Education:
BA 1974 Biology - University of Texas at Austin
MD 1979 University of Texas Southwestern Medical School, Dallas, TX
PhD 1979 Cell Biology - University of Texas at Austin
Postdoctoral Research Fellowship:
1980 UT Southwestern Medical School, Dallas, Texas
1981 National Naval Medical Center, Bethesda Maryland
Started at USC: 1989
Research Topics: Cancer Treatment, Cell Cycle, Growth & Proliferation, Drug Design, Delivery, Pharmacology
Research Description
Our laboratory, and our Developmental Therapeutics Program (www.ipcr.us)m focuses on identifying novel agents or combinations of agents that are effective against childhood and adult malignancies, both solid tumors and leukemias. We develop laboratory data which supports a biologically-based approach to designing new therapies. We then use that laboratory data to design phase I and II clinical trials, paving the way for phase III trials that determine if the new approach has a role as standard therapy for a given disease. As required, we develop formulations of new drugs and we sponsor several investigational new drug (IND) applications with the FDA.
To effectively study anti-cancer agents in vitro, especially combinations of drugs, one must have an accurate assay for evaluating cytotoxicity of tumor cell lines that will measure at least 3 logs of cell kill. We have developed a novel assay (DIMSCAN) based on Digital Image Microscopy which can be used with 96 well plates and has a 4 log dynamic range (www.DIMSCAN.com). We have also established a large panel of human neuroblastoma cell lines and we are currently using this unique panel of cell lines with DIMSCAN to characterize drug resistance in neuroblastoma and to identify drugs and drug combinations which are effective against drug-resistant tumor cells.
To extend our approach to other cancers, we are developing new cell lines from leukemias, sarcomas, and brain tumors. We are studying the biology of these cell lines in culture and in mouse models of cancer, which allows us to develop improved models for testing anti-cancer drugs. Our laboratory serves as a national reference lab for the Childrens Oncology Group and the National Cancer Institute for establishing new cell cultures from childhood cancers and for testing new anti-cancer drugs against such cell cultures.
One drug we work on is buthionine sulfoximine (BSO), which sensitizes the cells to alkylating agents (such as melphalan). We are exploring the molecular mechanisms by which BSO kills neuroblastoma and the mechanisms by which BSO enhances alkylating agent efficacy. Based on our pre-clinical studies we have carried out a clinical trial of BSO and melphalan for neuroblastoma and we saw some remarkable responses in that trial, which has led us to conduct other clinical studies that are in progress and to continue to understand how this unique drug improves cancer cell killing.
A major focus of our research is to identify drugs or unique drug combinations that have anti-cancer activity via novel mechanisms. Derivatives of vitamin A (retinoids) can have major effects on cancer cells while not harming normal cells, so retinoids are ideal candidates for novel cancer therapies. We identified that the differentiation inducer 13-cis-retinoic acid (13-cis-RA) could down-regulate an important oncogene in neuroblastoma (MYCN) and that 13-cis-RA could stop highly malignant neuroblastoma cells from growing at drug concentrations that cause very little systemic toxicity to patients.
We tested 13-cis-RA in a Children's Cancer Group nationwide phase III randomized trial for high risk neuroblastoma and showed that 13-cis-RA improved survival when given after either non-myeloablative consolidation therapy or high-dose chemotherapy and autologous marrow transplantation (ABMT). Survival in that trial was highest for patients receiving both ABMT and 13-cis-RA (55%) as compared to the 16% survival of patients receiving chemotherapy without 13-cis-RA (New Eng J Med 341:1165-1173, 1999).
Our current work on retinoids focuses on fenretinide (4-HPR), a synthetic retinoid which induces apoptosis and non-apoptotic cell death in a variety of cancer cells. We have shown fenretinide is effective against cell lines resistant to 13-cis-RA and we are currently studying the molecular mechanism of action for fenretinide. In collaboration with Dr. Barry Maurer, we discovered that a major mechanism of action of 4-HPR is increasing tumor cell ceramide and that ceramide modulators synergistically enhance the anti-tumor activity of 4-HPR against cancer cells but not normal cells. This latter discovery has led to a wide variety of research projects to understand how manipulating ceramides can kill cancer cells and to identify new drugs and drug combinations that enhance ceramide-mediated cancer cell killing.
Selected Publications
Kang MH, Wan Z, Kang YH, Sposto R, Reynolds CP. - Mechanism of Synergy of N-(4-Hydroxyphenyl)Retinamide and ABT-737 in Acute Lymphoblastic Leukemia Cell Lines: Mcl-1 Inactivation. - J Natl Cancer Inst [ 2008 ] Apr 8; . PubMed
Maris JM, Courtright J, Houghton PJ, Morton CL, Kolb EA, Lock R, Tajbakhsh M, Reynolds CP, Keir ST, Wu J, Smith MA. - Initial testing (stage 1) of sunitinib by the pediatric preclinical testing program. - Pediatr Blood Cancer [ 2008 ] Feb 21; . PubMed
Smith MA, Morton CL, Phelps DA, Kolb EA, Lock R, Carol H, Reynolds CP, Maris JM, Keir ST, Wu J, Houghton PJ. - Stage 1 testing and pharmacodynamic evaluation of the HSP90 inhibitor alvespimycin (17-DMAG, KOS-1022) by the pediatric preclinical testing program. - Pediatr Blood Cancer [ 2008 ] Feb 7; . PubMed
Kolb EA, Gorlick R, Houghton PJ, Morton CL, Lock R, Carol H, Reynolds CP, Maris JM, Keir ST, Billups CA, Smith MA. - Initial testing (stage 1) of a monoclonal antibody (SCH 717454) against the IGF-1 receptor by the pediatric preclinical testing program. - Pediatr Blood Cancer [ 2008 ] Jun;50(6):1190-7 . PubMed
Harned TM, Kalous O, Neuwelt A, Loera J, Ji L, Iovine P, Sposto R, Neuwelt EA, Reynolds CP. - Sodium thiosulfate administered six hours after cisplatin does not compromise antineuroblastoma activity. - Clin Cancer Res [ 2008 ] Jan 15;14(2):533-40 . PubMed
Lock R, Carol H, Houghton PJ, Morton CL, Kolb EA, Gorlick R, Reynolds CP, Maris JM, Keir ST, Wu J, Smith MA. - Initial testing (stage 1) of the BH3 mimetic ABT-263 by the pediatric preclinical testing program. - Pediatr Blood Cancer [ 2008 ] Jun;50(6):1181-9 . PubMed
Kolb EA, Gorlick R, Houghton PJ, Morton CL, Lock RB, Tajbakhsh M, Reynolds CP, Maris JM, Keir ST, Billups CA, Smith MA. - Initial testing of dasatinib by the pediatric preclinical testing program. - Pediatr Blood Cancer [ 2008 ] Jun;50(6):1198-206 . PubMed
Houghton PJ, Morton CL, Kolb EA, Gorlick R, Lock R, Carol H, Reynolds CP, Maris JM, Keir ST, Billups CA, Smith MA. - Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program. - Pediatr Blood Cancer [ 2008 ] Apr;50(4):799-805 . PubMed
Tajbakhsh M, Houghton PJ, Morton CL, Kolb EA, Gorlick R, Maris JM, Keir ST, Wu J, Reynolds CP, Smith MA, Lock RB. - Initial testing of cisplatin by the pediatric preclinical testing program. - Pediatr Blood Cancer [ 2008 ] May;50(5):992-1000 . PubMed
Maris JM, Courtright J, Houghton PJ, Morton CL, Gorlick R, Kolb EA, Lock R, Tajbakhsh M, Reynolds CP, Keir ST, Wu J, Smith MA. - Initial testing of the VEGFR inhibitor AZD2171 by the pediatric preclinical testing program. - Pediatr Blood Cancer [ 2008 ] Mar;50(3):581-7 . PubMed
