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Change of Grantee Institution: Role of Cytochrome P450 3A5 in the Metabolism and Hepatotoxicity of Lapatinib

Award Number: K01CA190711
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/21/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2020

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Change of Grantee Institution: Role of Cytochrome P450 3A5 in the Metabolism and Hepatotoxicity of Lapatinib - DESCRIPTION (provided by applicant): The overall goal of this research career development proposal is to foster my development to becoming an independent research scientist. My long-term career goal is to make significant contributions towards understanding the molecular toxicology of clinically relevant anti-cancer agents to improve their safe use in patients. Drug-induced liver injury associated with tyrosine kinase inhibitors is a growing clinical problem in cancer therapy. Lapatinib, a dual tyrosine kinase inhibitor, is a targeted therapy for the treatmen of advanced or metastatic breast cancer. However, idiosyncratic hepatotoxicity associated with lapatinib may limit its use in certain patient populations. The mechanism(s) of this toxicity are unknown. Lapatinib can undergo metabolic activation by cytochrome P450 (CYP) 3A4/5 to form a reactive quinoneimine, potentially toxic metabolite. My central hypothesis is that polymorphic expression of CYP3A5 contributes to inter-individual differences in the generation of reactive metabolites of lapatinib, which may be a risk factor for the development of hepatotoxicity. The overall goal of this project is to define the contribution of CYP3A5 to the metabolism and bioactivation of lapatinib in vitro, and evaluate the impact of CYP3A5 genetic variation on the generation of reactive metabolites of lapatinib. To address the hypothesis, the following specific aims are proposed: 1) Determine the role of CYP3A5 in the overall metabolism and bioactivation of lapatinib; 2) Evaluate the effect of CYP3A5 genetic polymorphisms on the metabolic profile of lapatinib; and 3) Examine the metabolism and cytotoxicity of lapatinib in genotyped human hepatocyte cultures. These in vitro investigations will be carried out using recombinant P450 enzymes, individual genotyped human liver microsomal preparations, and primary human hepatocytes utilizing enzyme selective inhibitors. This project will advance the field by providing insight into the role of CYP3A5 polymorphism in the hepatotoxic potential of lapatinib in special patient populations. To further develop my research skills, I will benefit fro additional training in research design focused on utilizing biochemical techniques, in vitro models, and analytical approaches to characterize drug biotransformation and identify potential toxicity pathways. Gaining more knowledge and new skills in these areas will help improve my ability to develop high quality research projects to address unanswered questions in related to cancer treatment and drug toxicity. The proposed research career development plan involves cross-institutional mentorship with mentors at Lipscomb University and Vanderbilt University to allow me to capitalize on the outstanding strengths that each mentor offers. Key elements of this career development plan include regular interactions with my mentoring committee, participation in seminars relevant to my research, and engaging in opportunities for training in career skills.


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 = $0 )
2021	2018	LIPSCOMB UNIVERSITY	ONE UNIVERSITY PARK DR	NASHVILLE	TN	37204	DAVIDSON	USA	Cancer Research Manpower	000	5	3/22/2021	NON-COMPETING CONTINUATION	$0
2021	2018	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Research Manpower	001	6	3/24/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	LIPSCOMB UNIVERSITY	ONE UNIVERSITY PARK DR	NASHVILLE	TN	37204	DAVIDSON	USA	Cancer Research Manpower	000	5	11/25/2019	NON-COMPETING CONTINUATION	-$50,949
2020	2018	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Research Manpower	001	6	11/25/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$50,949
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $131,828 )
2018	2018	LIPSCOMB UNIVERSITY	ONE UNIVERSITY PARK DR	NASHVILLE	TN	37204	DAVIDSON	USA	Cancer Research Manpower	000	5	8/16/2018	NON-COMPETING CONTINUATION	$131,828
														Subtotal = $131,828

Issue Date FY: 2017 ( Subtotal = $131,828 )
2017	2017	LIPSCOMB UNIVERSITY	ONE UNIVERSITY PARK DR	NASHVILLE	TN	37204	DAVIDSON	USA	Cancer Research Manpower	000	4	8/17/2017	NON-COMPETING CONTINUATION	$131,828
														Subtotal = $131,828

Issue Date FY: 2016 ( Subtotal = $131,863 )
2016	2016	LIPSCOMB UNIVERSITY	ONE UNIVERSITY PARK DRIVE	NASHVILLE	TN	37204	DAVIDSON	USA	Cancer Research Manpower	000	3	8/2/2016	NON-COMPETING CONTINUATION	$131,863
														Subtotal = $131,863

Issue Date FY: 2015 ( Subtotal = $132,136 )
2015	2015	LIPSCOMB UNIVERSITY	ONE UNIVERSITY PARK DRIVE	NASHVILLE	TN	37204	DAVIDSON	USA	Cancer Research Manpower	000	2	8/10/2015	NON-COMPETING CONTINUATION	$132,136
														Subtotal = $132,136

Issue Date FY: 2014 ( Subtotal = $131,056 )
2014	2014	LIPSCOMB UNIVERSITY	ONE UNIVERSITY PARK DRIVE	NASHVILLE	TN	37204	DAVIDSON	USA	Cancer Research Manpower	000	1	9/17/2014	NEW	$131,056
														Subtotal = $131,056

Grand Total All Awards = $658,711

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Change of Grantee Institution: Role of Cytochrome P450 3A5 in the Metabolism and Hepatotoxicity of Lapatinib

Award Number: K01CA190711

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/21/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2020

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