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Combination Therapy for the Treatment of Cancer

(Ref. No. 151-EG)

Description

Researchers at Fox Chase Cancer Center have collaborated with investigators at the Lombardi Comprehensive Cancer Center at Georgetown University to identify a strong synergistic interaction between a Src kinase inhibitor such as the cancer drug dasatinib and inhibitors of Aurora kinase A in cell lines derived from multiple human cancer types including colorectal and ovarian cancer cells. There was no drug synergy found in normal ovarian epithelial cell lines, suggesting differential toxicity to rapidly dividing malignant cells. Mechanistically, we have shown that combination of Aurora and SRC inhibitors selectively killed cells that have undergone a preceding aberrant mitosis, and was associated with a postmitotic reattachment defect, and selective removal of aneuploid cell populations.
Background: Src is the cellular counterpart of the first identified viral oncogene v-Src. It forms part of a large family of nonreceptor tyrosine kinases that have been extensively studied over the last few decades. Increased protein levels and kinase activities of Src family kinases have been observed in a wide diversity of human cancers. One of the Src inhibitors – dasatinib - is approved by the FDA for patient with CML and Ph+ ALL, and is also being evaluated for use in numerous other cancer types.

The Aurora kinase A is active in the G2/M transition of the cell cycle, regulating spindle assembly. The Aurora kinase A is a critical component of normal cell proliferation and is often overexpressed in tumors. Several agents have been developed to inhibit the functions of Aurora kinase A, and have undergone clinical testing in patients with cancer.

Applications

The synergy discovered between Scr kinase inhibitors and an Aurora kinase A inhibitor provides a method for modulating tumor growth or metastasis. Patients can develop resistance to dasatinib treatment and since Aurora kinase A targets a completely different process in cancer cells, in combination with dasatinib, it prolongs the time to development of therapy resistance and induces synergistic and selective cancer cell death. Therefore, our synergistic combination can be used to maximize the response rates to two agents which have limited single agent efficacy. The synergistic inhibition of Aurora kinase A and Src may be useful in multiple cancer types ranging from colorectal cancer to ovarian, breast, prostate, and head and neck squamous cell carcinoma and CML. The clinical inhibitors of Aurora kinase A and Src do not have overlapping toxicities, thus further nominating them to be effective combinatorial agents in the clinic.

Patent Status: US Patent No. 9101631 issued in August 2015.