Tumor Reversion: From Bench To Potential Clinical Applications Using Sertraline And Thioridazine.

This presentation aims at summarizing today9s knowledge on tumor reversion (ref.1) with recent applications and new findings for potential cancer treatment. In order to study the molecular program of tumor reversion we have provided with a series of biological models. In this approach, we derived revertant cells from tumor cell lines ranging from leukemia to solid tumors such as breast, colon, lung cancer and melanoma. Using differential gene profiling, between the parental tumor cells and the revertants, over 300 genes were identified, as implicated in reversion such as Siah-1, TSAP6, PS1 and most importantly Translationally Controlled Tumor Protein (TPT1/TCTP) (ref. 2). Notably TPT1/TCTP is highly expressed in the tumor cells and almost undetectable in the revertants. Knocking down TPT1/TCTP reorganized breast cancer cells into ductal structures reminiscent of normal breast morphology. More recently, we identified a strong reciprocal repressive feedback loop between TPT1/TCTP and p53 (ref.3). P53 represses the transcription of TPT1/TCTP by binding to the promoter of TPT1/TCTP. Conversely, TPT1/TCTP interacts directly with p53, Numb and MDM2. TPT1/TCTP competes with Numb. Importantly, TPT1/TCTP stabilizes MDM2, promoting hereby MDM2-dependent ubiquitination and proteasomal degradation of p53. Screening of a large cohort of breast cancer patients (508) shows high expression of TPT1/TCTP in the most aggressive G3 tumors, predicting poor prognosis. TPT1/TCTP is also highly expressed in normal and cancer breast stem cells. Decreasing TPT1/TCTP by siRNA in a mammosphere assay significantly reduces the colony forming efficiency. Thus, TPT1/TCTP also regulates the stem cell compartment. We found two drugs, Sertraline and Thioridazine, which bind and inactivate TPT1/TCTP, restoring elevated levels of wild type p53. Pilot studies on ex vivo cells derived from AML-patients indicate that Sertraline and Ara-C act synergistically in reducing the viability of AML cells. The implication of tumor reversion in reprogramming cancer cells and in disclosing new therapeutic targets as well as its potential role in tumor heterogeneity will be discussed. Citation Format: Robert Amson, Salvatore Pece, Pier Paolo Di Fiore, Judith Karp, Jean-Christophe Marine, Adam Telerman. Tumor reversion: From bench to potential clinical applications using sertraline and thioridazine. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4338. doi:10.1158/1538-7445.AM2013-4338