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Strategies to Disrupt Oncogenic Transcription in RCC Tumors

Award Number: R01CA263630
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/05/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Strategies to Disrupt Oncogenic Transcription in RCC Tumors - • PROJECT SUMMARY • Renal cell carcinoma (RCC) is the 8th most common form of adult cancer in the US. Despite recent improvement in treatment options, the majority of patients with metastatic RCC continue to succumb to this disease, resulting in over 100,000 deaths per year worldwide. Thus, it is important to identify novel therapeutic strategies to more effectively treat this deadly disease. Our preliminary studies suggest that YAP/TAZ function as master regulators of the core oncogenic transcriptional network across most subtypes of RCC and are required for maintaining the transcriptional and metabolic homeostasis of RCC tumors. The first major aim of our proposal is to determine the therapeutic efficacies and mechanisms of action of first-in-class YAP/TAZ inhibitors in patient-derived RCC tumor models. Besides in vivo efficacy studies, we will employ cutting-edge epigenomic techniques including Cut&Tag, omni-ATAC-seq and 3’-RNAseq to probe how genetic and pharmacological inhibition of YAP/TAZ affect the compositions and activities of the YAP/TAZ transcriptional complexes and the global epigenetic and transcriptional landscape in RCC tumors. Through these analyses, we will be able to gain critical insights into the molecular functions of YAP/TAZ in RCC tumors, but also reconstruct the core ensemble of the RCC oncogenic transcriptional network. The second major aim of this proposal is to develop mechanism-driven combination strategies to more effectively treat RCC tumors. Through high-throughput drug screening and extensive mechanistic studies, we recently identified MEK and BET inhibitors as two major classes of drugs that strongly synergize with genetic or pharmacological inhibition of YAP/TAZ to suppress oncogenic transcription and eliminate YAP/TAZ-addicted tumor cells in vitro and in vivo. Based on these results, we will investigate whether combining low doses of MEK or BET inhibitors with YAP/TAZ inhibitors could lead to durable tumor regression without increasing systematic toxicities in RCC PDX models. Furthermore, we will conduct functional genomic studies to elucidate how MEK and BET inhibitors amply the effects of YAP/TAZ inactivation, leading to the collapse of the RCC oncogenic transcriptional network. Finally, we will investigate how YAP/TAZ inhibitors affect the RCC tumor secretome and immune infiltrates and whether they could be used to overcome resistance to immune checkpoint inhibitors. Together, these studies will greatly enhance our understanding of the crosstalk and redundancies between the oncogenic pathways that govern the growth and survival of RCC cells, potentially yielding more effective combination strategies to overcome treatment resistance in RCC patients.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $356,850 )
2025	2025	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Treatment Research	000	5	6/25/2025	NON-COMPETING CONTINUATION	$356,850
														Subtotal = $356,850

Issue Date FY: 2024 ( Subtotal = $339,008 )
2024	2024	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Treatment Research	000	4	6/11/2024	NON-COMPETING CONTINUATION	$339,008
														Subtotal = $339,008

Issue Date FY: 2023 ( Subtotal = $349,713 )
2023	2023	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Treatment Research	000	3	6/20/2023	NON-COMPETING CONTINUATION	$349,713
														Subtotal = $349,713

Issue Date FY: 2022 ( Subtotal = $349,713 )
2022	2022	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Treatment Research	000	2	6/28/2022	NON-COMPETING CONTINUATION	$349,713
														Subtotal = $349,713

Issue Date FY: 2021 ( Subtotal = $356,850 )
2021	2021	GEORGETOWN UNIVERSITY (THE)	37TH AND O ST NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Treatment Research	000	1	7/5/2021	NEW	$356,850
														Subtotal = $356,850

Grand Total All Awards = $1,752,134

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Strategies to Disrupt Oncogenic Transcription in RCC Tumors

Award Number: R01CA263630

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/05/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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