Abstract PD2-02: SFX-01 targets Wnt signalling to inhibit stem-like cells in breast cancer patient-derived xenograft tumours
Authors: SJ Howell, BM Simoes, D Alferez, R Eyre, K Spence, A Santiago-Gomez, A Sarmiento-Castro, I Tanaka, D Howat, RB Clarke
Journal: Cancer Research (2017)

Abstract Background: SFX-01 is a novel therapeutic comprising synthetic sulforaphane (SFN) stabilised within a-cyclodextrin. Breast cancer stem-like cells (CSCs) have been identified in all molecular subtypes and are likely drivers of breast cancer metastasis and treatment resistance. We recently established that CSC activity in ER+ BC, represent a source of therapeutic resistance (Simões et al, Cell Reports, 2015). Material and methods: We investigated SFX-01 effects on breast CSC activity using mammosphere formation efficiency (MFE) and aldehyde dehydrogenase (ALDH) activity using the ALDEFLUOR assay in patient samples and patient-derived xenograft (PDX) tumours. Cells from primary (n=12) and metastatic (n=15) samples were treated with SFX-01 (5 μM) or vehicle control.Using a 2 or 8 week in vivo treatment, early (HBCx34) and metastatic (BB3RC31) ER+ PDX tumours were treated with SFX-01 (300mg/Kg/day) alone or in combination with tamoxifen (TAM, 10 mg/kg/day) or fulvestrant (FULV, 200 mg/kg/week). Tumours were dissociated and MFE and ALDH activity assessed. Results: SFX-01 in vitro reduced MFE of both primary (0.19%±0.02 vs control 0.52%±0.06: p&amp;lt;0.001) and metastatic patient samples (0.43±0.04 vs control 0.93%±0.07: p&amp;lt;0.001). SFX-01 treatment in vivo for 2 weeks reduced MFE of HBCx34 (0.35%±0.03 vs control 0.64%±0.09; p&amp;lt;0.01) and BB3RC31 (0.78%±0.04 vs control 0.89%±0.06: p&amp;lt;0.05) and also ALDH activity of HBCx34 (3%±0.6 vs control 6.3%±0.4: p&amp;lt;0.01) and BB3RC31 (1%±0.2 vs control 3%±0.6: p&amp;lt;0.05). TAM and FULV increased MFE and ALDH activity after 2 weeks of treatment in vivo, which was abrogated by combination with SFX-01; for example HBCx34 MFE with TAM alone: 0.81%±0.07 vs TAM+SFX-01: 0.34%±0.02 (p&amp;lt;0.01) and ALDH+ with TAM alone 10%±0.4 vs TAM+SFX 4.2%±0.4 (p&amp;lt;0.01). TAM+SFX-01 suppressed tumour growth at 8 weeks vs TAM alone in HBCx34 but not BB3RC31. FULV treatment maintained tumour growth suppression at 8 weeks and no additive effect was seen with SFX-01, although MFE and ALDH activity were suppressed. Mechanistically, SFX-01 potently inhibited the canonical Wnt pathway in MCF-7 cells and their endocrine-resistant derivatives and we are currently exploring SFX-01 activity on other CSC regulatory pathways. SFX-01 has been shown to be well tolerated in SAD and MAD studies in normal volunteers and clinical studies designed to test tolerability and efficacy in combination with the three major classes of endocrine therapy (AI, TAM and FULV) in advanced BC will begin in Q4 2016. Conclusions: Our data demonstrate the potential of SFX-01 for clinically meaningful improvements to endocrine therapy in ER+ breast cancer by reversing CSC mediated resistance. Citation Format: Howell SJ, Simoes BM, Alferez D, Eyre R, Spence K, Santiago-Gomez A, Sarmiento-Castro A, Tanaka I, Howat D, Clarke RB. SFX-01 targets Wnt signalling to inhibit stem-like cells in breast cancer patient-derived xenograft tumours [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD2-02.