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Mcl-1 drives resistance of luminal breast cancers to targeted therapies

Award Number: F31CA195989
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2015
PERIOD OF PERFORMANCE END DATE: 08/11/2017

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Mcl-1 drives resistance of luminal breast cancers to targeted therapies - ¿ DESCRIPTION (provided by applicant): Bcl-2 family proteins use complex intra-family interactions to regulate the intrinsic apoptotic pathway. In particular, anti-apoptotic Bcl-2 famil members (A1, Bcl-2, Bcl-xL, Bcl-w and Mcl-1) inhibit apoptosis by sequestering pro-apoptotic Bcl-2 family members (Bak, Bax, Bid, Bim and Puma). Thus, the balance of pro- to anti-apoptotic Bcl-2 proteins regulates the cellular life-death switch. In cancers, sustained overexpression of anti-apoptotic Bcl-2 family members promotes tumor cell survival. Further, anti-apoptotic Bcl-2 proteins often drive resistance of cancers to chemotherapies and targeted therapies. BH3-mimetics, small molecules designed to sequester the activity of anti-apoptotic Bcl-2 family members, were designed to combat therapeutic resistance caused by anti-apoptotic Bcl-2 proteins. In breast cancers, BH3-mimetics increase treatment-induced tumor cell killing in some but not all tumors. The mechanisms underlying resistance to these BH3-mimetics remain unclear. Our preliminary data suggest that human-derived breast cancer cell lines with MCL1 amplification display limited sensitivity to ABT-263, a BH3-mimetic targeting Bcl-2, Bcl-xL and Bcl-w, and up regulate Mcl-1 protein expression upon treatment with ABT-263. Mcl-1 knock-down increased sensitivity of breast cancer cells to ABT-263, while ectopic Mcl-1 expression enhanced ABT-263 resistance. Given the clinical impact of the Bcl-2 family in breast and other cancers, it is critical to investigate further the role of Mcl-1 in ABT-263 resistance, which we wil study in Aim 1. We further propose to study how Mcl-1 affects response of breast cancers to estrogen deprivation. Approximately 65% of breast cancers are dependent upon estrogen receptor-a (ERa) signaling, and thus are treated with ERa-targeting agents. The impact of Mcl-1 remains under-studied in this context. Our preliminary data show that Mcl-1 levels increase upon long term estrogen deprivation (LTED), a model used to mimic the estrogen-depleted conditions caused by treatment with aromatase inhibitors. We designed to combat therapeutic resistance caused by anti-apoptotic Bcl-2 proteins in Aim 2. Together, these studies will determine if Mcl-1 inhibitors, including a novel Mcl-1- specific BH3-mimetic developed by our collaborator, could be exploited clinically to improve tumor cell killing and to increase patient survival.


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 = -$3,097 )
2021	2016	VANDERBILT UNIVERSITY, THE	2301 VANDERBILT PL	NASHVILLE	TN	37235	DAVIDSON	USA	Cancer Research Manpower	000	2	1/12/2021	NON-COMPETING CONTINUATION	-$3,097
														Subtotal = -$3,097

Issue Date FY: 2017 ( Subtotal = -$1,234 )
2017	2016	VANDERBILT UNIVERSITY, THE	211 KIRKLAND HALL	NASHVILLE	TN	37240	DAVIDSON	USA	Cancer Research Manpower	000	2	9/8/2017	NON-COMPETING CONTINUATION	-$1,234
														Subtotal = -$1,234

Issue Date FY: 2016 ( Subtotal = $27,936 )
2016	2016	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Research Manpower	000	2	7/14/2016	NON-COMPETING CONTINUATION	$27,936
														Subtotal = $27,936

Issue Date FY: 2015 ( Subtotal = $30,113 )
2015	2015	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Research Manpower	001	1	5/6/2015	NEW	$0
2015	2015	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Research Manpower	000	1	5/6/2015	NEW	$30,113
														Subtotal = $30,113

Grand Total All Awards = $53,718

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Mcl-1 drives resistance of luminal breast cancers to targeted therapies

Award Number: F31CA195989

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2015

PERIOD OF PERFORMANCE END DATE: 08/11/2017

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