Wednesday, December 31, 2025 12/31/2025

Investigating Rational Combination Therapies for Triple-Negative Breast Cancer

Award Number: R01CA258833
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Investigating Rational Combination Therapies for Triple-Negative Breast Cancer - PROJECT SUMMARY/ABSTRACT Triple-negative breast cancer (TNBC) refers to a collection of heterogeneous breast tumors that lack expression of immediately druggable molecules, such as the estrogen and progesterone receptors and human epidermal growth factor receptor 2. No targeted therapy is currently approved for the vast majority of TNBC patients. TNBC patients who have received the current standard of care, consisting of chemotherapy, radiation, and surgery, often experience early tumor recurrence and a significantly worse mortality rate. Therefore, it is critical to identify and validate clinically viable, life-saving targeted therapies for patients with TNBC. We previously reported that the oncogenic MYC pathways were activated in ~50% of TNBC cases compared with non-TNBC cases and that MYC levels were associated with poor outcomes among TNBC patients. Unfortunately, clinical development of inhibitors that directly target MYC activity has remained challenging. To overcome this challenge, we previously took an alternative approach known as the synthetic lethal screening approach to identify readily druggable targets required for MYC-driven tumor viability but that are not essential in non-tumor cells. Our screen identified the PIM family of kinases, which is composed of the closely related nonessential kinase isoforms PIM1, -2, and -3 (PIM hereafter), as a promising target in MYC-driven TNBC. We found that PIM expression was elevated in triple-negative (TN) tumors in clinical samples and was associated with poor patient outcomes. Clinically relevant pan-PIM inhibitors showed activity in various experimental models of TNBC. However, our single-agent efficacy studies using preclinical PIM inhibitors showed that although PIM inhibition significantly slowed the growth of TN tumors, it induced only modest in vivo tumor cell death and regression, suggesting the need for combination therapies. We have taken robust drug screening approaches and have unexpectedly found that the drug combination that targets PIM kinases and the proteasome can acutely induce toxic levels of proteotoxic stress selectively in MYC-overexpressing TNBC cells. Mechanistically, our preliminary observations indicate that PIM inhibition, which elevates the levels of reactive oxygen species, when combined with proteasome inhibition, overwhelms the capacity of TNBC cells to continuously degrade damaged proteins, resulting in proteotoxic crisis. Thus, our observations raise the possibility—and our study will test the hypothesis—that PIM inhibition represents a unique and clinically viable tool to sensitize TNBC tumors to proteasome inhibition. The successful execution of this research will allow for the identification and interrogation of clinically exploitable vulnerabilities in MYC-driven solid-cancer types such as TNBC. The outcomes of this research could also encourage the FDA- approved proteasome inhibitors (e.g., carfilzomib), which have not been successfully used outside of liquid tumor types, to be rapidly evaluated in combination with pan-PIM kinase inhibitors in early-stage MYC-driven solid- tumor trials.


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 = $309,112 )
2026	2026	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	000	5	12/18/2025	NON-COMPETING CONTINUATION	$309,112
														Subtotal = $309,112

Issue Date FY: 2025 ( Subtotal = $343,458 )
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	001	4	2/12/2025	NON-COMPETING CONTINUATION	$309,112
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	002	4	7/4/2025	NON-COMPETING CONTINUATION	$34,346
2025	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	000	3	1/7/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $343,458

Issue Date FY: 2024 ( Subtotal = $326,284 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	001	3	4/16/2024	NON-COMPETING CONTINUATION	$17,172
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	000	3	1/3/2024	NON-COMPETING CONTINUATION	$309,112
														Subtotal = $326,284

Issue Date FY: 2023 ( Subtotal = $336,588 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	000	2	12/12/2022	NON-COMPETING CONTINUATION	$309,112
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	001	2	3/17/2023	NON-COMPETING CONTINUATION	$27,476
														Subtotal = $336,588

Issue Date FY: 2022 ( Subtotal = $343,458 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	000	1	12/24/2021	NEW	$343,458
														Subtotal = $343,458

Grand Total All Awards = $1,658,900

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Investigating Rational Combination Therapies for Triple-Negative Breast Cancer

Award Number: R01CA258833

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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