This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The Aurora family of serine/threonine protein kinases plays a critical role in the regulation of chromosomal segregation and cytokinesis during mitotic progression. Aurora A and B are expressed in all actively dividing cells, while Aurora C expression is largely restricted to dividing germ cells. The Aurora A kinase gene is amplified or overexpressed in many tumors, including colon, breast, pancreatic, and bladder cancers. Aurora A overexpression is associated with aneuploidy and centrosome amplification, and overexpression of Aurora A kinase results in the transformation of normal cells, supporting the hypothesis that Aurora A is an oncogene. Reports have demonstrated that in cultured cells, reduction of Aurora A using ribonucleic acid interference (RNAi) reduces Aurora A protein content and results in mitotic spindle defects, mitotic delay, and apoptosis. MLN8237 is a selective small molecule inhibitor of Aurora A kinase being developed for treatment of advanced malignancies. This inhibitor is expected to have potential application across a broad range of human tumors, given the central role of mitosis in the progression of virtually all malignancies. MLN8237 has demonstrated activity against a broad range of both in vitro and in vivo preclinical models, as described in the Background section of the protocol. MLN8237 is a small molecule, ATP-competitive, reversible inhibitor of Aurora A kinase that is being developed for the treatment of advanced malignancies. Such an inhibitor would be expected to have potential application across a broad range of human tumors, given the central role of mitosis in the progression of virtually all malignancies. MLN8237 has demonstrated activity against a broad range of both in vitro and in vivo preclinical tumor models. This drug is also expected to be toxic to proliferating normal tissues, such as bone marrow and GI epithelium, since any cell that is in mitosis where Aurora A is expressed and active should be susceptible to the effects of an Aurora A kinase inhibitor. Primary Aims-1. To estimate the maximum tolerated dose (MTD) and recommended Phase II dose of MLN8237 administered orally once daily for 7 days every 21 days to children with refractory solid tumors. 2. To define and describe the toxicities of MLN8237 administered on this schedule. 3. To characterize the pharmacokinetics of MLN8237 in children with refractory cancer.
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