This proposal describes my research training program for the development of an academic career as a physician-scientist. The scientific environment in which I will pursue my studies could not be better suited to support the work and assist me in becoming an outstanding sarcoma translational researcher. I joined the faculty at UTMDACC as an Assistant Professor (tenure track) in August, 2011. I was appointed to the Department of Surgical Oncology, with an emphasis on laboratory research (75% effort). I have chosen to accept the sarcoma challenge, focusing specifically on malignant peripheral nerve sheath tumors (MPNST). The essential lack of effective systemic treatment renders MPNST a particular challenge if we are to improve the grim prognosis for these patients. The main objectives of the current application are to determine the role of the tyrosine kinase receptor (TKR) AXL as a node of MPNST vulnerability and thus its potential as a target for therapeutic intervention. The mechanisms underlying ligand (GAS6)-independent AXL crosstalk with other MPNST relevant TKRs (specifically MET) will be evaluated. Knowing that cancer therapeutic resistance commonly emerges versus agents that inhibit single targets, and realizing that effective molecular therapies will most probably mandate simultaneous inhibition of multiple cellular nodes, we seek to identify co-targets that can be attacked in combination with AXL, resulting in enhanced efficacy. The study plan is designed so that Sub-Aims can be pursued in parallel with impact on each other, leading to additional studies likely to be conducted, both during the study period and thereafter as a platform for my future investigational agenda. Importantly, knowledge acquired will facilitate appropriate patient selection for treatment while enhancing development of effective strategies to maximize the efficacy of AXL inhibition-based therapies. The opportunity to carry out the studies outlined in this proposal will provide the training necessary for me to become an independent physician-scientist. This award, in combination with the support of my mentors, advisors and the resource-rich environment of UTMDACC, will provide the ideal vehicle for establishing my career and aiding me in becoming a successful laboratory investigator who is competitive for funding from national sources. This proposal presents a comprehensive plan to prepare me for an anticipated professional lifelong involvement in sarcoma research. My short term goals are to develop a deeper scientific grasp of signal transduction, targeted therapies, biostatistics/bioinformatics, and high-throughput methodologies such as reverse phase protein array (RPPA) and siRNA library screens. Midterm goals include attaining my own independent funding through a mechanism such as R01 or ACS grants, as well as developing my abilities to mentor and teach other trainees such that I can achieve my long term goal developing new approaches to the management and treatment of patients with MPNST, building on clinically relevant and translatable knowledge acquired through my laboratory investigations, culminating with my ultimately becoming the principal investigator of a sarcoma research laboratory.
Resource Sharing Plan(s) Our studies will provide insight into promising new approaches for treatment of a devastating 'orphan cancer'affecting young adults for which curative means are currently not available. A better understanding of the molecular deregulations driving MPNST will result from our studies and bioresources developed as part of this proposal will expand the limited tools currently available for MPNST investigations. Such resources will create a comprehensive foundation for my future studies and will be made available to other interested investigators.
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|Zhang, Pingyu; Torres, Keila; Liu, Xiuping et al. (2016) An Overview of Chromatin-Regulating Proteins in Cells. Curr Protein Pept Sci 17:401-10|
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|Kivlin, Christine M; Watson, Kelsey L; Al Sannaa, Ghadah A et al. (2016) Poly (ADP) ribose polymerase inhibition: A potential treatment of malignant peripheral nerve sheath tumor. Cancer Biol Ther 17:129-38|
|Roland, Christina L; Boland, Genevieve M; Demicco, Elizabeth G et al. (2016) Clinical Observations and Molecular Variables of Primary Vascular Leiomyosarcoma. JAMA Surg 151:347-54|
|Demicco, Elizabeth G; Boland, Genevieve M; Brewer Savannah, Kari J et al. (2015) Progressive loss of myogenic differentiation in leiomyosarcoma has prognostic value. Histopathology 66:627-38|
|Chinyengetere, Fadzai; Sekula, David J; Lu, Yun et al. (2015) Mice null for the deubiquitinase USP18 spontaneously develop leiomyosarcomas. BMC Cancer 15:886|
|Demicco, Elizabeth G; Harms, Paul W; Patel, Rajiv M et al. (2015) Extensive survey of STAT6 expression in a large series of mesenchymal tumors. Am J Clin Pathol 143:672-82|
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