Src-Family Inhibitors, Signal Transduction Pathways

Victor A. Levin, M.D.

My laboratory focuses on developing more effective chemotherapy approaches for primary and secondary brain tumors. My laboratory conducts research to understand how potential anticancer therapies inhibit signal transduction pathways and how multiple signal transduction inhibitors can be used to reduce the tumor-cell burden in cultured cells, against intracerebral murine tumor models, and ultimately as therapy in patients. To that end, we have developed tissue-based quantitative assays for ornithine decarboxylase (ODC), an enzyme critical to the production of polyamines that are, in turn, critical to the structure and function of DNA, full-size RNA and miRNA. ODC is also the target for difluoromethylornithine (DFMO), a drug that we have studied extensively over the past 25 years and found to be active in the treatment of human anaplastic gliomas. In fact, when DFMO is added to the PCV combination, it produces the longest progression-free and overall survival durations of any study published to date. Because survival appears to be inversely related to tumor ODC levels, we believe patients can be selected who are most likely to respond to DFMO-based treatment. We are working with industry and on a final pre-NDA IND study for patients with anaplastic gliomas.

We are also continuing a 24-year effort to develop inhibitors of Src, a nonreceptor protein tyrosine kinase involved in at least six discrete intracellular signaling pathways. These inhibitors are active against glioblastoma, colon, breast and pancreas cell lines. Using quantitative reverse lysate arrays, we have measured more than 20 antibodies that reflect the amount of cellular phosphorylation and other signaling protein levels in response to Src-kinase inhibitors. We have extended our study to 15 cell lines stressed by shifting serum in the medium 20-fold to determine how cells respond to stress to better understand which signaling pathways are invoked when these cell lines are then treated with a potent selective Src- and Lck-kinase inhibitor. These studies will also be extended to 3D agarose colonies to better understand how individual signal-inhibiting drugs work and how best to combine such drugs in more effective treatments.

Selected Publications

Levin VA, Jochec JL, Shantz LM, Aldape KD. Relationship between ornithine decarboxylase levels in anaplastic gliomas and progression-free survival in patients treated with DFMO-PCV chemotherapy. Int J Cancer. 2007 Nov 15;121(10):2279-83.

Shantz LM, Levin VA. Regulation of ornithine decarboxylase during oncogenic transformation: mechanisms and therapeutic potential. Amino Acids. 2007 Aug;33(2):213-23. Epub 2007 Apr 19.

Levin VA, Ictech S, Hess KR. Impact of phase II trials with progression-free survival as end-points on survival-based phase III studies in patients with anaplastic gliomas. BMC Cancer. 2007 Jun 22;7:106.

Gonzalez J, Kumar AJ, Conrad CA, Levin VA. Effect of bevacizumab on radiation necrosis of the brain. Int J Radiat Oncol Biol Phys. 2007 Feb 1;67(2):323-6.

Levin VA. Are gliomas preventable? Recent Results Cancer Res 174: 205-215, 2007.

Loghin M, Levin VA. Headache related to brain tumors. Curr Treat Options Neurol 8: 21-32, 2006.

Levin VA, Giglio P, Puduvalli VK, Jochec J, Groves MD, Yung WK, Hess K. Combination chemotherapy with 13-cis-retinoic acid and celecoxib in the treatment of glioblastoma multiforme. J Neurooncol 78: 85-90, 2006.

Levin VA, Phuphanich S, Yung WK, Forsyth PA, Maestro RD, Perry JR, Fuller GN, Baillet M. Randomized, double-blind, placebo-controlled trial of marimastat in glioblastoma multiforme patients following surgery and irradiation. J Neurooncol 78: 295-302, 2006.

Levin VA, Jochec JL, Shantz LM, Koch PE, Pegg AE. Tissue-based assay for ornithine decarboxylase to identify patients likely to respond to difluoromethylornithine. J Histochem Cytochem. 2004 Nov;52(11):1467-74.