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Non-Canonical Phosphatidylinositol Kinases in Triple Negative Breast Cancer

Award Number: R01CA237536
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Non-Canonical Phosphatidylinositol Kinases in Triple Negative Breast Cancer - PROJECT SUMMARY Triple negative breast cancer (TNBC) accounts for 15–20% of all breast cancers. Women with TNBC are three times more likely to experience death compared to other subtypes. The poor prognosis of TNBC can be attributed to the lack of effective targeted therapy. Although TP53 mutations are frequently found in TNBC, it is difficult to target p53-deficiency with drugs. We have identified a family of non-canonical phosphatidylinositol kinases, the phosphatidylinositol-5-phosphate 4-kinases (PI5P4Ks) and their crucial role in the growth of cancers with TP53 aberrations. Furthermore, we discovered a role for the PI5P4Ks in autophagy, and for the first time, showed that these enzymes localize to lysosomes, suggesting that the PI5P4Ks may be important for lysosome function, as well as shedding light on the anti-cancer mechanism of PI5P4K inhibition in p53 mutant cancers. Using preclinical studies in novel genetically engineered mouse breast tumor models, human breast cancer cell lines, and patient breast tumor samples we propose to investigate the biochemical basis for the function of these ‘druggable’ enzymes. We will also validate them as targets for pharmaceutical intervention in human cancers, especially for TNBC where targeted therapies have not been successful. Our overarching hypothesis is that the PI5P4Ks act as sensors of metabolic stress that allow cells to modulate lysosomal events, including autophagy, in order to maintain cellular homeostasis. Further, we posit that the metabolic rewiring associated with p53 mutations, create a novel dependency on the PI5P4Ks for TNBC cell growth and survival. In Aim 1 we will determine the mechanism of synthetic vulnerability by which the PI5P4Ks become essential for tumor cell growth when p53 is defective. To this end we will characterize how mutant p53, both loss of function and gain of function, contributes to the synthetic lethality as well as dissect the metabolic consequences of PI5P4K loss in p53 mutant TNBC cells. In Aim 2 we will test the therapeutic effectiveness of targeting the PI5P4Ks in TNBC using our genetically engineered mouse breast tumor models and patient breast tumor samples. The ultimate goal and the overall impact of this project are to characterize PI5P4Ks as a novel liability for tumors with TP53 mutations in order to define opportunities for therapeutic intervention for TNBC patients with these mutations, which currently lack targeted therapy.


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	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	000	5	9/5/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $423,760 )
2024	2024	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	000	5	5/22/2024	NON-COMPETING CONTINUATION	$423,760
														Subtotal = $423,760

Issue Date FY: 2023 ( Subtotal = $437,141 )
2023	2023	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	000	4	5/31/2023	NON-COMPETING CONTINUATION	$437,141
														Subtotal = $437,141

Issue Date FY: 2022 ( Subtotal = $446,063 )
2022	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	000	3	5/17/2022	NON-COMPETING CONTINUATION	$446,063
														Subtotal = $446,063

Issue Date FY: 2021 ( Subtotal = $446,063 )
2021	2021	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	000	2	5/3/2021	NON-COMPETING CONTINUATION	$446,063
														Subtotal = $446,063

Issue Date FY: 2020 ( Subtotal = $446,063 )
2020	2020	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	000	1	5/1/2020	NEW	$446,063
														Subtotal = $446,063

Grand Total All Awards = $2,199,090

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Non-Canonical Phosphatidylinositol Kinases in Triple Negative Breast Cancer

Award Number: R01CA237536

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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