This five-year mentored career development award is structured to facilitate my development into an independent, laboratory-based physician scientist in the field of translational thoracic oncology. As an MD-PhD physician scientist, my clinical experiences as a medical oncologist caring for patients with lung cancer inspire the bench science in which I engage. These clinical experiences also provide opportunities to translate scientific discoveries to improve the treatment of patients with lung cancer. My primary mentor is Dr. Charles Sawyers, an international leader in translational oncology. Memorial Sloan-Kettering Cancer Center provides an ideal setting in which to perform patient-oriented, lab-based research. In the laboratory we investigate the mechanism(s) by which some cancer cells acquire dependence upon signaling by an oncoprotein for their survival (""""""""oncogene addiction""""""""). We have focused on human lung cancers that harbor activating mutations in the epidermal growth factor receptor (EGFR). Human lung adenocarcinomas with activating mutations in EGFR often respond to treatment with EGFR tyrosine kinase inhibitors (TKIs) but the magnitude of tumor regression is variable and transient. We hypothesized that the heterogeneity of treatment response may result from genetic modifiers that regulate the degree to which tumor cells are dependent on the mutant EGFR and, hence, the magnitude and duration of response in patients treated with EGFR TKIs. We used an RNA- interference (RNAi) screening strategy to rationally identify companion therapeutic targets that, when inhibited, might enhance the response of EGFR-mutant lung cancers to the EGFR TKI erlotinib. In initial experiments, we showed that knockdown of CD95/Fas and several components of the NF?B pathway specifically enhanced cell death induced by the EGFR TKI erlotinib in EGFR-mutant lung cancer cells. Activation of NF?B through overexpression of the intermediates c-FLIP or IKK, or silencing of I?B, rescued EGFR-mutant lung cancer cells from EGFR TKI. Genetic or pharmacologic inhibition of NF?B enhanced erlotinib-induced apoptosis in erlotinib-sensitive and erlotinib-resistant EGFR-mutant lung cancer models. Increased expression of the NF?B inhibitor I?B predicted for improved response and survival EGFR-mutant lung cancer patients treated with EGFR TKI. These data identify NF?B as a potential companion drug target, together with EGFR, in EGFR-mutant lung cancers. We propose to further test the hypothesis that the CD95/Fas-NF?B pathway and EGFR are rational companion therapeutic targets in EGFR-mutant lung cancers using state-of- the-art murine models, additional human clinical data, and pathway-selective NF?B pharmacologic inhibitors in the following Specific Aims: 1) Determine if CD95/Fas-NF?B signaling is sufficient to induce EGFR TKI resistance using in vivo models of EGFR- mutant lung cancer, 2) Determine if increased CD95/Fas-NF?B signaling occurs in EGFR-mutant transgenic lung cancer models and patients that are resistant to EGFR TKI, 3) Determine if pathway-selective NF?B inhibitors enhance EGFR TKI responses in EGFR-mutant lung cancer models as a prelude to a clinical trial in appropriately selected patients. More broadly, these studies provide insight into the mechanisms by which tumor cells acquire oncogene dependence and escape from oncogene inhibition.

Public Health Relevance

Lung cancer is a major public health problem because it is the most common cause of cancer-related death in the US. Most lung cancer patients die within 5 years of diagnosis since treatments are ineffective because we do not fully understand the mechanisms driving the growth of lung cancer cells. Our research aims to characterize the functions of genes that drive lung cancer growth. These efforts may lead to improved personalized therapies for patients with lung cancer to enhance outcomes. The written critiques and criteria scores of individual reviewers are provided in essentially unedited form in the Critique section below. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The Resume and Summary of Discussion section above summarizes the final opinions of the committee.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA154787-04
Application #
8708513
Study Section
Subcommittee B - Comprehensiveness (NCI)
Program Officer
Perkins, Susan N
Project Start
2011-09-21
Project End
2016-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Rho, Jin Kyung; Lee, In Yong; Choi, Yun Jung et al. (2017) Superior Efficacy and Selectivity of Novel Small-Molecule Kinase Inhibitors of T790M-Mutant EGFR in Preclinical Models of Lung Cancer. Cancer Res 77:1200-1211
Okimoto, Ross A; Bivona, Trever G (2016) Tracking Down Response and Resistance to TRK Inhibitors. Cancer Discov 6:14-6
Pazarentzos, E; Bivona, T G (2015) Adaptive stress signaling in targeted cancer therapy resistance. Oncogene 34:5599-606
Blakely, Collin M; Pazarentzos, Evangelos; Olivas, Victor et al. (2015) NF-?B-activating complex engaged in response to EGFR oncogene inhibition drives tumor cell survival and residual disease in lung cancer. Cell Rep 11:98-110
Hrustanovic, Gorjan; Olivas, Victor; Pazarentzos, Evangelos et al. (2015) RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer. Nat Med 21:1038-47
Okimoto, Ross A; Bivona, Trever G (2014) Recent advances in personalized lung cancer medicine. Per Med 11:309-321
Sabnis, Amit J; Bivona, Trever G (2013) FGFR fusions in the driver's seat. Cancer Discov 3:607-9
Neel, Dana S; Bivona, Trever G (2013) Secrets of drug resistance in NSCLC exposed by new molecular definition of EMT. Clin Cancer Res 19:3-5
Blakely, Collin M; Bivona, Trever G (2012) Resiliency of lung cancers to EGFR inhibitor treatment unveiled, offering opportunities to divide and conquer EGFR inhibitor resistance. Cancer Discov 2:872-5
Zhang, Zhenfeng; Lee, Jae Cheol; Lin, Luping et al. (2012) Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat Genet 44:852-60