Programs
Departments & Divisions
Institutes & Centers
Raushan Kurmasheva, Ph.D.
Assistant Professor
Greehey Children's Cancer Research Institute
The overall focus of Dr. Kurmasheva’s lab is to improve the current treatment of childhood sarcoma. Understanding the mechanisms of resistance of Ewing sarcoma cells to DNA damage with the ultimate goal of developing more effective and less toxic therapy for the patients is the major research focus of the lab. There are several projects that are ongoing:
DNA Damage in Ewing Sarcoma Therapy
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 – ‘synthetic lethal’ interactions - that can be exploited therapeutically. Our lab investigation attempts to elucidate why Ewing sarcoma cells are either sensitive or resistant to combinations of PARP1 inhibitors and DNA damage. We are applying single-cell RNA sequencing and CyTOF approaches to better understand the dependence of these cells on PARP1 or ATR pathways; and to determine the correlation between EWSR1-FLI1 expression in individual cells and response to DNA replication stress. We apply this knowledge to test efficacy of the drug combinations in mice with the goal to develop novel and improved therapy of Ewing sarcoma.
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.
GCCRI Xenograft Core
A GCCRI-based Xenograft Core provides the service of preclinical testing in mouse models. This Core is available to the UT Health San Antonio research community, the pharmaceutical companies, and any lab interested in conducting the research. The methods used for performing testing and analysis of the data were established in PPTP (Establishment of human tumor xenografts in immunodeficient mice. Morton CL, Houghton PJ., Nat Protoc. 2007;2(2):247-50; Molecular characterization of the pediatric preclinical testing panel. Neale G, Su X, Morton CL, Phelps D, Gorlick R, et al. Clin Cancer Res. 2008 Jul 5;14(14):4572-83).The team is highly skilled in conducting in vivo studies, including toxicity testing, single-agent and combination efficacy testing, and pharmacodynamic studies. We have developed a biobank of a broad range of pediatric solid tumors xenograft models, including patient- and cell-derived xenografts. For most of these we also carry matching cell lines.
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Professional Background
Education
- 2004 - Postdoctoral Training - St. Jude Children`s Research Hospital
- 1998 - PhD - Biochemistry - Kazakh State National University
Appointments
- 10/2018 - Assistant Professor on Tenure Track - University of Texas Health at San Antonio/GCCRI, Molecular Medicine, San Antonio
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Research & Grants
Grants
Federal
Funding Agency NIH-NCI Title Pediatric Preclinical Testing Consortium. Research Programs: Sarcoma and Renal Tumors Status Active Period 7/2015 - 6/2020 Role Co-Investigator Grant Detail
Private
Funding Agency Eli Lilly & Company Title Evaluation of Olaratumab (IMC--3G3) an Anti--PDGFR Antibody, with or without ConcomitantChemotherapy Against Pediatric Cancer Xenografts with High Level PDGFR Expression Status Active Period 5/2017 - 5/2019 Role Contributor Grant Detail Funding Agency Incyte Corporation Title Proposal to Evaluate INCB054329 (BET Inhibitor), INCB059872 (LSD1 Inhibitor) and INCB062079 (FGFR4 inhibitor) in Alveolar and Rhabdomyosarcoma Xenograft Models Harboring the t(2;;13) Chromosomal Translocation Encoding Pax3--Foxo1. Status Active Period 8/2017 - 2/2019 Role Contributor Grant Detail Funding Agency Eisai Title Evaluation of lenvantinib in pediatric sarcoma patient--derived mouse xenograft (PDX) models. Status Active Period 6/2016 - 6/2018 Role Contributor Grant Detail
State
Funding Agency CPRIT Title Texas Pediatric Patient Derived Xenograft Facility Status Active Period 6/2016 - 5/2021 Role Contributor Grant Detail Funding Agency GCCRI Title GCCRI Basic and Translational Science Award Status Active Period 5/2017 - 4/2019 Role Principal Investigator Grant Detail
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Publications
Journal Article
Bandyopadhyay A, Favours E, Phelps DA, Pozo VD, Ghilu S, Kurmashev D, Michalek J, Trevino A, Guttridge D, London C, Hirotani K, Zhang L, Kurmasheva RT, Houghton PJ. Evaluation of patritumab with or without erlotinib in combination with standard cytotoxic agents against pediatric sarcoma xenograft models Pediatric blood & cancer 2018 Jan;65(2). Kurmasheva RT, Kurmashev D, Reynolds CP, Kang M, Wu J, Houghton PJ, Smith MA. Initial testing (stage 1) of M6620 (formerly VX-970), a novel ATR inhibitor, alone and combined with cisplatin and melphalan, by the Pediatric Preclinical Testing Program 2018 Jan;65(2). Kurmasheva RT, Sammons M, Favours E, Wu J, Kurmashev D, Cosmopoulos K, Keilhack H, Klaus CR, Houghton PJ, Smith MA. Initial testing (stage 1) of tazemetostat (EPZ-6438), a novel EZH2 inhibitor, by the Pediatric Preclinical Testing Program Pediatric blood & cancer 2017 Jan;64(3). Jones L, Richmond J, Evans K, Carol H, Jing D, Kurmasheva RT, Billups CA, Houghton PJ, Smith MA, Lock RB. Bioluminescence Imaging Enhances Analysis of Drug Responses in a Patient-Derived Xenograft Model of Pediatric ALL Clinical cancer research : an official journal of the American Association for Cancer Research 2017 Jan;23(14):3744-3755. Lock R, Carol H, Maris JM, Kolb EA, Gorlick R, Reynolds CP, Kang MH, Keir ST, Wu J, Purmal A, Gudkov A, Kurmashev D, Kurmasheva RT, Houghton PJ, Smith MA. Initial testing (stage 1) of the curaxin CBL0137 by the pediatric preclinical testing program Pediatric blood & cancer 2017 Jan;64(4). Kurmasheva RT, Gorlick R, Kolb EA, Keir ST, Maris JM, Lock RB, Carol H, Kang M, Reynolds CP, Wu J, Houghton PJ, Smith MA. Initial testing of VS-4718, a novel inhibitor of focal adhesion kinase (FAK), against pediatric tumor models by the Pediatric Preclinical Testing Program Pediatric blood & cancer 2017 Jan;64(4). 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. Evaluation of Alternative In Vivo Drug Screening Methodology: A Single Mouse Analysis Cancer research 2016 Jan;76(19):5798-5809. Attiyeh EF, Maris JM, Lock R, Reynolds CP, Kang MH, Carol H, Gorlick R, Kolb EA, Keir ST, Wu J, Landesman Y, Shacham S, Lyalin D, Kurmasheva RT, Houghton PJ, Smith MA. Pharmacodynamic and genomic markers associated with response to the XPO1/CRM1 inhibitor selinexor (KPT-330): A report from the pediatric preclinical testing program Pediatric blood & cancer 2016 Jan;63(2):276-286. Richmond J, Robbins A, Evans K, Beck D, Kurmasheva RT, Billups CA, Carol H, Heatley S, Sutton R, Marshall GM, White D, Pimanda J, Houghton PJ, Smith MA, Lock RB. Acute Sensitivity of Ph-like Acute Lymphoblastic Leukemia to the SMAC-Mimetic Birinapant Cancer research 2016 Jan;76(15):4579-4591. Gorlick R, Kolb EA, Keir ST, Maris JM, Lock RB, Carol H, Reynolds CP, Kang MH, Billups CA, Collins J, Kurmashev D, Kurmasheva RT, Houghton PJ, Smith MA. Initial Testing of NSC 750854, a Novel Purine Analog, Against Pediatric Tumor Models by the Pediatric Preclinical Testing Program Pediatric blood & cancer 2016 Jan;63(3):443-450. Dolai S, Sia KC, Robbins AK, Zhong L, Heatley SL, Vincent TL, Hochgrafe F, Sutton R, Kurmasheva RT, Revesz T, White DL, Houghton PJ, Smith MA, Teachey DT, Daly RJ, Raftery MJ, Lock RB. Quantitative phosphotyrosine profiling of patient-derived xenografts identifies therapeutic targets in pediatric leukemia Cancer research 2016 Jan;. Kang MH, Reynolds CP, Kolb EA, Gorlick R, Carol H, Lock R, Keir ST, Maris JM, Wu J, Lyalin D, Kurmasheva RT, Houghton PJ, Smith MA. Initial Testing (Stage 1) of MK-8242-A Novel MDM2 Inhibitor-by the Pediatric Preclinical Testing Program Pediatric blood & cancer 2016 Jan;63(01):1744-1752. Khaw SL, Suryani S, Evans K, Richmond J, Robbins A, Kurmasheva RT, Billups CA, Erickson SW, Guo Y, Houghton PJ, Smith MA, Carol H, Roberts AW, Huang DC, Lock RB. Venetoclax responses of pediatric ALL xenografts reveal sensitivity of MLL-rearranged leukemia Blood 2016 Jan;128(01):1382-1395. Suryani S, Bracken LS, Harvey RC, Sia KC, Carol H, Chen IM, Evans K, Dietrich PA, Roberts KG, Kurmasheva RT, Billups CA, Mullighan CG, Willman CL, Loh ML, Hunger SP, Houghton PJ, Smith MA, Lock RB. Evaluation of the in vitro and in vivo efficacy of the JAK inhibitor AZD1480 against JAK-mutated acute lymphoblastic leukemia Molecular cancer therapeutics 2015 Jan;14(2):364-374. Smith MA, Hampton OA, Reynolds CP, Kang MH, Maris JM, Gorlick R, Kolb EA, Lock R, Carol H, Keir ST, Wu J, Kurmasheva RT, Wheeler DA, Houghton PJ. 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 Pediatric blood & cancer 2015 Jan;62(1):91-98. Richmond J, Carol H, Evans K, High L, Mendomo A, Robbins A, Meyer C, Venn NC, Marschalek R, Henderson M, Sutton R, Kurmasheva RT, Kees UR, Houghton PJ, Smith MA, Lock RB. Effective targeting of the P53-MDM2 axis in preclinical models of infant MLL-rearranged acute lymphoblastic leukemia Clinical cancer research : an official journal of the American Association for Cancer Research 2015 Jan;21(6):1395-1405. 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. Synergistic activity of PARP inhibition by talazoparib (BMN 673) with temozolomide in pediatric cancer models in the pediatric preclinical testing program Clinical cancer research : an official journal of the American Association for Cancer Research 2015 Jan;21(4):819-832. Moradi Manesh D, El-Hoss J, Evans K, Richmond J, Toscan CE, Bracken LS, Hedrick A, Sutton R, Marshall GM, Wilson WR, Kurmasheva RT, Billups C, Houghton PJ, Smith MA, Carol H, Lock RB. AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia Blood 2015 Jan;126(10):1193-1202. Kolb EA, Gorlick R, Keir ST, Maris JM, Kang MH, Reynolds CP, Lock RB, Carol H, Wu J, Kurmasheva RT, Houghton PJ, Smith MA. Initial testing (stage 1) of BAL101553, a novel tubulin binding agent, by the pediatric preclinical testing program Pediatric blood & cancer 2015 Jan;62(6):1106-1109. Studebaker A, Bondra K, Seum S, Shen C, Phelps DA, Chronowski C, Leasure J, Smith PD, Kurmasheva RT, Mo X, Fouladi M, Houghton PJ. Inhibition of MEK confers hypersensitivity to X-radiation in the context of BRAF mutation in a model of childhood astrocytoma Pediatric blood & cancer 2015 Jan;62(10):1768-1774. Houghton PJ, Kurmasheva RT, Kolb EA, Gorlick R, Maris JM, Wu J, Tong Z, Arnold MA, Chatterjee M, Williams TM, Smith MA. Initial testing (stage 1) of the tubulin binding agent nanoparticle albumin-bound (nab) paclitaxel (Abraxane(?)) by the Pediatric Preclinical Testing Program (PPTP) Pediatric blood & cancer 2015 Jan;62(7):1214-1221. Reynolds CP, Kang MH, Maris JM, Kolb EA, Gorlick R, Wu J, Kurmasheva RT, Houghton PJ, Smith MA. Initial testing (stage 1) of the anti-microtubule agents cabazitaxel and docetaxel, by the pediatric preclinical testing program Pediatric blood & cancer 2015 Jan;62(11):1897-1905. Phelps D, Bondra K, Seum S, Chronowski C, Leasure J, Kurmasheva RT, Middleton S, Wang D, Mo X, Houghton PJ. Inhibition of MDM2 by RG7388 confers hypersensitivity to X-radiation in xenograft models of childhood sarcoma Pediatric blood & cancer 2015 Jan;62(8):1345-1352. Carol H1, Maris JM, Kang MH, Reynolds CP, Kolb EA, Gorlick R, Keir ST, Wu J, Lyalin D, Kurmasheva RT, Houghton PJ, Smith MA, Lock RB. Initial testing (stage 1) of the notch inhibitor PF-03084014, by the pediatric preclinical testing program Pediatric Blood Cancer 2014 Aug;61(8):1493-1496. Kang MH1, Reynolds CP, Maris JM, Gorlick R, Kolb EA, Lock R, Carol H, Keir ST, Wu J, Lyalin D, Kurmasheva RT, Houghton PJ, Smith MA. Initial testing (stage 1) of the investigational mTOR kinase inhibitor MLN0128 by the pediatric preclinical testing program Pediatric Blood Cancer 2014 Aug;61(8):1486-1489. Kurmasheva RT, Reynolds CP, Kang MH, Allievi C, Houghton PJ, Smith MA. Initial testing (stage 1) of the topoisomerase II inhibitor pixantrone, by the pediatric preclinical testing program Pediatric Blood Cancer 2014 May;61(5):922-924. Bid HK, Zhan J, Phelps DA, Kurmasheva RT, Houghton PJ. Potent inhibition of angiogenesis by the IGF-1 receptor-targeting antibody SCH717454 is reversed by IGF-2 Molecular cancer therapeutics 2012 Jan;11(3):649-659.
Review Article
Kurmasheva RT, Houghton PJ. Identifying novel therapeutic agents using xenograft models of pediatric cancer Cancer chemotherapy and pharmacology 2016 Jan;78(2):221-232. Geier B, Kurmashev D, Kurmasheva RT, Houghton PJ. Preclinical Childhood Sarcoma Models: Drug Efficacy Biomarker Identification and Validation Frontiers in oncology 2015 Jan;5.