There is a growing body of literature showing that steroid hormone pathways are involved in the development and progression of lung cancer in both men and women. Primary non-small cell lung carcinomas (NSCLCs) have been found to express the estrogen receptors a and p (ERa and ER(3), the progesterone receptor (PR), and aromatase, the enzyme that synthesizes p-estradiol from steroid precursors. This project is a continuation of SPORE Project 1 from the previous grant period, where we found that non-genomic ERP signaling to epidermal growth factor receptor (EGFR) is important in mediating NSCLC growth. Co-inhibition of ER and EGFR also showed enhanced anti-tumor effects. We recentiy discovered in a lung cancer tissue microarray (TMA) that ERp is a negative prognostic indicator in NSCLC while PR is a positive prognostic indicator. We will translate these findings to optimally target steroid hormones for lung cancer treatment and to understand the mechanism of PR down-regulation in lung cancer.
Specific Aim 1 will carry out an immunohistochemical (IHC) validation study of the combined association of ERP and PR with patient survival in NSCLC tumors of known EGFR and K-ras mutation status. The hypothesis of Aim 1 is that elevated ERp expression is associated with poor outcome in NSCLC, while elevated PR expression is associated with good outcome. Extent of tumor expression of EGFR and aromatase may modulate the associations of ERp and PR with NSCLC outcome. Presence of EGFR mutations or increased EGFR copy number may also modify these survival associations.
Specific Aim 2 will determine which form of PR, PRA and/or PRB, is important in NSCLC survival and determine the mechanism of loss of PR expression in lung tumor cells. The hypothesis of Aim 2 is that PR subtypes A and B may by differentially involved in biology or survival of NSCLC patients and that PR may be reduced in lung tumor cells as a result of heightened growth factor signaling.
Specific Aim 3 will develop an mRNA expression-based molecular classification of NSCLC by comparing gene expression arrays in tumors characterized by ERp/PR level.
Specific Aim 4 will examine the relationship of pathway biomarkers that show survival effects in Aims 1-3 to clinical response in tissues from lung cancer patients enrolled in two SPORE phase II clinical trials utilizing anti-estrogens. Completion of these Aims will demonstrate which patients are most likely to benefit from treatment with anti-estrogens and provide additional survival biomarkers related to hormonal pathways for assessing aggressiveness of NSCLCs.

Public Health Relevance

Estrogen receptors (ERs) and progesterone receptors (PRs) are now believed to be active in lung cancers from men and women and to be involved in lung cancer progression. Anti-estrogens may have potential to treat lung cancer patients and patient selection may be important in determining who is likely to benefit. This project will show if ERs and PRs predict outcome and response to anti-estrogens in lung cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA090440-14
Application #
8729244
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
14
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Type
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Tarhini, Ahmad A; Rafique, Imran; Floros, Theofanis et al. (2017) Phase 1/2 study of rilotumumab (AMG 102), a hepatocyte growth factor inhibitor, and erlotinib in patients with advanced non-small cell lung cancer. Cancer 123:2936-2944
Sun, Fan; Xiao, Gutian; Qu, Zhaoxia (2017) Isolation of Murine Alveolar Type II Epithelial Cells. Bio Protoc 7:
Chatterjee, Suman; Huang, Eric H-B; Christie, Ian et al. (2017) Acquired Resistance to the Hsp90 Inhibitor, Ganetespib, in KRAS-Mutant NSCLC Is Mediated via Reactivation of the ERK-p90RSK-mTOR Signaling Network. Mol Cancer Ther 16:793-804
Moiseeva, Tatiana; Hood, Brian; Schamus, Sandy et al. (2017) ATR kinase inhibition induces unscheduled origin firing through a Cdc7-dependent association between GINS and And-1. Nat Commun 8:1392
Vendetti, Frank P; Leibowitz, Brian J; Barnes, Jennifer et al. (2017) Pharmacologic ATM but not ATR kinase inhibition abrogates p21-dependent G1 arrest and promotes gastrointestinal syndrome after total body irradiation. Sci Rep 7:41892
Chatterjee, Suman; Huang, Eric H-B; Christie, Ian et al. (2017) Reactivation of the p90RSK-CDC25C Pathway Leads to Bypass of the Ganetespib-Induced G2-M Arrest and Mediates Acquired Resistance to Ganetespib in KRAS-Mutant NSCLC. Mol Cancer Ther 16:1658-1668
Dandachi, Nadine; Kelly, Neil J; Wood, John P et al. (2017) Macrophage Elastase Induces TRAIL-mediated Tumor Cell Death through Its Carboxy-Terminal Domain. Am J Respir Crit Care Med 196:353-363
Sun, Fan; Xiao, Gutian; Qu, Zhaoxia (2017) Murine Bronchoalveolar Lavage. Bio Protoc 7:
Yochum, Zachary A; Cades, Jessica; Mazzacurati, Lucia et al. (2017) A First-in-Class TWIST1 Inhibitor with Activity in Oncogene-Driven Lung Cancer. Mol Cancer Res 15:1764-1776
Zhou, Jingjiao; Qu, Zhaoxia; Sun, Fan et al. (2017) Myeloid STAT3 Promotes Lung Tumorigenesis by Transforming Tumor Immunosurveillance into Tumor-Promoting Inflammation. Cancer Immunol Res 5:257-268

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