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Targeting Altered Redox Metabolism in Lapatinib-resistant Breast Cancer

Award Number: F31CA174365
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/30/2012
PERIOD OF PERFORMANCE END DATE: 06/29/2017

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Targeting Altered Redox Metabolism in Lapatinib-resistant Breast Cancer - DESCRIPTION (provided by applicant): Overexpression and amplification of HER2 denotes a poor prognosis and outcome for breast cancer patients. Despite the availability of targeted anti-HER2 therapies, the clinical benefit of anti-HER2 agents is short-lived. We have made the unexpected observation that HER2+ human BC cell line HCC1954 exhibits a switch from aerobic glycolysis to oxidative phosphorylation metabolism as resistance to the anti-HER2 kinase inhibitor, lapatinib, sets in. Additionally, we have found that the dual EGFR/HER2 kinase inhibitor lapatinib lengthens the cell cycle time of HER2+ HCC1954 breast cancer cells without increasing apoptosis or cell death. This lengthening of the cell cycle correlates to reduced proliferation and population doublings under lapatinib treatment, as well as metabolic changes. Upon generating lapatinib-resistant HER2+ breast cancer cells, we discovered that lapatinib resistance conferred sensitivity to the metabolic inhibitor phenformin. These data suggest that HER2+ breast cancer cells may have adapted altered ErbB signaling networks to overcome anti- HER2 treatment and use alternative metabolic strategies to fuel uncontrolled proliferation. The goal of this application is to investigate HER2+ breast cancers switch from glycolytic to oxidative metabolism in response to lapatinib treatment, and its relationship to resistance. We will use paired parental and drug-resistant cell lines to assess the metabolic effect of targeted anti-HER2 treatment on a functional and molecular level with single cell resolution. Furthermore, the population dynamics of sensitive and resistant cells treated with anti- HER2 and phenformin will be interrogated using acute and chronic animal models. We believe that lapatinib resistant cells will be more sensitive to phenformin in vivo, and the use of phenformin will reduce tumor burden. Our approach includes an assessment of drug treatment perturbations at a cellular level, complemented with a more focused analysis of the altered redox metabolism at a molecular level. Collectively, we hope to gain a better understanding of the mechanism of anti-HER2 resistance, probe the feasibility of metabolic inhibitors as anti-cancer therapy, and recapitulate drug action and response. If we are successful, our results may open the door to novel combination therapy including lapatinib and metabolic inhibitors such as metformin, which may improve performance of anti-HER2 targeted therapy and inhibit resistance.


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: 2021 ( Subtotal = -$3,976 )
2021	2016	VANDERBILT UNIVERSITY, THE	2301 VANDERBILT PL	NASHVILLE	TN	37235	DAVIDSON	USA	Cancer Research Manpower	000	5	1/4/2021	EXTENSION WITH OR WITHOUT FUNDS	-$3,976
														Subtotal = -$3,976

Issue Date FY: 2017 ( Subtotal = -$15,841 )
2017	2015	VANDERBILT UNIVERSITY, THE	211 KIRKLAND HALL	NASHVILLE	TN	37240	DAVIDSON	USA	Cancer Research Manpower	000	4	3/29/2017	NON-COMPETING CONTINUATION	-$15,841
														Subtotal = -$15,841

Issue Date FY: 2016 ( Subtotal = $21,948 )
2016	2016	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Research Manpower	000	5	8/19/2016	EXTENSION WITH OR WITHOUT FUNDS	$21,948
														Subtotal = $21,948

Issue Date FY: 2015 ( Subtotal = $27,766 )
2015	2015	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Research Manpower	000	4	8/21/2015	NON-COMPETING CONTINUATION	$27,766
														Subtotal = $27,766

Issue Date FY: 2014 ( Subtotal = $27,322 )
2014	2014	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Research Manpower	000	3	8/25/2014	NON-COMPETING CONTINUATION	$27,322
														Subtotal = $27,322

Issue Date FY: 2013 ( Subtotal = $35,237 )
2013	2013	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Research Manpower	000	2	8/23/2013	NON-COMPETING CONTINUATION	$35,237
														Subtotal = $35,237

Issue Date FY: 2012 ( Subtotal = $42,232 )
2012	2012	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Research Manpower	000	1	9/11/2012	NEW	$42,232
2012	2012	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Research Manpower	001	1	9/11/2012	NEW	$0
														Subtotal = $42,232

Grand Total All Awards = $134,688

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Targeting Altered Redox Metabolism in Lapatinib-resistant Breast Cancer

Award Number: F31CA174365

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/30/2012

PERIOD OF PERFORMANCE END DATE: 06/29/2017

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