S1-5: Modulation of Cancer and Stem Cell Biomarkers by the Notch Inhibitor MK-0752 Added to Endocrine Therapy for Early Stage ER+ Breast Cancer.

Abstract

Background: New strategies to enhance endocrine therapy (ET) efficacy and/or overcome resistance by targeting key survival pathways are needed. Preclinical data indicate that unwanted effects of ET include reactivation of the Notch pathway, critical for breast tumor initiating (stem) cells. Notch inhibition with gamma secretase inhibitors (GSI) enhances tamoxifen (tam) efficacy in xenografts, but impact of GSI+ET in human breast cancer (BC) is unknown. Our objective was to add short exposure of the GSI MK-0752 to ongoing tam or letrozole (let) in the presurgical window to assess feasibility, safety and biomarker/pathway impact in a 20-patient (pt) pilot study (ClinTrials.gov NCT00756717). We previously evaluated several biomarkers in the first cohort, which showed promise with Notch and proliferation inhibition. We present new results adding the final cohort, plus additional biomarkers and microarray analyses. Methods: Pts with early stage ER+ BC received 25 days (d) of ET. MK-0752 was added d15 (350 mg PO 3d on, 4d off, 3d on) with definitive surgery d25. Core biopsies were done at baseline, d14 and d25, with qRT-PCR for Notch-related and other genes critical to stem cell renewal/proliferation. Gene expression levels after GSI (d25) vs ET alone (d14) were analyzed and d25 changes in all pts combined for each gene were compared. Microarray expression estimates and modeling were performed using dCHip and Red-R, implementing gene-wise comparisons using Limma. Probes were defined as significantly regulated by paired t tests if p ≤ 0.001 for the comparisons of baseline to tam/let and tam/let to tam/let+GSI. Data were exploratory so all probe data were included in the modeling, and no corrections for multiple comparisons were used. Differentially expressed genes were submitted to DAVID for pathway analysis. Results: Of 22 pts accrued, 20 (11 tam, 9 let) were evaluable, meeting accrual goals (2 withdrew before MK-0752); 19 completed therapy to date. Toxicity was minimal. Significant (p<.05) changes in mRNA levels after GSI+ET vs end of ET in 17 pts (3 in progress) were down-regulation of Notch4 in 13; Ki67, 13; Notch1, 12; RUNX1 (stem cell transcription factor), 13; ADAM19 (disintegrin/metalloproteinase), 12; MMP7 (Wnt target), 11; CCND1 (cyclin D1), 10; and up-regulation of NOXA (pro-apoptotic BH3-only gene), 13. Microarray analyses (10 completed, remainder underway) found significant numbers of GSI-regulated genes that were independent of tam/let. Of 4036 genes increased by GSI, 2777 were unchanged by tam/let; of 3978 genes decreased by GSI, 1017 were not impacted by tam/let. For example, of genes regulated by GSI alone, there was modulation of important cancer pathways: Wnt5a, FGFs, FGFR, IGF-1R were decreased; Fas and caspases were increased. These changes in gene expression are being compared with ET resistance profiles. Conclusions: Short exposure of MK-0752 added to ET was feasible, well tolerated, and resulted in significant biomarker response in all tumors. MK-0752 favorably modulated proliferation, apoptosis, stem cell and metastasis-related targets, and impacted critical cancer pathways. This suggests potential roles for MK-0752 in optimizing endocrine therapy and overcoming endocrine resistance. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S1-5.

Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update

“…These investigational agents should, therefore, be tested in combinations with established drugs (and if warranted, in combinations with other novel agents), on the basis of the available preclinical mechanistic rationale. Examples include combinations of Notch-pathway inhibitors with endocrine therapy in ER-positive breast cancer, 46,47,78 with HER2 inhibitors in HER2 -amplified breast cancer, 32,79 and with taxanes and MET inhibitors in TNBC. 80,81 In fact, combinations of inhibitors of Notch signalling with endocrine therapy have been translated to the clinic with promising results in terms of safety and preliminary efficacy signals.…”

Targeting Notch signaling pathway in cancer: Clinical development advances and challenges

“…A trial with MK-0752 in combination with tamoxifen or letrozole is assessed for the treatment of early stage hormone receptor-positive breast cancer (Albain et al, 2011). MK-0752 plus gemcitabine is being conducted for the treatment of patients with stage IV surgically unresectable stage IV pancreatic cancer (Table 1).…”

Notch inhibitors for cancer treatment

“…It is currently in several Phase 1 clinical trial for pediatric and adult oncology treatment (Macy et al, 2008; Zweidler-McKay, 2008; Zhou et al, 2009; Fouladi et al, 2011). We have completed a pilot clinical trial with MK-0752 in combination with endocrine therapy in the preclinical setting (Albain, 2011). This combination was safe and well tolerated, and, importantly, showed molecular evidence of anti-proliferative and pro-apoptotic effects in tumor tissue.…”