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The Oncogenic functions of YAP/TAZ in Renal Cell Carcinoma

Award Number: F30CA264884
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/07/2022
PERIOD OF PERFORMANCE END DATE: 04/06/2027

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The Oncogenic functions of YAP/TAZ in Renal Cell Carcinoma - PROJECT ABSTRACT 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. My preliminary studies suggest that YAP/TAZ function as master regulators of the core oncogenic transcriptional network and are required for maintaining the transcriptional homeostasis of RCC tumors. The first major aim of my proposal is to determine the effects of pharmacologic and genetic inhibition of YAP/TAZ on oncogenic transcription and super enhancer maintenance in patient-derived primary RCC cells. I will employ cutting-edge epigenomic techniques including Cut&Tag and QuantSeq to probe how genetic and pharmacological inhibition of YAP/TAZ affects the compositions and activities of the YAP/TAZ transcriptional complexes and the global RCC epigenetic and transcriptional landscape. Given the reported functions of YAP/TAZ in orchestrating phase-separated transcriptional condensates at super enhancers, I will combine immunofluorescence analysis of endogenous YAP/TAZ and other components of the YAP/TAZ transcriptional complexes, along with DNA fluorescent in situ hybridization (DNA-FISH) against YAP/TAZ-bound enhancer regions, to investigate how genetic or pharmacological inhibition of YAP/TAZ affects the formation of active transcriptional condensates at these particular genetic elements and their necessity in regulating YAP/TAZ target genes. Through these analyses, I 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 determine how YAP/TAZ functionally interacts with hypoxia-inducible factor 2 alpha (HIF2A) and whether YAP/TAZ co- inhibition can overcome resistance to HIF2A inhibitors in an in vivo model. While HIF2A inhibitors are in late stage clinical trials, upfront and acquired resistance to this small molecule inhibitor is prevalent. My preliminary findings suggest that YAP/TAZ signaling may contribute to resistance to HIF2A inhibitors. Using pharmacological inhibitors of YAP/TAZ and HIF2A, I intend to use Cut&Tag and QuantSeq to investigate the functional interactions between HIF2A and YAP/TAZ in maintaining clear cell RCC oncogenic transcription, as well as possible YAP/TAZ regulated genes mediating resistance to HIF2A inhibitors. Furthermore, I will investigate how YAP/TAZ inhibitors, in combination with HIF2A inhibitors, impact the in vivo growth of HIF2A-i- resistant patient-derived ccRCC xenografts, performing QuantSeq on harvested tumors to validate my in vitro findings. 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: 2026 ( Subtotal = $55,114 )
2026	2026	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Research Manpower	000	5	4/6/2026	NON-COMPETING CONTINUATION	$55,114
														Subtotal = $55,114

Issue Date FY: 2025 ( Subtotal = $54,538 )
2025	2025	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Research Manpower	001	4	5/26/2025	NON-COMPETING CONTINUATION	$564
2025	2025	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Research Manpower	000	4	5/5/2025	NON-COMPETING CONTINUATION	$53,974
														Subtotal = $54,538

Issue Date FY: 2024 ( Subtotal = $53,974 )
2024	2024	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Research Manpower	000	3	3/22/2024	NON-COMPETING CONTINUATION	$52,694
2024	2024	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Research Manpower	001	3	5/7/2024	NON-COMPETING CONTINUATION	$1,280
														Subtotal = $53,974

Issue Date FY: 2023 ( Subtotal = $34,994 )
2023	2023	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Research Manpower	000	2	3/22/2023	NON-COMPETING CONTINUATION	$34,994
														Subtotal = $34,994

Issue Date FY: 2022 ( Subtotal = $34,052 )
2022	2022	GEORGETOWN UNIVERSITY (THE)	37TH AND O ST NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Research Manpower	000	1	4/7/2022	NEW	$33,336
2022	2022	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Research Manpower	001	1	4/7/2022	NEW	$0
2022	2022	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Research Manpower	002	1	8/12/2022	NEW	$716
														Subtotal = $34,052

Grand Total All Awards = $232,672

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The Oncogenic functions of YAP/TAZ in Renal Cell Carcinoma

Award Number: F30CA264884

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/07/2022

PERIOD OF PERFORMANCE END DATE: 04/06/2027

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