The AACR-AstraZeneca Fellowship for Translational Lung Cancer Research is open to postdoctoral and clinical research fellows working at an academic, medical or research institution who will be in the first five years of their postdoctoral training at the start of the grant term. Proposed research projects must relate directly to translational lung cancer research.
2010 GRANTEE
Timothy F. Burns, M.D., Ph.D.Clinical Fellow, Johns Hopkins University School of Medicine, Baltimore, MD
The Development of Targeted Therapeutic Approaches in Kras Mutant NSCLC
"A significant fraction of non-small cell lung cancers (NSCLC) have mutant Kras, which predicts poor response to current cytotoxic therapy and may portend a poor prognosis. Although the Kras signaling pathway has been well characterized, no current NSCLC therapies target this critical oncogene. An emerging concept of “non-oncogene addiction,” the dependency of tumor cells on factors which are not inherently oncogenic, but which are now required for survival due to the oncogenic state of the tumor, is gaining acceptance. We propose to target the “non-oncogene addiction” pathways required for the survival of Kras mutant NSCLC tumors. The requirement of activated Kras mutant for initiation and maintenance of adenocarcinoma of lung has been established in activated-mutant Kras mice model, however, it is not clear whether mutant Kras is necessary for maintenance of NSCLC in humans. To explore these observations, we will first characterize a series of Kras mutant NSCLC cells lines and primary xenografts of NSCLC for Kras dependency. Elucidating the factors that contribute to Kras dependency would greatly enhance our understanding of Kras tumor biology and may lead to the identification of novel drug targets. Recent work has also suggested that Kras mutant NSCLC may be uniquely sensitive to mitotic stress induced by anti-microtubule agents, inhibition of the polo like kinases, or inhibition of the proteosome. We will assess the relative sensitivity of Kras mutant and wild type NSCLC cell lines/primary NSCLC xenografts to several anti-microtubule agents currently used in the treatment of NSCLC, polo like kinase family member inhibition via a small molecule inhibitor or RNA interference and proteosome inhibition via bortezomib administration. Finally, bypass of senescence in Kras-mediated adenocarcinoma mouse models is essential for tumorigenesis; therefore, reactivation of the senescence pathway in Kras mutant NSCLC may be an effective therapeutic strategy. We will explore therapeutic strategies to induce Kras mediated senescence in Kras mutant NSCLC. Initial studies will examine the relative sensitivity of Kras mutant NSCLC tumors to a variety of senescence inducing agents. In addition, we will examine whether inhibition or re-expression of key regulators of the Kras mediated senescence can induce senescence in Kras mutant NSCLC. Exploration of “non-oncogene addiction” pathways in Kras mutant NSCLC may lead to significant therapeutic advances in the treatment of NSCLC and possibly other Kras-dependent tumor types.
"Receiving the AACR-AstraZeneca Fellowship for Translational Lung Cancer Research is a true honor. This award will not only lend significant support to this project but will also allow me to develop the skills and tools necessary to establish an independent research laboratory with a clinical focus in thoracic oncology. I am extremely grateful to the AACR, my past mentor Dr. Wafik El-Deiry and my current mentor, Dr. Charles Rudin for all their support and guidance."
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