Abstract B134: The p38MAPK inhibitor LY2228820 dimesylate, in combination with cytotoxic agents, displays strong antitumor activity in human glioblastoma, multiple myeloma, and other mouse xenograft models.

Abstract

Abstract Activated p38MAPK offers a survival advantage to tumor cells following exposure to a variety of cytotoxic agents, such as those that directly damage DNA or inhibit lysosome function. Cytotoxic-dependent upregulation of activated p38MAPK can lead to a diminished response to standard-of-care (SOC) agents and ultimately resistance. Inhibition of p38MAPK with selective small molecule inhibitors is therefore an attractive clinical combination strategy to enhance SOC efficacy. LY2228820 dimesylate is a potent and selective p38MAPK small molecule inhibitor that is capable of inducing tumor growth delay in multiple preclinical human xenograft mouse models. In addition, LY2228820 dimesylate is anti-angiogenic both in vitro and in vivo. This molecule is therefore an excellent candidate for combination studies in preclinical cancer models. DNA alkylating agents such as nitrosoureas are mainstays in glioblastoma therapy and were found to activate p38MAPK-dependent signaling in a variety of preclinical cell culture cancer models, suggesting that p38MAPK activation may blunt DNA alkylation-induced apoptosis. In the human U-87 MG glioblastoma mouse xenograft model a synergistic tumor growth delay is reported for LY2228820 dimesylate in combination with bis-chloroethylnitrosourea (these results are supported by a previously published report on LY2228820 dimesylate in combination with another DNA alkylating agent, temozolomide1). Similarly, in preclinical multiple myeloma models in vitro LY2228820 dimesylate is found to enhance the cytolethal effects of the small molecule proteosome inhibitor bortezomib. Bortezomib treatment induces upregulation of the p38MAPK pathway and, much like the effects of the DNA alkylators, this upregulation is thought to reduce bortezomib-induced apoptosis. When tested in human multiple myeloma mouse xenograft models in vivo, including the OPM-2 model, LY2228820 dimesylate displays tumor growth delay as both a single agent and in combination with bortezomib. LY2228820 dimesylate has also shown activity in combination with other chemotherapeutic agents across a range of tumor histologies. Therefore in addition to its single agent activity across a variety of human tumor mouse xenograft models, the combination of LY2228820 dimesylate with approved chemotherapeutic agents is a potentially viable clinical approach. Reference: 1. Starling, J., et al., p38MAPK inhibitor LY2228820, causes significant potentiation of temozolomide in U-87MG human glioblastoma xenografts. AACR Annual Meeting, Abstract #2429, 2006. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B134.