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CCNE1 is synthetically lethal with drug induced nuclear Cathepsin L (nCTSL)

Award Number: R21CA302968
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2025
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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CCNE1 is synthetically lethal with drug induced nuclear Cathepsin L (nCTSL) - PROJECT SUMMARY/ABSTRACT Therapy for high-grade serous ovarian cancer (HGSOC) relies on DNA damaging agents, with a high percentage of cancer with cyclin E amplification or overexpression having de novo or acquired chemoresistance due in part to homologous recombination (HR) proficiency. We recently discovered that the anti-leukemic drug clofarabine (CLF) + olaparib combination aided in the nuclear translocation of cathepsin L (nCTSL) to induce DNA damage and sensitize OC cells to PARP inhibitors (Funding by DoDIIRA, OCRP venue.) Although our ongoing studies substantiate the role of nCTSL in the DNA damage response (DDR), the precise mechanism by which nCTSL induces DNA damage remains unclear. Our preliminary data has uncovered a potential mechanism that promotes homologous repair deficiency (HRD) in CCNE1 high tumors. CLF + ATR inhibitor (ATRi), AZD6738 induced an increase in the replication stress (RS) marker pRPA2S33 foci validated through immunofluorescence (IF) and cell fractionated western blot analysis. This coincided with the presence of CTSL in the nucleus. ATR knockdown (KD) or ATRi combined with CLF, synergistically decreases OC cell survival, observed in both CCNE1 high and low expressing cell lines and in ex vivo cultures of patient derived xenograft models in vitro. Significantly, CTSL KD confirms nCTSL's role in CLF-induced replication stress. This proposal aims to develop novel approaches to evaluate drug induced replication stress marker as a means of developing novel drug combinations in high grade serous ovarian cancer in vivo and mechanistically determine the how nCTSL attenuates CCNE levels. Continued development of novel combinations targeting replication stress is essential, particularly in patients with PARPi resistant/recurrent tumors. The goal of this proposal is to test our hypothesis that nCTSL mediated CCNE1 downregulation may sensitize CCNE1 driven tumors to PARPi and ATRi treatment and restore homologous repair deficiency in vivo. The project will 1) Demonstrate that the cytotoxicity of CLF + ATRi and CLF + PARPi saruparib is associated with nCTSL in CCNE1 high PDX models in vivo and in syngeneic mouse model using KPCA cell line CCNE1 overexpression. 2) Determine the mechanism by which nCTSL targets CCNE1. Continued development of novel combinations targeting replication stress is essential, particularly in patients with PARPi resistant/recurrent tumors. Considering the challenge of resistance to first-line therapy and PARP inhibitors, the combination of CLF with ATRi holds promise in overcoming or delaying drug resistance in recurrent in high grade serous ovarian cancer.


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 = $412,429 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	1	7/23/2025	NEW	$412,429
														Subtotal = $412,429

Grand Total All Awards = $412,429

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CCNE1 is synthetically lethal with drug induced nuclear Cathepsin L (nCTSL)

Award Number: R21CA302968

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2025

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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