Combined antitumor effects of novel tubulin-polymerization inhibitor with some existing antitumor agents; capecitabine, irinotecan, cisplatin, trastuzumab and pertuzumab Free

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Tubulin is a clinically validated target for anti-cancer therapy. Taxanes (microtubule stabilizers) are amongst the most powerful chemotherapeutic agents in NSCLC, breast cancer, ovarian cancer and prostate cancer. However, the clinical benefit obtained with these drugs has been limited by drug resistance acquired by tumors and the safety profile. Mechanisms of resistance to taxanes include mutations in the tubulin genes and overexpression of transmembrane drug efflux pumps (e.g. MDR1 and BCRP). Adverse events associated with taxanes include hematological toxicity, neurotoxicity and hypersensitivity reactions. For patients who acquire resistance to, or who failed prior treatment with taxanes, the success of salvage chemotherapy has been reported to be modest. Therefore, there is a need to develop new drugs targeting tubulin structure with better safety profile and less resistance.

We previously presented the potent antitumor activity of our synthetic dolastatin analogue (Compound 1) in a broad range of human xenograft models of NSCLC, breast cancer, colorectal cancer, prostate cancer and hepatocellular cancers including a taxane resistant tumor cell line. In our studies, we examined the antitumor activity of the combination of Compound 1 plus existing antitumor agents such as capecitabine, irinotecan, cisplatin, trastuzumab and pertuzumab in several human cancer xenograft models compared to single agent activity. Compound 1 exhibited synergistic/additive antitumor effects in combination with irinotecan (CPT-11) or with cisplatin (CDDP) in NSCLC models, with capecitabine in CRC models and with trastuzumab or pertuzumab in a Her2 positive breast cancer model. Tumor growth inhibition (TGI) in these combinations was statistically significant compared to those in single agent administration. Notably, the combination of Compound 1 with trastuzumab resulted in a high antitumor efficacy and also showed complete regression in some animals.

Thus, this new tubulin polymerization inhibitor not only shows significantly improved TGI as single agent compared to other tubulin interacting drugs on the market, but also in combination with existing antitumor drugs including molecular targeting agents. Based on this favorable pre-clinical profile, clinical studies are ongoing.