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Investigating a hierarchical model for PI3K activation and inhibition in breast cancer by double PIK3CA mutations in cis

Award Number: K08CA245192
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/13/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Investigating a hierarchical model for PI3K activation and inhibition in breast cancer by double PIK3CA mutations in cis - PROJECT SUMMARY/ABSTRACT PIK3CA is the most frequently mutated oncogene in human cancer. PI3Kα inhibitors are a new standard of care in PIK3CA mutant ER+ metastatic breast cancer (ER+ MBC) and some patients have durable responses. In this proposal, I capitalize on our recent discovery of a novel mechanism of oncogene activation by double PIK3CA mutations. We have demonstrated that double PIK3CA mutations are frequent across all PIK3CA mutant cancers, occur at recurrent amino acid positions, and are in cis on the same allele. Double mutations activate PI3K signaling and growth more than single hotspot mutations in vitro and in vivo, and biochemically activate PI3K through disruption of p85 inhibition and increased membrane binding. Double mutations increase sensitivity to PI3Kα inhibition in cells and in PIK3CA mutant ER+ MBC patients. Our work has uncovered a hierarchical model for the activation and inhibition of PI3K based on mutation number (Vasan, et al. Science 2019). I will test the hypotheses that this hierarchical model extends to PI3K regulation, crosstalk with the estrogen receptor, and activation of novel AKT substrates. I will use recombinant double mutant PI3K complexes reconstituted with Ras and RTK to dissect the mechanisms of regulation (Aim 1.1) and the mechanisms of cellular generation of PIP3 (Aim 1.2). I will leverage knockin and overexpression cellular models to measure activation and inhibition of double mutant ER+ breast cancer (Aim 2.1) and modulation of ER-dependent transcription (Aim 2.2). These experiments will be performed in vitro, in vivo, in patient samples, and under PI3K inhibitor treatment. I will utilize unbiased phosphoproteomics on double mutant cells to credential new AKT protein kinase substrates (Aim 3.1) including the KMT family of histone lysine methyltransferases (Aim 3.2). Together these aims will validate our hierarchical model of oncogene activation by double PIK3CA mutants across a wide variety of cellular and biological processes and will lead to new strategies to inhibit PI3K including testing PI3Kα inhibitors in multiple PIK3CA mutant patients. I am an Assistant Attending with the Breast Medicine Service at Memorial Sloan Kettering Cancer Center (MSKCC), and I have outlined a 5-year career plan that builds upon my background studying structural biology and my clinical training in breast oncology. I have assembled an outstanding mentoring team of Dr. Lewis Cantley (primary mentor) and Dr. Maurizio Scaltriti (co-mentor). My advisory committee will include Dr. Neal Rosen, Dr. Ross Levine, and Dr. Komal Jhaveri. They are internationally renowned scientists in their respective fields who will provide me the mentorship and support to attain scientific independence. I will have access to unparalleled institutional support at MSKCC and Weill Cornell Medical College. Both institutions are at the leading edge of cancer research and are heavily invested in career development. Collectively, this training environment will enable me to achieve my goals of ultimately securing a tenure-track independent position.


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 = -$1 )
2026	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Research Manpower	000	5	11/25/2025	NON-COMPETING CONTINUATION	-$1
														Subtotal = -$1

Issue Date FY: 2024 ( Subtotal = $196,603 )
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Research Manpower	001	5	7/8/2024	NON-COMPETING CONTINUATION	$196,603
2024	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Research Manpower	000	4	10/18/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $196,603

Issue Date FY: 2023 ( Subtotal = $263,034 )
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Research Manpower	000	4	6/16/2023	NON-COMPETING CONTINUATION	$263,034
														Subtotal = $263,034

Issue Date FY: 2022 ( Subtotal = $263,034 )
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Research Manpower	002	3	7/5/2022	NON-COMPETING CONTINUATION	$263,034
2022	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Research Manpower	001	2	11/9/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$70,105
2022	2020	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Research Manpower	000	1	11/9/2021	NEW	-$70,105
														Subtotal = $263,034

Issue Date FY: 2021 ( Subtotal = $263,034 )
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Research Manpower	001	2	8/13/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$263,034
2021	2020	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Research Manpower	000	1	8/12/2021	NEW	$0
														Subtotal = $263,034

Issue Date FY: 2020 ( Subtotal = $263,034 )
2020	2020	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Research Manpower	000	1	8/12/2020	NEW	$263,034
														Subtotal = $263,034

Grand Total All Awards = $1,248,738

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Investigating a hierarchical model for PI3K activation and inhibition in breast cancer by double PIK3CA mutations in cis

Award Number: K08CA245192

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/13/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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