This federal Project Grant award from the National Cancer Institute (CFDA 93.396 Cancer Biology Research) provides funding of $465,404 to Case Western Reserve University to conduct research aimed at understanding the role of the SCFFBXO4 E3 ligase in regulating cancer cell proliferation and metabolism in head and neck squamous cell carcinomas (HNSCCs). The key research objectives are to: Determine the ability of the p53R172H mutation to cooperate with the cyclin D1 T286A mutation to drive...
This Project Grant award from the National Cancer Institute (CFDA 93.396 - Cancer Biology Research) provides $483,077 to Baylor College of Medicine to conduct research on the role of the transcription factor ESRRG in mediating 3D circadian enhancer-promoter interactions during the progression from nonalcoholic fatty liver disease (NAFLD) to hepatocellular carcinoma (HCC). The key objectives are to: 1) Use gene expression systems to introduce ESRRG in different rhythmic patterns in mouse...
This K08 Project Grant award from the National Cancer Institute's Cancer Research Manpower Program (CFDA 93.398) supports research to investigate the cooperative role of FOXR2 and ETS transcription factors in driving the formation of diffuse midline gliomas (DMGs), a type of devastating childhood brain tumor. The $262,863 award will enable the principal investigator, a pediatric neuro-oncologist, to gain expertise in in vivo animal modeling and high-throughput genetic perturbation techniques...
This Project Grant award from the National Cancer Institute (CFDA 93.395 Cancer Treatment Research) supports research by 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, spanning 2 years from February 2025 to January 2027, will fund genetic and pharmacological studies to assess the sensitivity of TRCC cells to CDK4/6...
This National Cancer Institute (CFDA 93.396 - Cancer Biology Research) Project Grant award of $447,944 to Baylor College of Medicine supports research to characterize the role of the transcription factor NRF2 in driving metastasis and therapy resistance in high-risk pediatric hepatoblastoma (HB) patients. The overarching goal is to thoroughly elucidate the molecular mechanisms underlying HB tumor cell dissemination, which can inform the development of targeted therapies to minimize metastasis,...
This $368,288 Project Grant award from the National Cancer Institute (CFDA 93.395 Cancer Treatment Research) aims to identify small molecule inhibitors that can disrupt the protein-protein interaction between the TFE3 transcription factor and its oncogenic fusion partners (TFE3-OS) in translocation renal cell carcinoma (TRCC). The research team at The Research Foundation for the State University of New York (RF SUNY) will optimize lead compounds like terfenedine and fexofenadine, and screen...
This $172,193 Project Grant award from the National Cancer Institute's Cancer Research Manpower program (CFDA 93.398) supports research by the Dana-Farber Cancer Institute (DFCI) to improve diagnosis and treatment of translocation renal cell carcinoma (TRCC), a rare and aggressive form of kidney cancer. The key objectives are to: 1) develop optimization methods to identify differential activity of transcription factors that drive TRCC progression, 2) build predictive metabolic models to discover...
The Project Grant award R01CA285856 from the National Cancer Institute's Cancer Biology Research program (CFDA 93.396) provides $583,127 to the Sloan-Kettering Institute For Cancer Research to investigate mechanisms through which deficiency of the SMARCA4 gene promotes metastasis in lung adenocarcinoma. The key objectives are to elucidate how SMARCA4 deficiency regulates transcription and drives metastasis via the ROR2/p-GSK3Bβ pathway, and to evaluate the therapeutic potential of targeting ROR2...
The National Cancer Institute (NCI) awarded a $551,848 Project Grant under the Cancer Cause and Prevention Research program (CFDA 93.393) to the Dana-Farber Cancer Institute, Inc. (DFCI) in Boston, MA. The grant supports a 5-year research project to investigate the molecular mechanisms by which the transcription factor SOX9 impairs differentiation and promotes developmental reprogramming in colorectal cancer (CRC). The key objectives are to: 1) apply unbiased analyses to identify regulators of...
The National Cancer Institute (NCI) awarded a $177,000 Project Grant under the Cancer Biology Research program (CFDA 93.396) to The Children's Hospital Corporation, doing business as Boston Children's Hospital. The funding supports research to investigate the role of the NLRC4 inflammasome and caspase-8 activation in the pathogenesis of fibrolamellar carcinoma (FLC), a rare and aggressive form of liver cancer. The researchers will use mouse liver organoids engineered with the DNAJB1-PRKACA...
MECHANISMS OF TUMOR INITIATION UPON DISRUPTION OF THE RB/E2F INTERACTION - ABSTRACT E2F (E2F1-8) TRANSCRIPTION FACTORS ARE CRITICAL REGULATORS OF CELL CYCLE AND THEIR ACTIVITY IS PHYSICALLY REGULATED BY RB FAMILY PROTEINS (RB, P107 AND P130). DISRUPTION OF THE RB/E2F INTERACTION IS A HALLMARK OF CANCER, AS DEFINED BY HANAHAN & WEINBERG. THE ACQUIRED RESISTANCE TO ANTIGROWTH SIGNALS RESULTING FROM THIS DISRUPTION IS THOUGHT TO BE NECESSARY FOR TUMOR INITIATION. HOWEVER, HOW DOES UNRESTRICTED E2F ACTIVITY INITIATES TUMORIGENESIS IN VIVO IS POORLY UNDERSTOOD AND REMAINS A FUNDAMENTAL GAP IN OUR UNDERSTANDING OF CANCER BIOLOGY. IN PARTICULAR, WHETHER THE DIFFERENTIATION STATUS AFFECT THE CAPACITY OF A CELL TO TRANSFORM UPON DISRUPTION OF RB/E2F INTERACTION IS UNKNOWN. IN ADDITION, WHETHER UNRESTRICTED E2F ACTIVATES OTHER ONCOGENIC FEATURES BESIDES ABERRANT PROLIFERATION IS STILL OBSCURE. HEPATOCELLULAR CARCINOMA (HCC) IS THE SECOND CANCER IN TERMS OF DEATH WORLDWIDE. LIMITED UNDERSTANDING OF THE FUNCTIONAL CONSEQUENCES FOR FREQUENT GENETIC EVENTS HAMPERS THE DEVELOPMENT OF EFFICIENT THERAPEUTICS. THE RB/E2F INTERACTION IS DISRUPTED IN THE VAST MAJORITY OF HCC, AS A CONSEQUENCE OF SEVERAL EVENTS THAT TARGET UPSTREAM COMPONENTS OF THE RB/E2F PATHWAY. THEREFORE, HCC IS A RELEVANT MODEL TO INVESTIGATE THE CONSEQUENCES OF UNRESTRICTED E2F ACTIVITY FOR CANCER INITIATION. ACCORDINGLY, PAN-LIVER INACTIVATION OF RB FAMILY GENES (TRIPLE KNOCK OUT, TKO) IS SUFFICIENT TO INITIATE HCC (TKO HCC) THAT RECAPITULATE MULTIPLE FEATURES OF THE HUMAN DISEASE. STUDIES OF CARCINOGEN-INDUCED MODELS OF HCC HAVE LED TO THE CONCLUSION THAT HEPATOCYTES ARE THE SOLE SOURCE OF HCC. SPECIFIC INACTIVATION OF RB FAMILY IN HEPATOCYTES TRIGGERS A SHORT PROLIFERATIVE BURST BUT FAILS TO INITIATE HCC. THIS RESULT CHALLENGES THE CURRENT HEPATO-CENTRIC MODEL IN THE FIELD AND SUGGESTS THAT OTHER LINEAGES CAN ALSO SERVE AS A CELL OF ORIGIN FOR HCC. ACCORDINGLY, INACTIVATION OF RB FAMILY IN MULTIPLE LIVER LINEAGES REVEALS THAT TKO HCC ARISES FROM A PERIDUCTAL PROGENITOR. IN PARTICULAR, OUR PRELIMINARY DATA INDICATES THAT UNRESTRICTED E2F ACTIVITY COUPLES ABERRANT PROLIFERATION WITH CELL FATE ALTERATION IN THIS POPULATION TO INITIATE HCC. BASED ON THESE DATA, WE PROPOSE TO:1) DETERMINE THE MOLECULAR MECHANISMS THAT ALTER THE CELL FATE OF A PERIDUCTAL PROGENITOR TO SERVE AS A CELL OF ORIGIN FOR TKO HCC. 2) DETERMINE THE INDIVIDUAL AND COMPOUND ROLE OF E2F FACTORS IN TKO HCC INITIATION AND DEVELOPMENT. 3) DETERMINE THERAPEUTIC VULNERABILITIES IN TKO HCC THAT COULD SERVE AS NOVEL TREATMENT FOR PATIENTS. WE BELIEVE THAT OUR PROPOSAL WILL ADDRESS FUNDAMENTAL QUESTIONS REGARDING THE ROLE OF E2F IN CANCER INITIATION, AS IDENTIFIED ABOVE. IN ADDITION, WE EXPECT THAT OUR RESULTS WILL ESTABLISH THAT DIFFERENT CELL LINEAGES CAN SERVE AS A CELL OF ORIGIN FOR HCC, WHICH WILL HAVE IMPORTANT CLINICAL IMPLICATIONS, IN PARTICULAR REGARDING THE CLASSIFICATION OF PATIENTS AND THE DEVELOPMENT OF THERAPIES TAILORED FOR DIFFERENT CLASSES OF HCC.