Lung cancer is the leading cause of cancer death in the United States and worldwide, accounting for over 150,000 deaths per year in the United States and over 1 million deaths per year world-wide. Non-small cell lung cancer accounts for slightly over 80% of all lung cancer cases. Therefore the development of novel targeted therapeutics for non-small cell lung cancer is of great clinical and public health importance. In recent years, the advent of targeted cancer therapies has led to major advances in the prognosis and survival of cancer patients. Our applicant group has contributed to one of the most dramatic of these advances, the deployment of EGFR inhibitors for patients whose lung cancers bear activating EGFR mutations. This has led to significant advances in treatment of such patients, as demonstrated in this last year by several clinical trials. Nevertheless, as shown by the still-grim mortality statistics, the efforts that lie in front of us far exceed the accomplishments that we and other investigators have achieved to date. The goal of this integrated research Program is to advance the scientific underpinnings of targeted therapies for non-small cell lung cancer. Specifically, we will generate and characterize genetically engineered mouse models based on each of the lung cancer kinase targets (EGFR, TBK1 and DDR2). We will then perform in vivo therapeutic efficacy studies using these mouse models and the appropriately matched targeted therapeutics generated in this Program. Lastly, we will perform in vivo chronic treatment studies with the mouse models and molecule inhibitors to determine in vivo mechanisms of acquired resistance.
Lung cancer is the leading cause of cancer death in the US and worldwide, accounting for over 150,000 deaths per year in the US and over 1 million deaths per year world-wide. Non-small cell lung cancer (NSCLC) accounts for slightly over 80% of all lung cancer cases. Core C is the animal core for the Program Project and will assist each project with animal models and in vivo therapeutic studies working toward the overall goal of developing novel targeted therapeutics for NSCLC which would be of great public health importance.
|Gannon, Hugh S; Kaplan, Nathan; Tsherniak, Aviad et al. (2016) Identification of an ""Exceptional Responder"" Cell Line to MEK1 Inhibition: Clinical Implications for MEK-Targeted Therapy. Mol Cancer Res 14:207-15|
|Jia, Yong; Yun, Cai-Hong; Park, Eunyoung et al. (2016) Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature 534:129-32|
|Kim, Eejung; Ilic, Nina; Shrestha, Yashaswi et al. (2016) Systematic Functional Interrogation of Rare Cancer Variants Identifies Oncogenic Alleles. Cancer Discov 6:714-26|
|Aguirre, Andrew J; Meyers, Robin M; Weir, Barbara A et al. (2016) Genomic Copy Number Dictates a Gene-Independent Cell Response to CRISPR/Cas9 Targeting. Cancer Discov 6:914-29|
|Zhang, Haikuo; Qi, Jun; Reyes, Jaime M et al. (2016) Oncogenic Deregulation of EZH2 as an Opportunity for Targeted Therapy in Lung Cancer. Cancer Discov 6:1006-21|
|Yang, Shenghong; Imamura, Yu; Jenkins, Russell W et al. (2016) Autophagy Inhibition Dysregulates TBK1 Signaling and Promotes Pancreatic Inflammation. Cancer Immunol Res 4:520-30|
|Wu, Hong; Wang, Aoli; Zhang, Wei et al. (2015) Ibrutinib selectively and irreversibly targets EGFR (L858R, Del19) mutant but is moderately resistant to EGFR (T790M) mutant NSCLC Cells. Oncotarget 6:31313-22|
|Lim, Sang Min; Xie, Ting; Westover, Kenneth D et al. (2015) Development of small molecules targeting the pseudokinase Her3. Bioorg Med Chem Lett 25:3382-9|
|Tricker, Erin M; Xu, Chunxiao; Uddin, Sharmeen et al. (2015) Combined EGFR/MEK Inhibition Prevents the Emergence of Resistance in EGFR-Mutant Lung Cancer. Cancer Discov 5:960-71|
|Shen, R R; Zhou, A Y; Kim, E et al. (2015) TRAF2 is an NF-*B-activating oncogene in epithelial cancers. Oncogene 34:209-16|
Showing the most recent 10 out of 66 publications