Robert Wood Johnson Medical School
Dept. of Medicine
The Cancer Institute of New Jersey, Rm 3041
195 Little Albany Street
New Brunswick, NJ 08903-2681
Lung cancer; Notch1; Sox9; stem cell signaling pathways; precision medicine
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 5th 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 African Americans, 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.
Molecular pathways that drive lung cancer progression
We study two stem cell signaling pathways, Notch1 and Sox9, which are upregulated in lung cancer and associated with poor lung cancer survival. We reported that Notch1 regulates Sox9 expression (Capaccione et al, Oncotarget, 2014). We recently discovered that increased stability of Sox9 protein leads to increased cell proliferation after exposure to DNA damaging agents, such as standard genotoxic chemotherapies. We also 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 cross-talk 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.
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. In collaboration with other laboratories at the Rutgers Cancer Institute of New Jersey and elsewhere, we are characterizing our PDXs through RNA-sequencing, copy number variations and proteomics, in order to identify the best targets for therapy. We are examining the pathways that are upregulated during therapy resistance as well as clonal evolution caused by targeted therapy. One specific project that is near completion is the combination of Notch inhibitors with paclitaxel in KRAS-wildtype lung adenocarcinoma.