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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA116201-08
Application #
8744905
Study Section
Special Emphasis Panel (ZCA1-RPRB-7 (M1))
Project Start
2013-09-01
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
8
Fiscal Year
2013
Total Cost
$260,004
Indirect Cost
$80,199
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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 TGFβ-Induced Invasion in Basal Breast Cancer. Cancer Res 76:3520-30
de la Hoya, Miguel; Soukarieh, Omar; López-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 γ. 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
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
(2016) Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus. Nat Commun 7:12675
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
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
Chiba, Akiko; Hoskin, Tanya L; Hallberg, Emily J et al. (2016) Impact that Timing of Genetic Mutation Diagnosis has on Surgical Decision Making and Outcome for BRCA1/BRCA2 Mutation Carriers with Breast Cancer. Ann Surg Oncol 23:3232-8

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