Lung cancer is the leading cause of cancer deaths world-wide and kills more than 160,000 people in the United States every year. In fact, lung cancer kills almost twice as many women than breast cancer and more than three times as many men than prostate cancer. Smoking is the largest factor contributing to the development of lung cancer. But most people are unaware that “lung cancer among never-smokers” has been on the rise for the past decade, and is the 6th leading cause of cancer deaths in the United States. Our research focuses on non-small cell lung cancer (NSCLC), the most common type of lung cancer representing approximately 85% to 90% of diagnoses. Our lab’s mission is to ease the global burden caused by lung cancer through 1) identifying those who are at an increased risk of developing lung cancer, particularly non-smokers, women and minorities, 2) defining the molecular pathways that drive lung cancer growth and metastases, and 3) applying a “multi-omics” approach to test novel treatments in pre-clinical studies.
Cancer health disparities
Compared with all other racial and ethnic groups in the United States, African Americans are disproportionally more affected by lung cancer, both in terms of incidence and survival. It is likely that smoking, as the main etiological factor associated with lung cancer, contributes to these disparities. Additional factors may include socio-economic status, access to healthcare, geographic location, and work exposures, among others, although the precise mechanisms are unclear. My lab aims to clarify the biological differences between African Americans and Caucasians that might contribute to lung cancer health disparities. In collaboration with Brid M. Ryan from the National Cancer Institute, we reported that lung cancers from African Americans have a higher prevalence of mutations in proteins in the JAK/STAT3 signaling pathway (Mitchell, K et al., Nature Communications, 2019), and have higher levels of certain pro-inflammatory proteins (Pine SR et al., CEBP, 2016; Meaney CL et al., J Thorac Oncol, 2019). As part of a multi-disciplinary team involving computational biologists, epidemiologists, structural biologists and clinicians, we are testing the functional consequences of these mutations on tumor development and progression, and we are carrying out preclinical studies to explore novel ways to treat lung cancers harboring JAK/STAT3 pathway mutations.
Molecular pathways that drive lung cancer progression
Notch1 and SOX9 are upregulated in lung cancer and associated with poor lung cancer survival. We reported that Notch1 regulates SOX9 expression. We also reported that increased stability of SOX9 protein leads to increased cell proliferation after exposure to DNA damaging agents, such as standard genotoxic chemotherapies. We elucidated the molecular mechanisms leading to Sox9 instability after DNA damage, primarily through the phosphorylation of SOX9 at T236 by GSK3-beta, and subsequent binding of SOX9 to the E3 ligase, FBW7, which then targets Sox9 for ubiquitination and proteasomal degradation (Hong et al, Nucleic Acids Research, 2016). Our on-going work suggests that SOX9 works as a hub for crosstalk among major oncogenic signaling pathways, and we are studying the molecular and functional consequences of SOX9 upregulation. We have developed a mouse model to define the role of SOX9 signaling as a driver of lung carcinogenesis and tumor preogression.
Use of “multi-omics” to test novel therapies for lung cancer
We have built a tumor bank of patient-derived xenografts (PDXs), in which human lung tumors are grown subcutaneously in mice. PDXs more closely mirror the heterogeneity and tumor microenvironment of human tumors than classical cancer cell lines. Therefore, PDXs are thought to be a better model to assess the efficacy of targeted therapies (Pine and Sabaawy, Front Oncol, 2018). We are characterizing our PDXs through RNA-sequencing, copy number variations and proteomics, in order to identify the best targets for therapy (Kulkarni A et al., Clin Canc Res, 2017). We determined the combination of Notch inhibitors with paclitaxel is highly effective in KRAS-wildtype lung adenocarcinoma (Morgan KM et al., Mol Canc Ther, 2017). We are also examining the pathways that are upregulated during therapy resistance as well as clonal evolution caused by targeted therapy (Epsi NJ et al., Commun Biol, 2019; Castellano G et al., J Thorac Oncol, 2019).