Preclinical evaluation of the simultaneous inhibition of MCL-1 and BCL-2 with the combination of S63845 and venetoclax in multiple myeloma

This work was supported by the Spanish ISCIII-FIS and FEDER Funds (PI 15/00067 and PI 15/02156) and the Regional Health Council of Castilla y León (GRS 1604/A/17). EMA was supported by a grant from the Regional Education Council of Castilla y León co-financed by the European Social Fund

Preclinical Antitumor Activity of a New Vinca Alkaloid Derivative, S 12363

S12363 is a new Vinca alkaloid derivative obtained by appending an optically active α-aminophosphonate at the C23 position of O4-deacetyl vinblastine. S 12363 was evaluated for cytotoxic and antitumor activity against a spectrum of murine and human tumors. This compound was, respectively, on average, 72- and 36-fold more cytotoxic than were vincristine and vinblastine, when tested on a panel of 2 murine and 37 human tumor cell lines using the microculture tetrazolium assay. S 12363 exhibited significant antitumor activity against murine transplantable tumors (i.p. and s.c. P388 leukemia, i.p. I 121(1leukemia, i.p. and i.v. B16 melanoma, i.p. M5076 sarcoma, and s.c. colon adenocarcinoma 38), while no activity was observed on s.c. Lewis lung carcinoma. S 12363, when administered i.p. showed moderate activity on human NCI-H460 lung and PANC-1 pancreas tumor xenografts in nude mice. However, when it was administered i.v. it exerted a significant activity against human MT-29 colon, NCI-H460 lung, NC1-H125 lung, PANC-1 pan creas, and A-431 vulvar tumor xenografts. S 12363 was also active in vivo against a P388 leukemia subline resistant to vincristine. On the in vivo panel of tumors used in this study, S 12363 was at least as active as reference compounds, while its optimal dosage was 10- to 40-fold lower than that of vinblastine, depending on the models studied. The effects of schedule and route of administration on the antitumor activity of S 12363 were studied in both i.p. inoculated P388 leukemia and B16 melanoma, in which the activity was improved by single and intermittent treatment (Days 1, 8, and 15) and i.p. route. S 12362, which differs only by the configuration of the asymmetric carbon atom of the side chain, was 300- fold less cytotoxic and 1000-fold less potent in vivo than was S 12363. These results suggest that S 12363 could present a therapeutic advantage over its congeners and deserves further pharmacological evaluations. © 1991, American Association for Cancer Research. All rights reserved.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Targeting Bcl-2/Bcl-XL induces antitumor activity in uveal melanoma patient-derived xenografts.

Uveal melanoma (UM) is associated with a high risk of metastases and lack of efficient therapies. Reduced capacity for apoptosis induction by chemotherapies is one obstacle to efficient treatments. Human UM is characterized by high expression of the anti-apoptotic protein Bcl-2. Consequently, regulators of apoptosis such as Bcl-2 family inhibitors may constitute an attractive approach to UM therapeutics. In this aim, we have investigated the efficacy of the Bcl-2/Bcl-XL inhibitor S44563 on 4 UM Patient-Derived Xenografts (PDXs) and derived-cell lines.Four well characterized UM PDXs were used for in vivo experiments. S44563 was administered alone or combined with fotemustine either concomitantly or after the alkylating agent. Bcl-2, Bcl-XL, and Mcl-1 expressions after S44563 administration were evaluated by immunohistochemistry (IHC).S44563 administered alone by at 50 and 100 mg/kg i.p. induced a significant tumour growth inhibition in only one xenograft model with a clear dose effect. However, when S44563 was concomitantly administered with fotemustine, we observed a synergistic activity in 3 out of the 4 tested models. In addition, S44563 administered after fotemustine induced a tumour growth delay in 2 out of 3 tested xenografts. Finally, IHC analyses showed that Bcl-2, Bcl-XL, and Mcl-1 expression were not modified after S44563 administration.The novel anti-apoptotic experimental compound S44563, despite a relative low efficacy when administered alone, increased the efficacy of fotemustine in either concomitant or sequential combinations or indeed subsequent to fotemustine. These data support further exploration of potential therapeutic effect of Bcl-2/Bcl-xl inhibition in human UM

The Histone Deacetylase Inhibitor Abexinostat Induces Cancer Stem Cells Differentiation in Breast Cancer with Low Xist Expression

International audiencePurpose: Cancer stem cells (CSC) are the tumorigenic cell population that has been shown to sustain tumor growth and to resist conventional therapies. The purpose of this study was to evaluate the potential of histone deacetylase inhibitors (HDACi) as anti-CSC therapies. Experimental Design: We evaluated the effect of the HDACi compound abexinostat on CSCs from 16 breast cancer cell lines (BCL) using ALDEFLUOR assay and tumorsphere formation. We performed gene expression profiling to identify biomarkers predicting drug response to abexinostat. Then, we used patient-derived xenograft (PDX) to confirm, in vivo, abexinostat treatment effect on breast CSCs according to the identified biomarkers. Results: We identified two drug-response profiles to abexinostat in BCLs. Abexinostat induced CSC differentiation in low-dose sensitive BCLs, whereas it did not have any effect on the CSC population from high-dose sensitive BCLs. Using gene expression profiling, we identified the long noncoding RNA Xist (X-inactive specific transcript) as a biomarker predicting BCL response to HDACi. We validated that low Xist expression predicts drug response in PDXs associated with a significant reduction of the breast CSC population. Conclusions: Our study opens promising perspectives for the use of HDACi as a differentiation therapy targeting the breast CSCs and identified a biomarker to select patients with breast cancer susceptible to responding to this treatment. Clin Cancer Res; 19(23); 6520-31. (C) 2013 AACR