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.
|Abubakar, Mustapha; Orr, Nick; Daley, Frances et al. (2016) Prognostic value of automated KI67 scoring in breast cancer: a centralised evaluation of 8088 patients from 10 study groups. Breast Cancer Res 18:104|
|Cichon, Magdalena A; Moruzzi, Megan E; Shqau, Tiziana A et al. (2016) MYC Is a Crucial Mediator of TGFÎ²-Induced Invasion in Basal Breast Cancer. Cancer Res 76:3520-30|
|de la Hoya, Miguel; Soukarieh, Omar; LÃ³pez-Perolio, Irene et al. (2016) Combined genetic and splicing analysis of BRCA1 c.[594-2A>C; 641A>G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms. Hum Mol Genet 25:2256-2268|
|Durand, Nisha; Bastea, Ligia I; Long, Jason et al. (2016) Protein Kinase D1 regulates focal adhesion dynamics and cell adhesion through Phosphatidylinositol-4-phosphate 5-kinase type-l Î³. Sci Rep 6:35963|
|Shi, Jiajun; Zhang, Yanfeng; Zheng, Wei et al. (2016) Fine-scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer. Int J Cancer 139:1303-17|
|(2016) Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus. Nat Commun 7:12675|
|Lei, Jieping; Rudolph, Anja; Moysich, Kirsten B et al. (2016) Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility: a pooled analysis of 42,510 cases and 40,577 controls from the Breast Cancer Association Consortium. Hum Genet 135:137-54|
|Schmidt, Marjanka K; Hogervorst, Frans; van Hien, Richard et al. (2016) Age- and Tumor Subtype-Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers. J Clin Oncol 34:2750-60|
|Li, Xu; Wang, Wenqi; Xi, Yuanxin et al. (2016) FOXR2 Interacts with MYC to Promote Its Transcriptional Activities and Tumorigenesis. Cell Rep 16:487-97|
|Petridis, Christos; Brook, Mark N; Shah, Vandna et al. (2016) Genetic predisposition to ductal carcinoma in situ of the breast. Breast Cancer Res 18:22|
Showing the most recent 10 out of 381 publications