John Heymach M.D., Ph.D.

Recipient of the LUNGevity Foundation/Joan’s Legacy Research Grant. Funded equally by Joan's Legacy and the LUNGevity Foundation.

Lay Description

Emerging evidence indicates that there are gender-specific differences in the biology of lung cancer and in the therapeutic response to new molecularly-targeted agents. Women, particularly non-smokers, are more likely to develop bronchioalveolar carcinoma (BAC), and their disease appears to be more responsive to inhibitors of the epidermal growth factor receptor (EGFR) pathway. A recent trial suggests that men derive greater benefit from the angiogenesis inhibitor bevacizumab, a drug that blocks vascular endothelial growth factor (VEGF), when it was given in combination with chemotherapy. Furthermore, we have recently completed two randomized phase II trials of the dual VEGF/EGFR inhibitor ZD6474 with chemotherapy and observed that women appeared to derive greater benefit than men from this agent (Heymach et al, Proc ASCO 2006; Heymach et al, Proc ASCO 2007). The goals of this grant are to investigate the molecular basis for these gender differences in the formation of BAC, and to learn why women and men with lung cancer respond differently to angiogenesis inhibitors such as bevacizumab and ZD6474. We hypothesize that interactions between EGFR and estrogen receptors (ER) are critical for these differences, and will investigate this hypothesis using both cell lines and preclinical models. This work has the potential to expand our understanding of how BAC develops, and to provide a means to identify who is most likely to benefit from antiangiogenic therapy and potentially to increase this benefit by intervening in these critical pathways.

Scientific Abstract

Non-small cell lung cancer is the most common cause of cancer related deaths in the US and novel agents targeting this disease have shown considerable promise. Some recent clinical trials evaluating receptor tyrosine kinase inhibitors such as bevacizumab and ZD6474 have shown gender specific differences in therapeutic efficacy. These differences suggest that factors inherent in the male/female biology may have a significant impact in RTK activities and their subsequent inhibition. Recent data suggests that estrogen and EGF can synergistically activate the EGFR downstream effectors, including ERK1/2, and may that each impact critical angiogenic pathways including HIF 1-alpha. We propose that the EGFR and ER pathways may cooperatively interact to increase angiogenesis and enhance EGFR dependence. We will evaluate this hypothesis by in vitro examining the role of estrogen and hypoxia in EGFR mediated signaling and the angiogenic factor production in bronchioalveolar, adenocarcinoma, and squamous carcinoma cell lines. Using the novel reverse phase lysate arrays (RPPA) and multiplex bead analysis, we will analyze differentially activated signal transduction pathways and secreted angiogenic factors. In Aim 2 we will utilize a transgenic preclinical model of bronchioalveolar carcinoma to analyze the effects of estrogen signaling in EGFR dependent tumor initiation and maintenance. Finally, by modulating estrogen signaling in an in vivo xenograft model of NSCLC we will examine the role of estrogen signaling in the therapeutic efficacy of RTK inhibitors. These studies aim to reveal the molecular mechanisms underlying gender specific differences in the development of BAC and the responsiveness to angiogenesis inhibitors. This knowledge may help guide therapeutic strategies to enhance the efficacy of antinagiogenic therapy.