Raushan Kurmasheva, Ph.D.
Rank: Assistant Professor
Department: Molecular Medicine
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.
- Preclinical Therapeutics
- DNA damage and repair
- PARP Inhibition
- DNA replication
- Pediatric Solid Tumors
- Ewing Sarcoma
- IGF-1R-mTOR Signaling
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 Pediatric Preclinical Testing Program 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 90% 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 dependance 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 also employ molecular and structural biology techniques to understand how two major DNA repair pathways – BER and MGMT – work together to repair damage induced by chemotherapeutic agents like temozolomide. Preclinically, we use nanoformulations of drugs to deliver the cytotoxic agents directly to tumor site without causing systemic toxicity. Both targeted (antibody-based) and passive (EPR-based) nanoparticle delivery approaches are being developed. We apply this knowledge to improve efficacy of the drug combinations in mice with the goal to develop novel and enhanced 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.
Dauren Alimbetov, Ph.D.