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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA070907-16A1
Application #
8747047
Study Section
Special Emphasis Panel (ZCA1-RPRB-C (M1))
Project Start
1996-09-30
Project End
2019-08-31
Budget Start
2014-09-23
Budget End
2015-08-31
Support Year
16
Fiscal Year
2014
Total Cost
$302,512
Indirect Cost
$60,618
Name
University of Texas Sw Medical Center Dallas
Department
Type
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Akbay, Esra A; Kim, James (2018) Autochthonous murine models for the study of smoker and never-smoker associated lung cancers. Transl Lung Cancer Res 7:464-486
Zhang, Wei; Girard, Luc; Zhang, Yu-An et al. (2018) Small cell lung cancer tumors and preclinical models display heterogeneity of neuroendocrine phenotypes. Transl Lung Cancer Res 7:32-49
Tan, Xiaochao; Banerjee, Priyam; Liu, Xin et al. (2018) The epithelial-to-mesenchymal transition activator ZEB1 initiates a prometastatic competing endogenous RNA network. J Clin Invest 128:1267-1282
McMillan, Elizabeth A; Ryu, Myung-Jeom; Diep, Caroline H et al. (2018) Chemistry-First Approach for Nomination of Personalized Treatment in Lung Cancer. Cell 173:864-878.e29
Skoulidis, Ferdinandos; Goldberg, Michael E; Greenawalt, Danielle M et al. (2018) STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma. Cancer Discov 8:822-835
Walser, Tonya C; Jing, Zhe; Tran, Linh M et al. (2018) Silencing the Snail-Dependent RNA Splice Regulator ESRP1 Drives Malignant Transformation of Human Pulmonary Epithelial Cells. Cancer Res 78:1986-1999
Ferdosi, Shadi; Rehder, Douglas S; Maranian, Paul et al. (2018) Stage Dependence, Cell-Origin Independence, and Prognostic Capacity of Serum Glycan Fucosylation, ?1-4 Branching, ?1-6 Branching, and ?2-6 Sialylation in Cancer. J Proteome Res 17:543-558
Zhou, Xiaorong; Padanad, Mahesh S; Evers, Bret M et al. (2018) Modulation of Mutant KrasG12D -Driven Lung Tumorigenesis In Vivo by Gain or Loss of PCDH7 Function. Mol Cancer Res :
Abrams, Zachary B; Zucker, Mark; Wang, Min et al. (2018) Thirty biologically interpretable clusters of transcription factors distinguish cancer type. BMC Genomics 19:738
Pietanza, M Catherine; Waqar, Saiama N; Krug, Lee M et al. (2018) Randomized, Double-Blind, Phase II Study of Temozolomide in Combination With Either Veliparib or Placebo in Patients With Relapsed-Sensitive or Refractory Small-Cell Lung Cancer. J Clin Oncol 36:2386-2394

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