Project Grant R01CA292851
- This Project Grant award from the National Cancer Institute (CFDA 93.395 - Cancer Treatment Research) provides funding to the Dana-Farber Cancer Institute (DFCI) to investigate targeting the CDK4/6 pathway as a potential therapeutic strategy for translocation renal cell carcinoma (TRCC), an aggressive form of kidney cancer. The $267,298 award, effective from February 1, 2025 to January 31, 2027, will support in vitro and in vivo studies to test the sensitivity of TRCC cells to CDK4/6 inhibition,...
- The federal Project Grant award for $172,193 was provided by the National Cancer Institute (NCI) under the Cancer Research Manpower program (CFDA 93.398) to the Dana-Farber Cancer Institute, Inc. (DFCI) located in Massachusetts. The goal of this 5-year project is to characterize subtype-specific gene regulatory elements in translocation renal cell carcinoma (TRCC), a rare and aggressive form of kidney cancer, by identifying differentially active transcription factors, determining their metabolic...
- The $178,999.00 Project Grant was awarded on May 15, 2025 by the Defense Health Agency under the Military Medical Research and Development program (CFDA 12.420) to Brigham & Women's Hospital Inc., a subsidiary of Partners Healthcare System. The grant is focused on "Targeting TFE3 Fusion Proteins Using PROTAC in Translocation Renal Cell Carcinoma (TRCC)," supporting advanced biomedical research to transform healthcare for military service members, veterans, and the public. Through...
- This $483,395 Project Grant award from the National Cancer Institute's Cancer Treatment Research program (CFDA 93.395) supports research by The Institute For Cancer Research (ICR) to investigate targeting the P300/CBP proteins as a novel therapeutic approach for renal cell carcinoma (RCC). The key objectives are to examine the therapeutic potential of inhibiting P300/CBP in clear cell RCC, and establish the association between P300/CBP expression and disease progression, drug-resistance, and...
- This $396,061 Project Grant award from the National Cancer Institute (CFDA 93.395 - Cancer Treatment Research) supports research to assess the efficacy of a novel class of hypoxia-inducible factor (HIF) inhibitors as a potential treatment for renal cell carcinoma (RCC). The principal investigator has developed boron-based HIF inhibitors derived from the natural compound honokiol, which have demonstrated promising anti-angiogenic properties in vitro. This 2-year project aims to (1) determine...
- The Department of the Army Medical Command awarded a $694,200 Project Grant to the Dana-Farber Cancer Institute, Inc. (doing business as Dfci) to support research developing a novel therapeutic target in XP11.2 translocation renal cell carcinoma. The grant was awarded on July 1, 2022 under the Military Medical Research and Development program (CFDA 12.420), with a completion date of June 30, 2025. Through this funding, Dfci will conduct research to investigate medical solutions for renal cell...
- The federal Project Grant award for "TARGETING P2X7 RECEPTOR IN RENAL CELL CARCINOMA", totaling $1,269,000.00, was awarded to The Institute For Cancer Research, a non-profit subsidiary of Temple University, by the Defense Health Agency under the Military Medical Research and Development program (CFDA 12.420). The award supports biomedical research focused on developing new treatments for kidney cancer, a key health concern for military service members and veterans. The Institute For...
- This Project Grant award from the Defense Health Agency under the Military Medical Research and Development program (CFDA 12.420) provides $999,096.00 to The University of Texas Southwestern Medical Center to conduct research on "Targeting DNA Damage Response to Treat Clear Cell Renal Cell Carcinoma." The award period runs from July 1, 2024 to June 30, 2028. The research aims to develop new treatments for clear cell renal cell carcinoma, a type of kidney cancer, by investigating...
- This R03 project grant, awarded by the National Center for Advancing Translational Sciences (NCATS) under CFDA Program 93.350, aims to comprehensively identify metabolic enzymes that control the generation of TCF1+ progenitor CD8+ T cells, which are critical for durable anti-tumor immune responses. The $169,500 award, spanning from September 1, 2024 to August 31, 2026, will fund two key research objectives: Identifying metabolic enzymes whose loss alters T cell differentiation and the TCF1+...
- This federal Project Grant award of $400,000 from the National Cancer Institute (CFDA 93.395 - Cancer Treatment Research) supports the advancement of next-generation CAR-T cell therapies for renal cell carcinoma (RCC). The award recipient, Cellinfinity Bio Inc., is developing novel CAR-T cell modifications, including a PRDM1 exon 3 knockout and a CTLA-4 cytoplasmic tail fusion, to enhance CAR-T cell efficacy against RCC tumors. The project aims to evaluate the combination of these...
THERAPEUTIC TARGETING FOR TRANSLOCATION RENAL CELL CARCINOMA - SUMMARY TRANSLOCATION RENAL CELL CARCINOMA (TRCC) REPRESENTS A RARE SUBTYPE OF KIDNEY CANCER ASSOCIATED WITH AGGRESSIVE BEHAVIOR AND POOR CLINICAL OUTCOME. THE PREVALENCE OF THIS DISEASE IS HIGH IN PEDIATRIC KIDNEY CANCER, REPRESENTING 20-40% OF TOTAL CASES OF RCC. NOTEWORTHY, THE TRUE INCIDENCE OF THIS DISEASE IN ADULTS IS LIKELY UNDERESTIMATED, AS A SIGNIFICANT NUMBER OF PATIENTS UNDERGOES HISTOLOGICAL MISCLASSIFICATION. TRCC IS CHARACTERIZED BY GENE FUSIONS RESULTING FROM CHROMOSOMAL REARRANGEMENT INVOLVING TFE3 (XP11.2) LOCUS OR TFEB (6P21 LOCUS), WITH VARIOUS PARTNER GENES. DESPITE THE IDENTIFICATION OF MULTIPLE TFE3 GENE FUSIONS IN TRCC (I.E. SFPQ-TFE3, NONO-TFE3, AND PRCC-TFE3) THERE ARE NO EFFECTIVE TARGETED THERAPIES FOR PATIENTS WITH TRCC. IN PRELIMINARY RESULTS SUPPORTED BY THE DOD (W81XWH1810586), OUR GROUP HAS GENERATED SFPQ- TFE3, NONO-TFE3, AND PRCC-TFE3 TFE3-OS AND ESTABLISHED THEIR ONCOGENIC POTENTIAL. KNOCKING DOWN TFE3-WILD TYPE OR FULL LENGTH (TFE3-WT) INHIBITED THE PROLIFERATION OF TRCC. BY USING FLUORESCENCE RESONANCE ENERGY TRANSFER (FRET) MICROSCOPY IMAGING OUR DATA SUGGEST THAT TFE3-OS DIMERIZE TFE3-WT AND SCREENED COMPOUNDS HAVE ANTI-PROLIFERATIVE EFFECT BY INHIBITING THIS PROTEIN-PROTEIN INTERACTION. THUS, THIS PROPOSAL AIMS TO IDENTIFY SMALL MOLECULES THAT SELECTIVELY BIND THE LEUCINE ZIPPER DOMAIN AND DISRUPT THE TFE3-OS/TFE3 INTERACTION. OUR CENTRAL HYPOTHESIS IS THAT TFE3 CHIMERIC PROTEINS (TFE3-OS) PLAY A KEY BIOLOGICAL ROLE IN TRANSLOCATION RENAL CELL CARCINOMA (TRCC) AND REPRESENT A RATIONAL TARGET FOR THERAPEUTIC INTERVENTIONS. OUR HYPOTHESIS IS THAT INHIBITING THE PROTEIN-PROTEIN HOMO AND/OR HETERO DIMERIZATION OF TFE3-OS/TFE3-WT MAY OFFER A NOVEL THERAPEUTIC OPPORTUNITY. OUR CENTRAL HYPOTHESIS AIMS TO ACCOMPLISH THE OBJECTIVES OF THIS APPLICATION BY PURSUING THE FOLLOWING SPECIFIC AIMS: AIM 1: TO OPTIMIZE TOOL COMPOUNDS AND TO IDENTIFY NEW SMALL MOLECULE INHIBITORS TARGETING TFE3-O DIMERIZATION. AIM 2: TO TEST THE BIOLOGICAL AND ANTITUMOR EFFECTS OF NEW SMALL MOLECULE INHIBITORS TARGETING TFE3-O DIMERIZATION. AIM 1 PROPOSES TO OPTIMIZE LEAD COMPOUND RECENTLY IDENTIFIED IN OUR LAB, TERFERNADINE AND ITS METABOLITE FEXOFENADINE. IT WILL ALSO SCREEN FOR NOVEL COMPOUNDS TARGETING TFE3 DIMERS WITH A CUSTOMIZED CELL-BASED ANTIPROLIFERATION ASSAY THAT SIMULTANEOUSLY MONITORS TFE3 DIMERIZATION STATUS THROUGH FRET. VALIDATED HIT MOLECULES COMPRISING SYNTHETICALLY TRACTABLE SCAFFOLDS WILL BE SUBJECT TO MEDICINAL CHEMISTRY OPTIMIZATION FOR STRUCTURE-ACTIVITY RELATIONSHIP, LIPOPHILICITY, ORAL BIOAVAILABILITY AND OTHER ESSENTIAL PROPERTIES. TO ACCELERATE THE GENERATION OF COMPOUNDS FOR BIOLOGICAL TESTING, OUR AIM IS TO EMPLOY COMPUTER-AIDED DOCKING OF LEAD COMPOUNDS WITH RELEVANT HUMAN TFE3 HOMOLOGY MODELS FOR FOCUSED RATIONAL DRUG DESIGN. AIM 2 WILL UTILIZE OUR ESTABLISHED IN VITRO MODELS TO DETERMINE THE ANTITUMOR EFFECT OF THE OPTIMIZED TOOL COMPOUNDS IDENTIFIED IN AIM 1 WHICH DISRUPT TFE3-OS PROTEIN-PROTEIN INTERACTION. THIS AIM WILL THEN DETERMINE THE ANTITUMOR EFFECT OF THE LEADING COMPOUNDS, AS SINGLE AGENTS AND IN RATIONAL COMBINATIONS.
Mod # | Description | ReasonForModification | Federal Obligation | Date |
|---|---|---|---|---|
| Not listed | $368.3k | 6/11/25 | ||
| Not listed | $368.3k | 7/5/24 | ||
| Not listed | $368.3k | 7/5/24 |