Melanoma is increasing among men more than any other cancer and is the 2nd fastest rising cancer in women in the U.S. The disease is curable if diagnosed early. However, disseminated disease has a 5 year survival of <6%. Chemotherapy has little benefit, while immunotherapy has an impact on only a few melanoma patients. Effective treatments are needed. The success of therapy targeted at specific signaling pathways in other cancers, has intensified the search for critical pathways in melanoma, with potential targets already identified. Aurora kinase A (AURKA) is essential for normal mitosis and cell cycle progression through the G2-M transition. AURKA is overexpressed or activated in a number of malignancies. Oncogenic properties of AURKA overexpression include aneuploidy, cytokinesis failure, impaired genomic integrity, and inhibition of signaling through p53. RNAi to AURKA leads to mitotic delay, mitotic spindle defects, and apoptosis in human cancer cells. MLN8237 is a selective small molecule inhibitor of AURKA developed by Millenium for treatment of advanced malignancies. The applicant has recently seen high levels of expression of AURKA in metastatic melanoma. They have also observed consistent anti-tumor activity with a less potent AURKA inhibitor in fresh human-nude mouse xenografts derived from numerous melanoma patients. The proposed trial of MLN8237 in melanoma is unique in its use of the pre-surgical patient to define markers of target inhibition in vivo at tumor sites, and then to use this knowledge to assess the relationship of target inhibition with clinical outcome in advanced melanoma. Identifying predictive biomarkers of response may allow the selection and monitoring of patients in subsequent clinical trials with this agent. The phase II trial will define the clinical activity of MLN8237 in advanced melanoma. Molecular characterization of the melanomas may allow the applicant to identify a responsive genotype. This trial should provide valuable information about the presence of a molecular target (AURKA), inhibition of the target, and effects on downstream events within the cancer cell and tumor microenvironment. A better understanding of the basis for effective or even the mechanism underlying ineffective therapy will be critical to understanding how to proceed in the development of this drug and may influence the evaluation of other drugs.
Metastatic melanoma is a fatal, therapy-resistant disease. Increased levels of Aurora kinase A (AURKA) are important to cancer cell growth. Melanoma obtained from a number of patients show that AURKA is overexpressed and blocking it can have a major impact, inhibiting human melanoma growth in mice. This trial will test a selective AURKA inhibitor, MLN8327 as treatment for advanced melanoma, define its effectiveness, and attempt to understand how it works in the melanoma by repeat biopsies of tumors.
|Liu, Yan; Hawkins, Oriana E; Su, Yingjun et al. (2013) Targeting aurora kinases limits tumour growth through DNA damage-mediated senescence and blockade of NF-?B impairs this drug-induced senescence. EMBO Mol Med 5:149-66|