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Carol J. Thiele, Ph.D.
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Dr. Thiele received her Ph.D. in Microbiology and Immunology from the University of California, Los Angeles. She completed her postdoctoral research as a Cancer Research Institute and a Damon Runyon-Walter Winchell Fellow at the NCI. Dr. Thiele was one of the founding editors of Cell Death & Differentiation, and has served on the editorial boards of Cell Death & Differentiation, Cancer Research and Molecular Cancer Therapeutics. Dr. Thiele was Chair of the AACR Women in Cancer Research and has a long-standing interest in developing programs so that young scientific investigators can realize their potential. As the Chief of the Cell and Molecular Biology Section in the Pediatric Oncology Branch, Dr. Thiele's scientific interest is in the field of cancer biology with a special emphasis on pediatric neuroectodermal tumors and neuronal development. Her research strives to understand molecular mechanisms involved in the pathogenesis of neuroblastoma tumors and utilizes insights gleaned from these studies to develop novel therapeutic strategies for pediatric tumors.
Every year approximately 700 cases of Neuroblastoma (NB) and 210 cases of Ewings' sarcoma (EWS) are diagnosed in children less than 20 yrs of age. Half will fail conventional therapy. Despite the progress made in the development of clinical/genetic staging systems for NB and EWS, the prognosis for patients with unfavorable features remains dismal. Over the last 15 years, we have focused our basic research on NB and retinoic acid (RA) induced differentiation. NB tumors contain a number of genetic alterations yet despite these alterations, RA can inhibit cell growth, suppress tumorigenicity and induce differentiation. Our finding that the RA induced growth arrest and differentiation of NB cell lines is accompanied by a transcriptional decrease in the expression of the N-myc proto-oncogene (whose amplification mark NB with the worst prognosis) provided an important pre-clinical rationale for RA-therapy in NB. Twice as many patients receiving RA had event-free survival compared to those receiving placebo.
Understanding the biology of neuroectodermal tumors will reveal clues to a potential 'Achilles heel(s)' in the tumor that can be targeted therapeutically. To date our RA induced differentiation model systems have told us a lot about the biology of NB yet have more to reveal. Under physiologic retinoid concentrations NB cells proliferate and express TrkB and N-myc (poor prognostic indicators) while in retinoid sensitive cell lines pharmacologic doses of retinoids arrest cell growth, induce TrkA and decrease N-myc expression (good prognosis indicators). We studied the molecular differences and biologic consequences of activation of TrkA and TrkB paths and extended work to in vivo models. Our understanding of BDNF induced chemoresistance has identified molecular targets (Trk-TK & PI-3 kinase) that have therapeutic potential. We have continued to define the mechanisms by which retinoids arrest the growth of NB cells by studying the effects of N-myc on cell cycle and proteosome regulation of the cdk inhibitor p27. We have initiated studies on epigenetic regulation of differentiation modulated by retinoids. Intersecting with this study has been the pre-clinical study of the histone deacetylase (HDAC) inhibitor MS-27-275 that targets and activates this path and suppresses angiogenesis in our mouse model of NB. We have also studied Rompidepsin a HDAC inhibitor that has been clinically developed by our collaborator Susan Bates. Our orthotopic xenograft models developed with Dr. Chand Khanna have been key in appreciating biologic complexity in vivo as well as determining the precursor frequency for tumor initiating cells in Neuroblastoma to be as high as 1 in every 4 cells.
Our overall strategy has been that once putative key genes or paths are identified we specifically target the path (activation or inhibition) using techniques such as gene transfection, RNAi or specific antibodies to determine the contribution of the gene and/or path to the biologic process being studied. If the regulated expression of a specific gene is determined to be important in the process, orthotopic murine xenograft models are used to determine effects in vivo. Further screens of NB patient samples will reveal information of a prognostic association. The in vitro and in vivo models allow for the development of chemical, biologic or genetic base therapeutic interventions to be tested.
A key focus of the Cell & Molecular Biology Section has been to translate our understanding of the biology of peripheral neuroectodermal tumors into clinically viable therapeutic strategies. To this point the CMBS collaborates with intramural investigators Drs. Javed Khan, Stephen Chanock, Chand Khanna, Susan Bates, Lino Tessarollo and Crystal Mackall to develop new therapies for the treatment of patients with advance stage neuroblastoma.
This page was last updated on 11/8/2013.