EntreMed Shows Increased Survival In Preclinical Renal Cell Cancer Model
EntreMed presented results for its cell cycle inhibitor, MKC-1, in preclinical cancer renal cell carcinoma (RCC) models.
Activation of the oncogenic kinase Akt and the mTOR pathway are known to be adverse prognostic factors and contributors to the pathology of metastatic RCC, therefore inhibitors of these pathways are of significant interest for treatment of this disease. Human RCC cell lines in vitro were shown to have marked sensitivity to MKC-1. MKC-1 inhibited both Akt and mTOR pathway activation in vitro, and was further evaluated in a preclinical model consisting of a xenograft of the human RCC cell line, Caki-1. Orally- administered MKC-1, but not sunitinib malate (Sutent(R)), significantly increased survival of tumor-bearing animals in this model. Examination of tumors following five days of oral treatment with MKC-1 revealed inhibition of the Akt-mTOR pathway, as well as decreased angiogenesis and cell proliferation within the tumors. These preclinical results support further evaluation of MKC-1 for the treatment of renal cell carcinoma.
MKC-1 is a novel, orally-active cell cycle inhibitor with in vitro and in vivo efficacy against a broad range of human solid tumor cell lines, including multi-drug resistant cell lines. Data from previous studies with MKC-1 demonstrate broad-acting antitumor effects, showing tumor growth inhibition or regression in multiple preclinical models, including paclitaxel-resistant models. MKC-1 has been shown to inhibit mitotic spindle formation, prevent chromosome segregation in the M-phase (mitosis) of the cell cycle, and induce apoptosis. Furthermore, MKC-1 inhibits the Akt-mTOR signaling pathways, which may occur through inhibition of the mTOR/rictor pathway. The Akt-mTOR pathway is the most frequently mutated pathway in human tumors and mutations have been shown to promote tumor progression and decrease survival in cancer patients.
Mark R. Bray, Ph.D., EntreMed Vice President, Research, commented on the results, "Data from preclinical studies with MKC-1 continue to support its therapeutic potential in a variety of tumor types. The data are consistent with MKC-1 targeting the mTOR pathway by a mechanism that is distinct from rapamycin-like agents, such as Temosirolimus. These results, along with the recent success of agents that target the mTOR pathway, provide validation that clinical studies with MKC-1 in cancers such as renal cell are warranted. MKC- 1 is currently in clinical trials in metastatic breast cancer, non-small cell lung cancer, and leukemia."