Nanoparticle formulation of Mediator kinase inhibitor for the treatment of peritoneal ovarian cancer

Senex Biotechnology, Inc., Columbia SC

Investigators

Abstract

Metastatic ovarian cancers (OC), the second most common gynecological malignancy, is a lethal disease, the treatment of which still relies primarily on conventional cytotoxic drugs. Metastatic OC in most patients is localized to the peritoneal cavity, including the peritoneum and omentum along with malignant ascites, making this cancer the primary target disease for intraperitoneal (IP) chemotherapy. Nevertheless, even IP therapy eventually fails in peritoneal OC, and new targeted drugs against the metastatic disease are urgently needed. We have found that non-toxic small-molecule inhibitors of transcription-regulating Mediator kinases CDK8/19, which are currently being developed as oral drugs for other cancers, are efficacious against metastatic tumors of different cancer types. In particular, SNX631-6, the current Mediator kinase inhibitor drug candidate, inhibits peritoneal growth of different types of OC, when given orally as a single oral agent or in combination with cisplatin. Since IP drug delivery offers a pharmacokinetic advantage over oral drug administration resulting from the peritoneal- plasma barrier, we expect that IP delivery of SNX631-6 should greatly increase its efficacy against peritoneal OC. However, this drug is poorly soluble at neutral pH and precipitates when administered IP. To overcome this problem, we have now developed a novel, stable and homogeneous nanoparticle formulation of SNX631-6, which provides favorable plasma pharmacokinetics upon IP administration. The goal of this Phase I STTR proposal is to optimize the nanoparticle formulation of SNX631-6 for IP delivery and to test its efficacy in peritoneal models of different subtypes of OC. To this end, we will generate and test nanoparticles based on copolymers with varying block lengths and structures and test the nanoparticles in regard to their size distribution, shape, stability at different temperatures, cell-based potency and lack of off-target cytotoxicity. Nanoparticles with the best characteristics will be analyzed for their plasma pharmacokinetics at different doses and tested for increased accumulation in perioteoneal OC tumors upon IP delivery, relative to orally administered SNX631-6. We will also analyze the safety and toxicokinetics of the IP-delivered nanoparticle formulation of SNX631-6 in mice. The optimized nanoparticle formulation of the Mediator kinase inhibitor will be tested for the suppression of peritoneal tumors formed by different types of OC, in parallel with orally delivered SNX631-6, to determine if the IP-delivered nanoparticles improve the efficacy of SNX631-6 relative to the oral drug, and if the response to Mediator kinase inhibition varies among different types of peritoneal OC. Transcriptomic analysis will be conducted to identify transcriptomic markers of the response of peritoneal OC to Mediator kinase inhibition. The future Phase II program envisions the identification of the optimal combinations of IP-delivered Mediator kinase inhibitor with standard-of-care chemotherapeutic drugs for the treatment of peritoneal OC and the development of SNX631-6 nanoparticles towards clinical trials in patients with the metastatic OC.