Project 1: Selective Targeting of Estrogen Pathways in Lung Cancer Using Biomarkers
Jill M. Siegfried, PhD, Project Co-Leader, Basic Science
Sanja Dacic, MD, Project Co-Leader, Clinical Science
Arjun Pennathur, MD, Project Co-Leader, Clinical Science
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 α and β (ERα and ERβ), the progesterone receptor (PR), and aromatase, the enzyme that synthesizes β-estradiol from steroid precursors. This project is a continuation of SPORE Project 1 from the previous grant period, where we found that non-genomic ERβ 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 recently discovered in a lung cancer tissue microarray (TMA) that ERβ 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 ERβ and PR with patient survival in NSCLC tumors of known EGFR and K-ras mutation status. The hypothesis of Aim 1 is that elevated ERβ 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 ERβ 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 ERÎ²/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.
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 detemining who is likely to benefit. This project will show if ERs and PRs predict outcome and response to anti-estrogens in lung cancer patients.