a project to identify genes involved in the causation of clear cell kidney cancer. Through FY2016, a total of over $10 million was awarded to 23 kidney cancer researchers as part of the PRMRP and PRCRP. The researchers and their projects are listed below.

In FY2017, thanks to the efforts of Rep. Nita Lowey (D-NY) and then Ranking Member of the House Appropriations Committee, we were successful in obtaining Congressional support for kidney cancer to receive its own targeted funding of $10 million Kidney Cancer Research Program (KCRP), also under CDMRP. Yes, that’s $10 million in one year rather than $10 million in 11 years. Kidney cancer joined a group of only five cancer programs that receive targeted funding from DoD – breast, prostate, lung, ovarian, and kidney. Therefore, after FY2016, kidney cancer was removed from the PRCRP and was given its own line item under CDMRP.

*The DoD, subsequent to FY2006, split their program into a Peer Reviewed Medical Research Program (PRMRP) and a Peer Reviewed Cancer Research Program (PRCRP).

Kidney Cancer Research Projects

Targeting PBRM1 in Metastatic Kidney Cancer

FY2016 — $540,000
Emily Dykhuizen
Purdue University

Project: The PBMR1 gene is mutated in 50% of clear cell RCC “patients.” The objective of this study is to determine the role of PBMR1 in tumor progression, metatstasis, and response to targeted therapies. PBMR1 (polybromo) is the second most commonly mutated gene in clear cell and probably acts with VHL mutations to cause renal cancer. The VHL mutation alone doesn’t cause cancer. PBMR1 is required for the set of genes that are activated by HIF that are involved in what is called the stress response, which causes cells to stop proliferating in response to what would be hypoxic stress. So if you delete PBMR1, you allow those hypoxia genes, which are cancer causing, to take over.

 

Prognostic and Predictive Markers of Immunogenicity in RCC

FY2016 — $1,591,000
Eric Jonasch
MD Anderson Cancer Center

Project: Project investigators hypothesize that mutations in genes that regulate and control chromosomes, called chromatin remodeling genes, modify the body’s immune system’s response to kidney cancer. The study will provide predictive biomarkers to identify which patients are most likely to respond to checkpoint antibody immune checkpoint therapy. The knowledge obtained will also help develop new ways to overcome resistance to therapy in patients who do not respond to these new therapies.

 

Engineering CAR-T Cell Therapy in Kidney Cancer

FY2016 — $645,000
Pin Wang
University of Southern California

Project: CAR-T cell (chimeric antigen receptor) therapy has proven to be very successful in hematological cancers such as leukemia but not in solid tumor cancers. One problem is toxicity whereby the CAR-T cells also attack normal cells. This project’s objective is to mitigate this phenomenon by developing a “switchable” peptide that prevents the CAR receptors from binding to normal cells, but, for which the tumor cells enzymes remove the peptide and allow the T-cell to kill the tumor cell.

 

Reprogramming Chromatin Modifiers in Kidney Cancer

FY2015 — $597,000
Thai Ho
Mayo Clinic, Scottsdale, AZ

Project: Identifying pathways that regulate the biochemical
changes in the DNA that drive the growth of metastatic
kidney cancer, test approved drugs to reverse the biochemical
changes in the DNA, and validate molecular signatures linked
to unexpected early recurrences in archived small kidney
tumors at Mayo Clinic.

 

IQGAP1 Scaffold-Kinase Interaction Blockade in Kidney Cancer

FY2015 — $569,000
John Leppert
Stanford University

IQGAP1 is a scaffold protein that has been shown to bind the kinase ERK. Blocking the IQGAP1-ERK scaffold kinase interaction has shown promise as a new approach to treat skin, pancreas, and lung cancers. The broad objective of this study is to apply cutting-edge methods to determine the expression of IQGAP1 in kidney cancer, and test the effect of inhibiting IQGAP1-ERK scaffold-kinase interactions in models of human kidney cancer.

 

Novel Hypoxia-Directed Cancer Therapeutics

FY2015 — $780,000
Fraydoon Rastinejad
Sanford-Burnham Medical Research Institute, Orlando

Project: Test the hypothesis that the ligand binding pockets of the HIF transcription factor can be targeted by small molecule inhibitors. The short-term objectives are to identify diverse novel small molecule inhibitors for each of HIF-1α and HIF-2α proteins. The long-term goals are to evaluate the most promising compounds through synthetic medicinal chemistry, pharmacology, and animal studies.

 

Enhancing Immune Checkpoint Inhibitor Therapy in Kidney Cancer

FY2014 — $486,000
Hans-Joerg Hammers
John Hopkins University, Baltimore

Project: Immune checkpoint inhibitors are showing promise in the treatment of metastatic kidney cancer, especially in some cases providing long-term of even complete response. However, the overall response rate hovers only around 20%. Dr. Hammers will alternately apply stereotactic radiation, cryoablation, or a toll-like receptor called imiquimod to metastatic kidney cancer cells to hopefully generate an immune response (called the abscopal effect) that will allow the body’s immune system to recognize the tumor antigen and thus significantly improve the response rate to subsequent treatment with the checkpoint inhibitor nivolumab (Opdivo).

 

Role of of Lisomal Transporters in Promoting the Growth of Clear Cell Kidney Cancer and Other Tumors

FY2014 — $585,000
David M. Sabatini

Whitehead Institute for Biomedical Research, Cambridge, MA

Project: MTORC1 Is a protein complex that controls protein synthesis. MTORC1, when activated, is also a key growth signaling pathway in clear cell carcinoma (ccRCC). MTORC1 activation occurs at the lysosome, a structure in the cell that contains enzymes and which is responsible for intra-cellular digestion. MTORC1 is activated by nutrients and proteins in the lysosome, but it is not known which and by what mechanism nutrients are “sensed” by the MTORC1 pathway. MTORC1 has been targeted by two ccRCC cancer drugs, Afinitor and Torisel, but not very effectively. Dr. Sabatini will study the mechanism by which the nutrient levels in the lysosome activate MTORC1 in order to more effectively target this complex in ccRCC.

 

Validation of ZHX2 as a Novel VHL E3Ligase Substrate and its Role in Kidney Cancer

FY2014 — $537,921
Qing Zhang
North Carolina University of Chapel Hill

Project: Disabling the VHL gene can lead to the development of clear cell renal cell carcinoma (ccRCC), and this relation is found in over 80% of ccRCC cases. It is known that VHL moderates the oncogenic transcription factor HIF-2α, whose presence promotes VEGF and other angiogenic factors that promote the growth and proliferation of ccRCC tumors. Dr. Zhang screened 17,000 proteins and found one called ZHX2, a transcription factor, similar to HIF-2α, that is also regulated by VHL, and which, based on preliminary research, may be linked to ccRCC tumor progression. His grant will answer the question if ZHX2 promotes the growth and spread of ccRCC, and, if so, will identify protein targets of kidney cancer therapy similar to anti-VEGF therapies.

 

Effects of Tobacco Smoke on Kidney Cancer

FY2013 — $474,560
Maria Czyzyk-Krzeska
University of Cincinnati

Project: There is very little information about the molecular mechanisms by which cigarette smoking promotes kidney cancer. This project will will perform a global analysis of gene sequences and activity in kidney tumors from male veterans who are heavy smokers (at least one pack of cigarettes a day for 20 years or longer), non-smokers (less than 100 cigarettes per lifetime), and data available for the general population of patients with kidney cancer, and compare the data from the three groups.

 

Engineering CAR-T Cell Therapy in Kidney Cancer

2012 — $364,000
Bhavani Krishnan
University of North Carolina

Project: Although nTOR inhibitors extend life of metastatic kidney cancer patients, they do not shrink tumors significantly, generating mostly stable disease. Project will identify those kinases (proteins) that are up-regulated under m-TOR treatment and target them, in a pre-clinical setting, with known kinase inhibitors that can be combined with mTOR to kill the tumors cells thus increasing overall response.

 

Kidney Cancer Immunologically Enhanced Vaccine

FY2012 — $381,000
Li Shen
Roswell Park Cancer Institute

Project: Vaccines have the promise of inducing a long-lasting immune response in metastatic kidney cancer, however, they are modulated by regulatory T-cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs), all of which inhibit an anti-tumor response. This project, in a pre-clinical setting, will incorporate, with the vaccine, Foxp3 to deplete Tregs and tasquinimod to target MDSCs and TAMs in order to generate an enhanced anti-tumor response with the goal of transferring this combination into a clinical trial.

 

Role of Grainyhead in Kidney Cancer

FY2011 — $296,000
Steven Frisch
West Virginia University

Project: Epithelial-mesenchymal transition (EMT), where cells change their behavior, is an important determinant of tumor progression. Inhibition of EMT may decrease tumor invasion and metastasis, and an increase in EMT may accelerate tumor progression. The “grainyhead” gene suppresses EMT. In this project, the grainyhead gene’s expression will be enhanced, and if it acts as a tumor suppressor, a therapy will be developed to help prevent recurrence of kidney cancer after initial diagnosis/treatment.

 

Using MRI to Diagnose Tumor Aggressiveness

FY2011 — $240,000
Renuka Sriram
University of California, San Francisco

Project: Test the hypothesis that the aggressiveness of a kidney tumor can be measured by the metabolism of the cancer cells, which the researcher will measure by the use of a non-invasive MRI to calibrate the production of lactate, a byproduct of metabolism. This would allow one to differentiate the tumors as being benign, low-grade, or metastatic. If successful, one could clinically determine whether nephrectomy is required for a kidney tumor without having to do an invasive biopsy of the tumor.

 

Nanotechnology to Develop Urine Test for Kidney Cancer

FY2010 — $454,900
Srikanth Singamaneni
Washington University

Project: Based on previous research, two specific proteins are found at much higher concentrations in the urine of people with clear cell and papillary kidney cancer than in healthy people. However, testing for these proteins is expensive and cumbersome. Project will develop an efficient and inexpensive test using nanotechn

ology to identify whether these proteins exist in the urine and thus to diagnose kidney cancer via a simple urine test.

 

Development of Kidney Cancer Blood Test

FY2010— $1,004,018
Maneesh Tewari

Fred Hutchinson Cancer Research Center

Jointly with:

FY2010 — $202,197
Allan Pantuck
UCLA

Project: Clear cell kidney cancer tumors generate specific minute particles that are released into the blood. This project will determine if the presence and density of these particles can be used to generate a simple blood test that would diagnose kidney cancer at an early stage. Eventually, want to develop a similar test to determine aggressiveness of the cancer.

Note: Dr. Maneesh Tewari from the Fred Hutchinson Cancer Research Center indicated to us that he would not have been able to pursue his idea to develop a blood test to diagnose kidney cancer if ACKC had not succeeded in having kidney cancer included as an eligible disease in the Department of Defense’s cancer research budget. He added that the DoD has a unique mechanism whereby a researcher can propose a project that can really break new ground. Their grant review process leads to cutting edge, innovative research being funded.

 

Use of MRSI to Investigate Tumors

FY2010 — $115,875
Zhen Jane Wang
University of California, San Francisco

Project: A new non-invasive imaging technique called magnetic resonance spectroscopic imaging (MRSI) can be used to determine the metabolic consistency of tumors. This project will investigate whether MRSI can determine kidney cancer tumor aggressiveness. If possible, MRSI could be used to diagnose small, indolent (slow growing) tumors that may not need invasive surgery. This technique has been successful in brain and prostate cancers.

 

Tissue and Metabolic Markers for Recurrent Kidney Cancer

FY2009 — $602,700
Alexander Parker
Mayo Clinic, Jacksonville

 

 

Jointly with:

FY2009 $503,600
Richard Drake
Eastern Virginia Medical College

Project: Identification of kidney cancer markers that could predict for aggressive or recurrent disease, which could then inform therapeutic options. The implication of this is that those patients at high risk of recurrence can be advised to have adjuvant therapy and those at low risk can be advised to further spread out their follow-up radiological exams, thus reducing their radiation exposure.

 

Targeted Nanoparticles for Kidney Cancer Therapy

FY2009 — $599,933
Suzy Torti
Wake Forest University

Project: Develop nanoparticles (1/1000 size of human hair) that will target and bind to kidney cancer tumors and metastases, which then will be illuminated and destroyed by infrared radiation that is directed only to the cancer cells thus preserving normal cells and reducing toxicity.

 

The Role of RASSF1A Tumor Suppressor in Kidney Cancer

FY2008 — $721,800
Geoffrey Clark
University of Louisville

Project: Create kidney cancer in a mouse (rather than implanting human cancer in a mouse) to develop an exceptionally useful tool for cancer researchers. Also will determine the role of RASSF1A, a cancer suppressor gene, which is silenced in clear cell kidney cancer.

 

Identification of Genes in Kidney Cancer Oncogenesis

FY2006 — $932,900
Maria F. Czyzyk-Krzeska
University of Cincinnati

Project: Identification of genes involved in the causation of clear cell kidney cancer, which could then be targeted by therapy.