My medical career has been strongly focused towards neuro-oncology. Through clinical research during medical school and residency, then moving on to basic science research during my fellowship, I have been driven by the need to cure children with brain tumors. Having recently completed my fellowship in Pediatric Hematology/Oncology, I am now seeking to continue my line of investigation through a Mentored Clinician Scientist Award. I feel that the University of California, San Francisco provides an excellent environment in which to do so. My mentor, William Weiss MD,PhD, has a nurturing lab that will allow me to reach my goals. [My co-mentor Kevin Shannon has expertise in mouse models of cancer and has mentored several pediatric physician scientists with K08 awards.] In addition, through productive collaborations with Kevan Shokat (an expert in tyrosine kinases) and C. David James (an expert in brain tumor models), I believe I am uniquely situated to achieve my goals. My research focus is on malignant gliomas. Current therapies are inadequate, with most patients succumbing to their disease and survivors having significant long-term deficits. The Epidermal Growth Factor Receptor (EGFR) features prominently in this disease, through over-expression, amplification and mutation. EGFR-targeted therapy using small molecule inhibitors or monoclonal antibodies have shown only brief responses in a small fraction of patients. We believe that current targeted approaches fail because current inhibitors result in inadequate blockade of EGFR and recovery of downstream signaling pathways. Our preliminary data argues that irreversible EGFR inhibitors and combination therapy approaches can significantly improve therapeutic efficacy. In our proposed studies, we seek to further study these mechanisms and to investigate these approaches in a highly relevant in vivo model.

Public Health Relevance

Malignant gliomas are an aggressive and common cancer in both children and adults.
This research aims to improve therapy for these patients by understanding why current therapies fail and proposing novel strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS065268-04
Application #
8528740
Study Section
NST-2 Subcommittee (NST)
Program Officer
Fountain, Jane W
Project Start
2010-09-01
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2013
Total Cost
$167,300
Indirect Cost
$12,393
Name
University of California San Francisco
Department
Pediatrics
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Truong, A Y; Nicolaides, T P (2015) Targeted Therapy for MAPK Alterations in Pediatric Gliomas. Brain Disord Ther Suppl 2:
Yoshida, Yasuyuki; Ozawa, Tomoko; Yao, Tsun-Wen et al. (2014) NT113, a pan-ERBB inhibitor with high brain penetrance, inhibits the growth of glioblastoma xenografts with EGFR amplification. Mol Cancer Ther 13:2919-29
Barkovich, Krister J; Hariono, Sujatmi; Garske, Adam L et al. (2012) Kinetics of inhibitor cycling underlie therapeutic disparities between EGFR-driven lung and brain cancers. Cancer Discov 2:450-7
Huillard, Emmanuelle; Hashizume, Rintaro; Phillips, Joanna J et al. (2012) Cooperative interactions of BRAFV600E kinase and CDKN2A locus deficiency in pediatric malignant astrocytoma as a basis for rational therapy. Proc Natl Acad Sci U S A 109:8710-5