Summary

Studying the regulation of Cdk9 in gynecological cancer and leukemia

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy and the fifth most common cause of cancer-related death in women. The estimated annual incidence of this disease worldwide is over 200,000 individuals, with approximately 125,000 deaths. Significant advances in the understanding of the natural history of the disease and thorough initial staging, along with surgical and chemotherapeutic management, have improved the short-term course of ovarian carcinoma. However, despite such improvements, most patients relapse after primary treatment and succumb to disease progression. Chemotherapy remains the principal form of adjuvant and neoadjuvant treatment for EOC. The most significant recent advance in chemotherapeutic management was the introduction of paclitaxel to the treatment of EOC patients in which the combination of cisplatin and paclitaxel conferred a substantial survival advantage over cisplatin and cyclophosphamide. The toxicity profile favoring the carboplatin/paclitaxel regimen has now established this as standard of care in the first-line setting. Although changes to both chemotherapy schedules and routes of administration are associated with improved survival, it appears that a therapeutic ceiling with these drugs has been reached. Intensive efforts are required for an improved understanding of signaling in ovarian cancer cells to improve therapeutic and diagnostic strategies for EOC.
Caspase 8 (C8) initiates apoptotic cell death in response to cell surface receptor activation. Recent work provides strong evidence for the idea that suppression of RIPK1–RIPK3 signaling defines the non-apoptotic roles of FADD and C8. However, because the non-apoptotic roles of C8 are so poorly understood, we have started to analyze this aspect in more detail by generating various C8 knock-out/-down (KO) cancer cell lines by CRISPR/Cas9. The comparison of different phenotypes between the pro-C8 KO and WT cells demonstrated that lack of C8 expression slows down cell proliferation, possibly by prolonging the duration of the S-phase while simultaneously increasing their 2D migration and invasiveness. These evidences indicated novel non-apoptotic roles of pro-C8 in cancer cells. One of the key proteins we identified as partner of C8 by Mass Spec. is a Cyclin-dependent kinase (Cdk). Cdks have emerged as novel targets for anti-cancer strategies. Here we will study transcriptional reprogramming of ovarian/breast cancer cells and leukemia induced by modulating Cdk activity comparing different types of modulators (C8, Cdk inhibitors currently used in AML therapy). The impact of Cdk modulation on the phosphorylation of relevant targets in concert with proteomics and RNA Seq will help to define novel routes of transcriptional reprogramming in cancer cell lines and primary cancer cells (ovarian, breast, leukemia, cells from patients treated with Cdk inhibitors), which represents a novel mechanism of Cdk regulation and a new function of C8.