Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Targeting the ER Stress Response in ARID1A-mutant Ovarian Clear Cell Carcinoma

Award Number: F31CA247336
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/30/2019
PERIOD OF PERFORMANCE END DATE: 12/29/2021

Group Awards By:

View Award Description

Targeting the ER Stress Response in ARID1A-mutant Ovarian Clear Cell Carcinoma - Project Summary / Abstract ARID1A is a DNA binding subunit of the SWI/SNF complex that is mutated in over 50% of ovarian clear cell carcinoma (OCCC) cases, which results in its loss of expression in over 90% of ARID1A-mutated OCCC cases. There is an urgent need for effective treatment approaches for ARID1A-mutated OCCCs since OCCCs are generally refractory to standard agents used to treat ovarian cancer and, when diagnosed in advanced stages, OCCCs carry the worst prognosis of all ovarian cancer subtypes. The overall goal of my application is to develop a novel therapeutic approach for ARID1A-mutated OCCCs by targeting the endoplasmic reticulum (ER) stress response. The ER stress response restores intracellular integrity and promotes tumor cell survival, which has emerged as a viable therapeutic target for developing cancer therapeutics. However, whether ARID1A plays a role in regulating the ER stress response has never been explored. I have discovered that ARID1A mutation drives an increase in the ER stress response in OCCCs. Using the TCGA database and ARID1A ChIP-seq analysis, my preliminary data suggests that ARID1A containing SWI/SNF directly represses the transcription of XBP1, a key mediator of the ER stress response. Consistently, ARID1A mutation correlates with an increase in the ER stress response. I hypothesize that the SWI/SNF complex suppresses XBP1 expression under ER stress conditions and potentiates the ER stress response to promote tumor cell survival. I have produced preliminary data showing that the inhibition of XBP1 signaling reduces OCCC cell growth in an ARID1A status dependent manner. Accordingly, I have developed two Specific Aims to test my hypothesis. In Aim 1, I will investigate the mechanistic basis by which ARID1A mutation promotes the ER stress response in OCCCs. I will also explore whether the inhibition of the ER stress response is selective in ARID1A mutant tumors. In Aim 2, I will determine novel therapeutic strategies for ARID1A-mutated OCCCs by targeting the ER stress response in combination with platinum-based chemotherapy that is known to induce ER stress. To my knowledge, this data is the first of its kind linking ARID1A’s tumor suppressor function to the ER stress response. My data also presents a novel therapeutic strategy for the inhibition of XBP1 signaling in ARID1A-mutated OCCCs. Since ARID1A is the most frequently mutated epigenetic regulator across human cancers, the mechanistic insights gained from the current studies will have broad implications for many different types of cancers as well.


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: 2021 ( Subtotal = $46,036 )
2021	2021	UNIVERSITY OF THE SCIENCES IN PHILADELPHIA	600 S 43RD ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Research Manpower	001	2	2/1/2021	NON-COMPETING CONTINUATION	$516
2021	2021	UNIVERSITY OF THE SCIENCES IN PHILADELPHIA	600 S 43RD ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Research Manpower	000	2	12/1/2020	NON-COMPETING CONTINUATION	$45,520
														Subtotal = $46,036

Issue Date FY: 2020 ( Subtotal = $45,520 )
2020	2020	UNIVERSITY OF THE SCIENCES IN PHILADELPHIA	600 S 43RD ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Research Manpower	001	1	12/3/2019	NEW	$0
2020	2020	UNIVERSITY OF THE SCIENCES IN PHILADELPHIA	600 S 43RD ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Research Manpower	000	1	12/3/2019	NEW	$45,016
2020	2020	UNIVERSITY OF THE SCIENCES IN PHILADELPHIA	600 S 43RD ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Research Manpower	002	1	2/11/2020	NEW	$504
														Subtotal = $45,520

Grand Total All Awards = $91,556

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Targeting the ER Stress Response in ARID1A-mutant Ovarian Clear Cell Carcinoma

Award Number: F31CA247336

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/30/2019

PERIOD OF PERFORMANCE END DATE: 12/29/2021

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer