KRAS-mutant lung adenocarcinoma represents a therapeutic dilemma owing to a dearth of effective treatment options that specifically target cancer cells with oncogenic KRAS mutations. Thoracic radiation therapy is used in many lung adenocarcinomas but there is little or no information on how to sensitize lung cancers to radiation, particularly in the context of individual tumor oncogenotypes. Based on prior work in this SPORE Project we have preliminary data that provide a rationale approach to this important problem using both human and transgenic mouse preclinical models (KRAS-mutant human orthotopic xenograft lung adenocarcinoma model, and "KP", Kras-mutant/Tp53-mutant, mice, which develop metastatic lung adenocarcinomas owing to down-regulation of the microRNA-200 (miR-200) family). Based on these data, we hypothesize and plan to test that: (a) downstream signaling pathways activated by KRAS mutations and miR-200 down-regulation, namely those regulated by MAPK/ERK kinase (MEK1/2) and/or phosphatidylinositol 3-kinase (PI3K), are key mediators of radiation resistance in KRAS-mutant lung adenocarcinoma;and (b) KRAS codon 12 substitutions (G12D, G12V, and G12C) and microRNA-200 (miR- 200) family expression levels predict tumor cell sensitivity to PI3K targeted therapeutics. We propose to investigate these hypotheses with the following Specific Aims:
Specific Aim 1 : To carry out a "mouse-human co-clinical trial" with the MEK1/2 inhibitor Trametinib and examine mechanisms of acquired resistance to Trametinib.
Specific Aim 2 : To implement a human lung cancer clinical trial that examines whether Trametinib mediated MEK1/2 inhibition sensitizes KRAS-mutant lung adenocarcinomas to chemo-radiotherapy.
Specific Aim 3 : To examine whether specific KRAS codon 12 substitutions and/or miR-200 expression levels predict radiosensitization by PI3K pathway antagonism in our preclinical models. Findings from these studies on inhibitors of MEK1/2 and PI3K/mT0R as radiosensitizers can have immediate impact on personalizing lung cancer clinical care and lay the groundwork for future clinical trials. We have assembled a multidisciplinary team of applied and basic investigators fo ensure the success of this project.
KRAS is the most commonly activated oncogene in lung adenocarcinoma, accounting for about 40,000 cases/year in the USA. Thus, progress in the treatment of this cancer will have a large impact. We will examine whether inhibitors of MEK1/2 and PI3K/mTOR in advanced phase of clinical development are beneficial as radiation sensitizers. By integrating cellular and mouse studies with a human trial we will inform and promote the development of novel therapies for this devastating disease.
|Wen, Chi-Pang; Zhang, Fanmao; Liang, Dong et al. (2015) The ability of bilirubin in identifying smokers with higher risk of lung cancer: a large cohort study in conjunction with global metabolomic profiling. Clin Cancer Res 21:193-200|
|Chiappori, A A; Kolevska, T; Spigel, D R et al. (2015) A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer. Ann Oncol 26:354-62|
|Mender, Ilgen; Gryaznov, Sergei; Dikmen, Z Gunnur et al. (2015) Induction of telomere dysfunction mediated by the telomerase substrate precursor 6-thio-2'-deoxyguanosine. Cancer Discov 5:82-95|
|Kim, Eric S; Ye, Yuanqing; Vaporciyan, Ara A et al. (2015) Telomere length and recurrence risk after curative resection in patients with early-stage non-small-cell lung cancer: a prospective cohort study. J Thorac Oncol 10:302-8|
|Fujimoto, Junya; Wistuba, Ignacio I (2014) Current concepts on the molecular pathology of non-small cell lung carcinoma. Semin Diagn Pathol 31:306-13|
|Ludlow, Andrew T; Robin, Jerome D; Sayed, Mohammed et al. (2014) Quantitative telomerase enzyme activity determination using droplet digital PCR with single cell resolution. Nucleic Acids Res 42:e104|
|Lin, Steven H; Wang, Jing; Saintigny, Pierre et al. (2014) Genes suppressed by DNA methylation in non-small cell lung cancer reveal the epigenetics of epithelial-mesenchymal transition. BMC Genomics 15:1079|
|Yang, Yanan; Ahn, Young-Ho; Chen, Yulong et al. (2014) ZEB1 sensitizes lung adenocarcinoma to metastasis suppression by PI3K antagonism. J Clin Invest 124:2696-708|
|Holohan, Brody; Wright, Woodring E; Shay, Jerry W (2014) Cell biology of disease: Telomeropathies: an emerging spectrum disorder. J Cell Biol 205:289-99|
|Osborne, Jihan K; Guerra, Marcy L; Gonzales, Joshua X et al. (2014) NeuroD1 mediates nicotine-induced migration and invasion via regulation of the nicotinic acetylcholine receptor subunits in a subset of neural and neuroendocrine carcinomas. Mol Biol Cell 25:1782-92|
Showing the most recent 10 out of 647 publications