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Optogenetic profiling of functional signaling abnormalities in triple negative breast cancer

Award Number: F30CA206408
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 05/01/2016
PERIOD OF PERFORMANCE END DATE: 04/30/2022

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Optogenetic profiling of functional signaling abnormalities in triple negative breast cancer - DESCRIPTION (provided by applicant): Breast cancer will cause roughly 40,000 deaths in the U.S. in 2015. The 10-20% of cases classified as triple- negative (ER, PR, and HER2 negative) breast cancers (TNBCs) account for an inordinate number of these deaths, in part owing to a lack of unifying molecular features and thus a lack of targeted therapies. As such, deeper knowledge of the underlying biology is desperately needed to define therapeutic vulnerabilities and provide better treatment outcomes for patients. A subset of TNBCs has been shown to respond to therapeutic inhibition of Ras and PI3K signaling pathways; however, it has historically been challenging to predict which individual tumors will respond to these treatments because of the mutational complexity of this disease. As such, an ideal approach would be to directly assess Ras and PI3K pathway dynamics in live cells in order to identify which tumors harbor functional pathway alterations and are therefore more likely to respond to pathway inhibitors. To accomplish this goal I will employ a multidisciplinary approach to profile Ras and PI3K signaling in TNBC cells using optogenetics, microscopy, bioinformatics, and drug cytotoxicity assays. This work is based on our lab's development of parallel optogenetic systems that harnesses a protein interaction from plants (the Phy/PIF binding pair) to control either Ras or PI3K activity with high resolution in single cells. These pathways will be placed under light control in 30 well-characterized human TNBC cell lines by fusing the Phy/PIF domains to proteins that selectively activate the Ras or PI3K modules. By varying light inputs and measuring live-cell fluorescent reporters of downstream pathway activity, I will measure detailed responses of signaling dynamics in both pathways at a single-cell level across a representative panel of TNBC mutational backgrounds. In parallel, I will also examine the cytotoxic response of these cells to a panel of targeted kinase inhibitors. I will then use publicl available genomic data from each cell line to identify the mutational signatures that underlie signaling abnormalities and drug sensitivities. The proposed study will produce several advances in scientific knowledge. First, it will develop a method for rapid, precise control of the Ras and PI3K pathways in a panel of tumor cells, highlighting how cell signaling and protein dynamics are dysregulated by mutation. Second, it will constitute the first functional study of temporal signaling dynamics in TNBC, expanding the understanding of how uncharacterized Ras and PI3K pathway alterations contribute to neoplastic growth. Third, the relevance of these findings to each cell lines' drug sensitivity and genomic alterations will be assessed, highlightin targetable molecular and temporal processes involved in oncogenic signaling defects. Successful completion of my research will broaden our understanding of TNBC pathogenesis and facilitate the design of rational treatment strategies with immediate clinical applicability.


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: 2023 ( Subtotal = -$49,949 )
2023	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Cancer Research Manpower	000	7	5/15/2023	NON-COMPETING CONTINUATION	-$49,949
														Subtotal = -$49,949

Issue Date FY: 2022 ( Subtotal = -$15,352 )
2022	2019	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Cancer Research Manpower	001	4	4/22/2022	NON-COMPETING CONTINUATION	-$3,724
2022	2018	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Cancer Research Manpower	000	3	4/22/2022	NON-COMPETING CONTINUATION	-$11,628
														Subtotal = -$15,352

Issue Date FY: 2021 ( Subtotal = $51,036 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Cancer Research Manpower	000	7	3/18/2021	NON-COMPETING CONTINUATION	$51,036
														Subtotal = $51,036

Issue Date FY: 2020 ( Subtotal = $50,520 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Cancer Research Manpower	000	6	4/2/2020	NON-COMPETING CONTINUATION	$50,520
														Subtotal = $50,520

Issue Date FY: 2019 ( Subtotal = $50,016 )
2019	2019	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Cancer Research Manpower	000	4	4/29/2019	NON-COMPETING CONTINUATION	$50,016
2019	2019	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Cancer Research Manpower	001	4	5/9/2019	NON-COMPETING CONTINUATION	-$46,292
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Cancer Research Manpower	002	5	5/9/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$46,292
														Subtotal = $50,016

Issue Date FY: 2018 ( Subtotal = $49,524 )
2018	2018	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Cancer Research Manpower	001	3	5/31/2018	NON-COMPETING CONTINUATION	$480
2018	2018	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Cancer Research Manpower	000	3	3/12/2018	NON-COMPETING CONTINUATION	$49,044
														Subtotal = $49,524

Issue Date FY: 2017 ( Subtotal = $49,044 )
2017	2017	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Cancer Research Manpower	001	2	7/26/2017	NON-COMPETING CONTINUATION	$468
2017	2017	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Cancer Research Manpower	000	2	4/28/2017	NON-COMPETING CONTINUATION	$48,576
														Subtotal = $49,044

Issue Date FY: 2016 ( Subtotal = $48,576 )
2016	2016	PRINCETON UNIVERSITY	POST OFFICE BOX 5292	PRINCETON	NJ	08544	MERCER	USA	Cancer Research Manpower	000	1	3/25/2016	NEW	$48,576
2016	2016	PRINCETON UNIVERSITY	POST OFFICE BOX 5292	PRINCETON	NJ	08544	MERCER	USA	Cancer Research Manpower	001	1	3/25/2016	NEW	$0
														Subtotal = $48,576

Grand Total All Awards = $233,415

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Optogenetic profiling of functional signaling abnormalities in triple negative breast cancer

Award Number: F30CA206408

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 05/01/2016

PERIOD OF PERFORMANCE END DATE: 04/30/2022

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