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Synthetic lethality by targeting the core senescent mechanism in lung cancer.

Award Number: R01CA244564
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Synthetic lethality by targeting the core senescent mechanism in lung cancer. - Abstract Lung cancer is the most common cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancer cases and is generally diagnosed at advanced stages, requiring multimodal therapy involving radiation, chemotherapy, and targeted therapies. Despite these medical interventions, the five- year survival rates of NSCLC patients are less than 5%, highlighting the need for innovative and more effective strategies to treat NSCLC. Dysregulation of cyclin-dependent kinases (CDKs), such as CDK4 and CDK6, occurs in 70% of NSCLC patients and results in aberrant cellular proliferation and tumorigenesis. Palbociclib (PD-03329, trade name Ibrance) is the first cyclin dependent kinase 4 and 6 inhibitor to be approved for breast cancer and is currently investigated as a monotherapy for other solid tumors, including NSCLC. While palbociclib has shown initial improvements in progression-free survival in a phase II clinical trial for recurrent or metastatic NSCLC patients, over half of patients either experience adverse effects or develop resistance and disease progression after eight weeks of treatment. Palbociclib achieves its therapeutic effect by arresting cells in G1 phase and promoting an irreversible cell cycle arrest known as cellular senescence. Senescence was initially thought to suppress tumorigenesis; however, growing evidence has suggested that senescent cells can paradoxically promote tumorigenesis and cancer relapse by altering the surrounding tumor microenvironment. The use of senolytic therapies to promote synthetic lethality may bypass the negative side effects of senescence and enhance the efficacy of palbociclib by either driving palbociclib-treated cells towards apoptosis rather than senescence. Through genetic screening, we identified thrombomodulin (THBD), a potent anticoagulant endothelial receptor, as a novel senolytic target for palbociclib-induced senescence. THBD-mediated signaling was upregulated during palbociclib-induced senescence in NSCLC cancer cell lines and served as a critical regulator of NSCLC cell fate and survival, as inhibition of THBD signaling in NSCLC cells attenuated senescence and promoted apoptosis. Importantly, inhibiting the activity of THBD downstream signaling by an FDA-approved drug caused senescent NSCLC cells to apoptose under treatment of palbociclib. Built on these findings, we propose two specific aims to fully investigate the mechanism by which THBD signaling mediates the senescent program induced by palbociclib and validate this pathway as a target to induce synthetic lethality in palbociclib- treated NSCLC cells both in vitro and in vivo for combinational therapy with the ultimate goal to develop preclinical and clinical trials to improve overall NSCLC patient outcome.


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 = $0 )
2025	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cancer Treatment Research	000	5	4/14/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $464,562 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cancer Treatment Research	000	5	6/7/2024	NON-COMPETING CONTINUATION	$464,562
														Subtotal = $464,562

Issue Date FY: 2023 ( Subtotal = $478,350 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cancer Treatment Research	000	4	3/20/2023	NON-COMPETING CONTINUATION	$478,350
														Subtotal = $478,350

Issue Date FY: 2022 ( Subtotal = $480,907 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cancer Treatment Research	001	3	6/9/2022	NON-COMPETING CONTINUATION	$39,259
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cancer Treatment Research	000	3	1/31/2022	NON-COMPETING CONTINUATION	$441,648
														Subtotal = $480,907

Issue Date FY: 2021 ( Subtotal = $490,590 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cancer Treatment Research	000	2	3/8/2021	NON-COMPETING CONTINUATION	$490,590
														Subtotal = $490,590

Issue Date FY: 2020 ( Subtotal = $497,781 )
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cancer Treatment Research	000	1	1/28/2020	NEW	$497,781
														Subtotal = $497,781

Grand Total All Awards = $2,412,190

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Synthetic lethality by targeting the core senescent mechanism in lung cancer.

Award Number: R01CA244564

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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