Results a recent clinical trial confirm that COTI-2, a novel small molecule that acts by inhibiting Akt/PKB (Protein kinase B) phosphorylation leading to caspase-9 activation in cancer cells resulting in tumor cell death, is a promising new targeted therapy candidate. The trial clearly demonstrated that COTI-2 can significantly inhibit the growth of cancer cells that over express Akt/Akt2, which is a key component of the PI3K/Akt/mTOR
signaling pathway and is involved in cell proliferation, survival, motility, morphology and metabolism. [1]
The drug candidate has greater selectivity as well as an improved safety profile and pharmacokinetics in comparison to other Akt inhibitors. COTI-2 is easily synthesized and has good in vitro and in vivo efficacy against multiple human cancers including small cell lung, non-small cell lung, colon, brain, ovarian, endometrial, triple negative breast and pancreatic. Early test results show it to be highly effective as a single agent therapy and as a combination therapy in a number of animal models of human cancers.
A unique development process
COTI-2 is the first drug developed using the Critical Outcome Technologies’ Chemsas?, a multi-staged computational platform technology based upon a hybrid of machine learning technologies and proprietary algorithms that allow accurate prediction of biological activity from the molecular structure. ?These results and their implications represent a significant milestone in the development of COTI-2. Prior research and ongoing development provide new insights into a specific mechanism of action and support a first-in-class distinction for this promising anti-cancer drug candidate,? noted Wayne Danter, MD, FRCPC, Critical Outcome Technologies’s Chief Executive Officer. ?We have established a clear relationship between the dose of COTI-2 and reduced levels of Akt/Akt2 protein, activated Akt/Akt2 in tumor tissues, and observed tumor growth inhibition. This is powerful evidence that COTI-2 is a potent modulator of Akt/Akt2 in cancer cells that over express the target.?
Detailed analysis of these new data confirmed that there was a complete remission rate of 30% (p<0.01) in the high dose IV treatment group (40 mg/kg) and a 10% complete (p = NS) remission rate in the low dose IV treatment group (20 mg/kg). Tumor Growth Inhibition (TGI) was greater than 84% in all treatment groups and was strongly associated with the dose of COTI-2 and there was strong evidence that the increase in COTI-2 dose and TGI is associated with a decrease in total tumor Akt, Akt2 and Ser473 phosphoAkt, but not Thr308 phosphoAkt proteins.
Well tolerated
The results of the trialalso show that the combined evidence indicates that a significant component of the COTI-2 effect is mediated through a decrease in both the amount and phospho-activation of the Akt2 component of total Akt protein and that the drug candidate appeared to be well tolerated.
Tailoring cancer treatment
At the recent American Society for Clinical Oncology (ASCO) annual meeting, researchers from the M.D. Anderson Cancer Center in Houston (Texas) suggested that customizing targeted therapies to a tumor?s specific molecular characteristics, rather than tumor type, may be more effective in certain types of cancers. According to the National Cancer Institute (NCI), targeted cancer therapies can improve a doctor?s ability to tailor cancer treatment and may result in fewer side effects.
A broad range of human cancers
COTI-2?s specific cellular targeting, low toxicity, and proven efficacy support a potentially dramatic change in the treatment of susceptible cancers consistent with the views expressed at ASCO. Over expression of Akt/Akt2 is common in a broad range of human cancers, including ovarian, endometrial, pancreatic, breast, colorectal and lung. The percent of tumors with active Akt/Akt2 range from 20% to 100% depending on the cancer type.
These results presented todayare from the first of three key studies related to the continued development of COTI-2 based on feedback from prospective licensing partners. This data is important to potential licensing partners as it provides specific insight into a clinical development strategy for COTI-2. COTI will share a detailed scientific report of this data with prospective licensing partners. COTI also plans to present this scientific data at key scientific conferences this fall. Additional data related to this study will be released in early fall.
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[1] Vivanco I, Sawyers CL. The phosphatidylinositol 3?kinase Akt pathway in human cancer. Nat Rev Cancer 2002; 2: 489?501.
