Tamoxifen (TAM) continues to be an important drug for the treatment of estrogen receptor positive (ER+) breast cancer. We have demonstrated that endoxifen, a potent metabolite resulting in part from Cytochrome P450 2D6 (CYP2D6) metabolism, is critical for TAM's antiproliferative effects. Our observation that reductions in CYP2D6 activity were associated with a higher risk of recurrence in TAM-treated breast cancer led us to focus our studies on endoxifen, providing the preliminary data for this proposal. In tumor bearing animals, endoxifen is superior to TAM. Furthermore, our in vitro data indicate that endoxifen can overcome TAM resistance associated with Human Epidermal growth factor Receptor 2 (HER2) expression because endoxifen does not stimulate ER/HER2 cross-talk as TAM does. We presented these data to NCI and they decided to proceed with endoxifen drug development, including production of clinical grade endoxifen hydrochloride and preclinical toxicology/pharmacology for IND submission. Our preliminary data indicate that the following questions should be addressed: 1) What are the metabolic pathways responsible for elimination of endoxifen, and are endoxifen-related toxicities similar to TAM (e.g. uterine stimulation)? 2) Does endoxifen have in vivo anti-tumor activity similar or greater than aromatase inhibitors (Al's) and does endoxifen exhibit anti-tumor activity in cells resistant to TAM or Al's? 3) In humans, can we identify a tolerable endoxifen dose and what is its toxicity profile? and, 4) Is this tolerable dose of endoxifen biologically relevant, as assessed by reductions in proliferation (Ki-67) and growth factor signaling in vivo, as well as clinical responses? To address these questions, we have proposed the following aims.
Aim 1 : to further characterize the pharmacokinetics, metabolism and toxicology of endoxifen;
Aim 2 : to study endoxifen antitumor activity and its effects on cell signaling in a murine xenograft model in comparison to TAM and letrozole and to describe the anti-tumor activity of endoxifen in TAM and letrozole resistant tumors;
and Aim 3 : to conduct a phase I study of endoxifen in humans to determine the maximum tolerated dose (MTD), and describe its toxicity profile. Following this determination, we will enroll additional patients to explore 2 different doses of endoxifen: a) the MTD and b) the endoxifen dose associated with steady state concentrations of 1 pM. At these doses, we will examine the impact of endoxifen on uterine thickness, frequency and severity of hot flashes, and perform paired tumor biopsies to determine endoxifen's effect on proteins important in growth factor signaling and proliferation.
This project is based on observations that endoxifen provides superior in vivo anti-tumor activity compared to TAM and inhibits the growth of HER2 expressing, ER positive breast cancer. In summary, endoxifen could be a superior alternative hormonal therapy for the treatment of both pre- and postmenopausal breast cancer, regardless of HER2 status.
|Yu, Jia; Qin, Bo; Moyer, Ann M et al. (2018) DNA methyltransferase expression in triple-negative breast cancer predicts sensitivity to decitabine. J Clin Invest 128:2376-2388|
|Kannan, Nagarajan; Eaves, Connie J (2018) Macrophages stimulate mammary stem cells. Science 360:1401-1402|
|Guidugli, Lucia; Shimelis, Hermela; Masica, David L et al. (2018) Assessment of the Clinical Relevance of BRCA2 Missense Variants by Functional and Computational Approaches. Am J Hum Genet 102:233-248|
|Kurmi, Kiran; Hitosugi, Sadae; Wiese, Elizabeth K et al. (2018) Carnitine Palmitoyltransferase 1A Has a Lysine Succinyltransferase Activity. Cell Rep 22:1365-1373|
|Goetz, Matthew P; Sangkuhl, Katrin; Guchelaar, Henk-Jan et al. (2018) Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and Tamoxifen Therapy. Clin Pharmacol Ther 103:770-777|
|Baheti, Saurabh; Tang, Xiaojia; O'Brien, Daniel R et al. (2018) HGT-ID: an efficient and sensitive workflow to detect human-viral insertion sites using next-generation sequencing data. BMC Bioinformatics 19:271|
|Hart, Steven N; Hoskin, Tanya; Shimelis, Hermela et al. (2018) Comprehensive annotation of BRCA1 and BRCA2 missense variants by functionally validated sequence-based computational prediction models. Genet Med :|
|Yang, Yuzhe; Chan, Jie Ying; Temiz, Nuri A et al. (2018) Insulin Receptor Substrate Suppression by the Tyrphostin NT157 Inhibits Responses to Insulin-Like Growth Factor-I and Insulin in Breast Cancer Cells. Horm Cancer 9:371-382|
|Ho, Ming-Fen; Correia, Cristina; Ingle, James N et al. (2018) Ketamine and ketamine metabolites as novel estrogen receptor ligands: Induction of cytochrome P450 and AMPA glutamate receptor gene expression. Biochem Pharmacol 152:279-292|
|Ingle, James N; Kalari, Krishna R; Wickerham, Donald Lawrence et al. (2018) Germline genome-wide association studies in women receiving neoadjuvant chemotherapy with or without bevacizumab. Pharmacogenet Genomics 28:147-152|
Showing the most recent 10 out of 473 publications