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.
Breast cancer is the leading cause of cancer death among women worldwide, and the targeted anti-cancer agent lapatinib is an important advancement in breast cancer treatment. However, severe liver toxicity associated with lapatinib may limit its use in certain patient populations. The proposed studies are aimed to elucidate the underlying molecular mechanisms of lapatinib-induced liver toxicity and identify the genetic factors that may contribute to patient risk of developing the toxicity. The written critiques of individual reviewers are provided in essentially unedited form in this section. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The Resume and Summary of Discussion section above summarizes the final opinions of the committee.