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Targeting cholesterol metabolism and replication stress response in cancer therapy

Award Number: R01CA249198
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Targeting cholesterol metabolism and replication stress response in cancer therapy - Project Summary: Lung cancer is the leading cause of cancer deaths in both men and women. Non-small cell lung cancer (NSCLC) accounts for large majority of lung cancer diagnoses, and novel treatment strategies for this disease are urgently needed. ATR and its downstream effector CHK1 are key component of replication stress (RS) response that specifically deal with the stalled replication forks during DNA replication and are critical for cell survival under RS. Inhibitors targeting ATR and CHK1 are currently being tested in clinical trials. However, only limited efficacy has been observed when those agents are combined with standard therapy. Identifying the new synergistic conditions that render cells sensitive to ATR/CHK1 inhibitors will be key to improving the efficacy of these agents. Squalene epoxidase (SQLE), an enzyme controlling cholesterol biosynthesis by converting squalene to oxidosqualene in endoplasmic reticulum (ER), is frequently overexpressed in human cancers, including lung cancer. High expression of SQLE is associated with poor prognosis. Our recent genome-wide loss of function screen discovered that SQLE reduction led to enhanced sensitivity to a CHK1 inhibitor. Thus, the goal of this application is to determine whether SQLE inhibition sensitizes NSCLC cells to ATR and CHK1 inhibitors and whether high SQLE-expressing NSCLC cancer can be specifically targeted by the combined inhibition of SQLE and ATR/CHK1. Our preliminary data suggest that SQLE inhibition by shRNA knockdown causes RS and activates ATR/CHK1 activation. In addition, SQLE inhibition lead to increased protein expression of WIP1, a phosphatase that suppress the activity of ATM, a master DNA damage response protein controlling DNA repair. We hypothesize that SQLE inhibition leads to increased RS by suppressing DNA repair, rendering cells sensitive to ATR and CHK1 inhibition. Thus, co-administration of an SQLE inhibitor and an ATR or CHK1 inhibitor could synergistically suppress tumor growth. To test our hypothesis, three Specific Aims are proposed. Specific Aim 1 will interrogate the mechanism by which SQLE inhibition leads to increased WIP1 expression. Specific Aim 2 will determine whether SQLE inhibition leads to increased RS by impairing DNA repair, particularly homologous recombination, a major repair pathway that prevents and antagonizes RS. Specific Aim 3 will assess the efficacy of combined SQLE inhibition and ATR/CHK1 inhibition in suppressing tumor cell growth using in vitro assays as well as cell line-based and patient-derived xenograft (PDX) models of NSCLC. If successful, our studies will reveal a new synthetic lethal interaction between inhibition of SQLE and ATR/CHK1 and will have a significant impact on improving the survival of lung cancer patients by identifying novel therapeutic approaches.


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	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Treatment Research	000	5	1/3/2025	NON-COMPETING CONTINUATION	$321,165
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Treatment Research	001	5	6/16/2025	NON-COMPETING CONTINUATION	$35,685
														Subtotal = $356,850

Issue Date FY: 2024 ( Subtotal = $339,008 )
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Treatment Research	001	4	4/18/2024	NON-COMPETING CONTINUATION	$17,843
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Treatment Research	000	4	1/4/2024	NON-COMPETING CONTINUATION	$321,165
														Subtotal = $339,008

Issue Date FY: 2023 ( Subtotal = $349,713 )
2023	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Treatment Research	000	3	2/16/2023	NON-COMPETING CONTINUATION	$349,713
														Subtotal = $349,713

Issue Date FY: 2022 ( Subtotal = $349,713 )
2022	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Treatment Research	000	2	1/10/2022	NON-COMPETING CONTINUATION	$321,165
2022	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Treatment Research	001	2	4/25/2022	NON-COMPETING CONTINUATION	$28,548
														Subtotal = $349,713

Issue Date FY: 2021 ( Subtotal = $356,850 )
2021	2021	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Treatment Research	000	1	1/14/2021	NEW	$356,850
														Subtotal = $356,850

Grand Total All Awards = $1,752,134

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Targeting cholesterol metabolism and replication stress response in cancer therapy

Award Number: R01CA249198

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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