The overall focus of our lab is to improve the treatment of childhood sarcoma. We currently work on understanding the mechanisms of resistance of Ewing sarcoma cells to PARP1 inhibition with the ultimate goal of developing more effective and less toxic therapy for Ewing sarcoma patients. Another project in which the lab is involved identifies novel drugs and drug combinations to treat pediatric sarcoma and renal tumors. This project is a part of the Pediatric Preclinical Testing Consortium (PPTC) that has been recently funded by NCI.
PARP1 inhibition in Ewing sarcoma
Ewing sarcoma is the fourth most common highly malignant childhood cancer; it is defined by a tumor-specific chromosomal translocation. In approximately 85% of all tumors, the EWSR1 gene on chromosome 22 is fused to a member of E26 transformation-specific sequence (ETS) family of transcription factors, the FLI1 gene on chromosome 11. In the remaining 15% of Ewing tumors, the EWSR1 is fused to other members of ETS family, mostly the ERG gene on chromosome 21. DNA damage induced by expression of EWSR1-FLI1 fusion gene is potentiated by PARP1 inhibition in Ewing cells, where EWSR1-FLI1 genes act in a positive feedback loop to maintain the expression of PARP1. The overall focus of the lab is to determine the differences between the tumors that respond to treatment with PARP1 inhibitor and those intrinsically resistant to it, and to understand the underlying mechanisms of such resistance.
Studies by the PPTP and others have shown that Ewing sarcoma cell lines are hypersensitive to inhibitors of poly-ADP ribose polymerase1 (PARP1), an enzyme involved in DNA repair, which can potentiate low-level damage to DNA in approximately 50% of Ewing sarcoma models. More than ninety percent of these tumors are characterized by chromosomal translocation between chromosomes 11 and 22 that results in oncogenic chimeric transcription factor EWSR1-FLI1. Such genomic rearrangements compromise cell survival, leading to specific defects in cellular metabolism that can be exploited therapeutically – so called ‘synthetic lethal’ interactions. Our lab investigation attempts to elucidate why Ewing sarcoma cells are either sensitive or resistant to combinations of PARP1 inhibitors and DNA damage.
The Pediatric Preclinical Testing Consortium (PPTC) – Sarcoma and Renal Tumors
The project is focused on developing more effective and less toxic therapy for pediatric solid tumors by combining novel cytotoxic agents, or signaling inhibitors with cytotoxic agents or ionizing radiation. This project is a continuation of the 10 years of testing within PPTP, where over 80 drugs have been tested in 50 models of childhood solid tumors, and identified novel drugs and drug combinations that are now in clinical trial.
Dr. Kurmasheva joined Greehey Children’s Cancer Research Institute in 2014, with secondary appointment at the department of Molecular Medicine. Dr. Kurmasheva’s research interest as Principal Investigator is in the area of Preclinical Therapeutics of Childhood Solid Tumors. From her position as Research Assistant Professor at the Nationwide Children’s Hospital and at the Ohio State University, she brings extensive expertise in testing novel agents and drug combinations effective in children with cancers through the Pediatric Preclinical Testing Program (PPTP), funded by NCI since 2005. Dr. Kurmasheva received her doctoral degree in 1999 from the Kazakh State National University in Kazakhstan. From 2002 to 2007 she completed post-doctoral fellowships at the University of Arkansas for Medical Sciences in Little Rock, Arkansas and at St. Jude Children’s Hospital in Memphis, Tennessee.
Preclinical Therapeutics, PARP Inhibition, Ewing Sarcoma, Pediatric Solid Tumors, PDX, IGF-1R Signaling
Initial testing of VS-4718, a novel inhibitor of focal adhesion kinase (FAK), against pediatric tumor models by the Pediatric Preclinical Testing Program. Kurmasheva RT, Gorlick R, Kolb EA, Keir ST, Maris JM, Lock RB, Carol H, Kang M, Reynolds CP, Wu J, Houghton PJ, Smith MA. Pediatr Blood Cancer. 2016 Oct 27.
Initial testing (stage 1) of tazemetostat (EPZ-6438), a novel EZH2 inhibitor, by the Pediatric Preclinical Testing Program. Kurmasheva RT, Sammons M, Favours E, Wu J, Kurmashev D, Cosmopoulos K, Keilhack H, Klaus CR, Houghton PJ, Smith MA. Pediatr Blood Cancer. 2016 Aug 24.
Identifying novel therapeutic agents using xenograft models of pediatric cancer. Kurmasheva RT, Houghton PJ. Cancer Chemother Pharmacol. 2016 Aug;78(2):221-32.
Evaluation of Alternative In Vivo Drug Screening Methodology: A Single Mouse Analysis. Murphy B, Yin H, Maris JM, Kolb EA, Gorlick R, Reynolds CP, Kang MH, Keir ST, Kurmasheva RT, Dvorchik I, Wu J, Billups CA, Boateng N, Smith MA, Lock RB, Houghton PJ. Cancer Res. 2016 Oct 1;76(19):5798-5809.
Preclinical Childhood Sarcoma Models: Drug Efficacy Biomarker Identification and Validation. Geier B, Kurmashev D, Kurmasheva RT, Houghton PJ. Front Oncol. 2015 Aug 26;5:193. doi: 10.3389/fonc.2015.00193. Review.
Synergistic activity of PARP inhibition by talazoparib (BMN 673) with temozolomide in pediatric cancer models in the pediatric preclinical testing program. Smith MA, Reynolds CP, Kang MH, Kolb EA, Gorlick R, Carol H, Lock RB, Keir ST, Maris JM, Billups CA, Lyalin D, Kurmasheva RT, Houghton PJ. Clin Cancer Res. 2015 Feb 15;21(4):819-32.
Initial testing (stage 1) of the PARP inhibitor BMN 673 by the pediatric preclinical testing program: PALB2 mutation predicts exceptional in vivo response to BMN 673. Smith MA, Pediatr Blood Cancer. 2015 Jan;62(1):91-8.
Initial testing (stage 1) of the topoisomerase II inhibitor pixantrone, by the pediatric preclinical testing program. Kurmasheva RT, Reynolds CP, Kang MH, Allievi C, Houghton PJ, Smith MA. Pediatr Blood Cancer. 2014 May;61(5):922-4.
The insulin-like growth factor-1 receptor-targeting antibody, CP-751,871, suppresses tumor-derived VEGF and synergizes with rapamycin in models of childhood sarcoma. Kurmasheva RT, Dudkin L, Billups C, Debelenko LV, Morton CL, Houghton PJ. Cancer Res. 2009 Oct 1;69(19):7662-71.
Differential regulation of vascular endothelial growth factor by Akt and mammalian target of rapamycin inhibitors in cell lines derived from childhood solid tumors. Kurmasheva RT, Harwood FC, Houghton PJ. Mol Cancer Ther. 2007 May;6(5):1620-8.
Upstream CpG island methylation of the PAX3 gene in human rhabdomyosarcomas. Kurmasheva RT, Peterson CA, Parham DM, Chen B, McDonald RE, Cooney CA. Pediatr Blood Cancer. 2005 Apr;44(4):328-37.