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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA160443-04
Application #
8912395
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Ojeifo, John O
Project Start
2012-09-07
Project End
2016-08-31
Budget Start
2015-09-01
Budget End
2016-08-31
Support Year
4
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Surgery
Type
Hospitals
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Young, Eric D; Ingram, Davis; Metcalf-Doetsch, William et al. (2018) Clinicopathological variables of sporadic schwannomas of peripheral nerve in 291 patients and expression of biologically relevant markers. J Neurosurg 129:805-814
Bishop, Andrew J; Zagars, Gunar K; Torres, Keila E et al. (2018) Malignant Peripheral Nerve Sheath Tumors: A Single Institution's Experience Using Combined Surgery and Radiation Therapy. Am J Clin Oncol 41:465-470
Voss, Rachel K; Chiang, Yi-Ju; Torres, Keila E et al. (2017) Adherence to National Comprehensive Cancer Network Guidelines is Associated with Improved Survival for Patients with Stage 2A and Stages 2B and 3 Extremity and Superficial Trunk Soft Tissue Sarcoma. Ann Surg Oncol 24:3271-3278
Watson, Kelsey L; Al Sannaa, Ghadah A; Kivlin, Christine M et al. (2017) Patterns of recurrence and survival in sporadic, neurofibromatosis Type 1-associated, and radiation-associated malignant peripheral nerve sheath tumors. J Neurosurg 126:319-329
May, Caitlin D; Landers, Sharon M; Bolshakov, Svetlana et al. (2017) Co-targeting PI3K, mTOR, and IGF1R with small molecule inhibitors for treating undifferentiated pleomorphic sarcoma. Cancer Biol Ther 18:816-826
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; May, Caitlin D; Watson, Kelsey L et al. (2016) Analysis of Clinical and Molecular Factors Impacting Oncologic Outcomes in Undifferentiated Pleomorphic Sarcoma. Ann Surg Oncol 23:2220-8
Zhang, Pingyu; Torres, Keila; Liu, Xiuping et al. (2016) An Overview of Chromatin-Regulating Proteins in Cells. Curr Protein Pept Sci 17:401-10
Cleven, Arjen H G; Sannaa, Ghadah A Al; Briaire-de Bruijn, Inge et al. (2016) Loss of H3K27 tri-methylation is a diagnostic marker for malignant peripheral nerve sheath tumors and an indicator for an inferior survival. Mod Pathol 29:582-90
Al Sannaa, Ghadah; Watson, Kelsey L; Olar, Adriana et al. (2016) Sarcoma Brain Metastases: 28 Years of Experience at a Single Institution. Ann Surg Oncol 23:962-967

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