Lurbinectedin (PM01183), a New DNA Minor Groove Binder, Inhibits Growth of Orthotopic Primary Graft of Cisplatin-Resistant Epithelial Ovarian Cancer

Abstract

Purpose: Epithelial ovarian cancer (EOC) is the fifth leading cause of death in women diagnosed with gynecologic malignancies. The low survival rate is because of its advanced-stage diagnosis and either intrinsic or acquired resistance to standard platinum-based chemotherapy. So, the development of effective innovative therapeutic strategies to overcome cisplatin resistance remains a high priority.Experimental Design: To investigate new treatments in in vivo models reproducing EOCs tumor growth, we generated a preclinical model of ovarian cancer after orthotopic implantation of a primary serous tumor in nude mice. Further, matched model of acquired cisplatin-resistant tumor version was successfully derived in mice. Effectiveness of lurbinectedin (PM01183) treatment, a novel marinederived DNA minor groove covalent binder, was assessed in both preclinical models as a single and a combined-cisplatin agent.Results: Orthotopically perpetuated tumor grafts mimic the histopathological characteristics of primary patients' tumors and they also recapitulate in mice characteristic features of tumor response to cisplatin treatments. We showed that single lurbinectedin or cisplatin-combined therapies were effective in treating cisplatin-sensitive and cisplatin-resistant preclinical ovarian tumor models. Furthermore, the strongest in vivo synergistic effect was observed for combined treatments, especially in cisplatin-resistant tumors. Lurbinectedin tumor growth inhibition was associated with reduced proliferation, increased rate of aberrant mitosis, and subsequent induced apoptosis.Conclusions: Taken together, preclinical orthotopic ovarian tumor grafts are useful tools for drug development, providing hard evidence that lurbinectedin might be a useful therapy in the treatment of EOC by overcoming cisplatin resistance.

Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells

“…In this sense, lurbinectedin is able to attenuate the repair of specific nucleotide excision repair (NER) substrates (17,18). In addition to its activity in tumor cells, it was recently shown that lurbinectedin affects the inflammatory microenvironment, with a selective apoptotic-inducing effect on mononuclear phagocytes and a specific inhibition of production of inflammatory cytokines (19,20). In this work, we show that, following its specific target on CG-rich sequences located at promoters of protein-coding genes, lurbinectedin induces the specific degradation of elongating (phosphorylated) RNA polymerase II (Pol II) by the ubiquitin-proteasome machinery.…”

Case 2 – A case of secondary platinum-resistant ovarian cancer

“…Furthermore, PM01183 affects the inflammatory microenvironment, with selective apoptotic-inducing effect on tumor-associated macrophages, and specific inhibition of inflammatory cytokines production [4]. Strong preclinical antitumor activity was observed in cisplatin-resistant epithelial ovarian cancer models [5]. 35%) were the main safety findings for PM01183 [6].…”

Ovarian and cervical cancer patient derived xenografts: The past, present, and future

“…When those PDX models were treated with carboplatin and paclitaxel, there was a significant decrease in tumor volume and mitotic index [22]. A decrease of 40% of tumor volume after treatment with cisplatin alone was seen in orthotopic models developed by Vidal et al when tumor was directly implanted into the ovary [32].…”