Dr. John V. Heymach
The University of Texas MD Anderson Cancer Center
Departments of Thoracic/Head & Neck Medical Oncology and Cancer Biology
The goal of the Heymach laboratory is to conduct translational and basic research that advances the development of targeted therapeutic agents, particularly angiogenesis inhibitors, for non-small cell lung cancer (NSCLC) and other solid tumors. Our efforts are focused on the following issues:
1. Investigating the regulation of angiogenic pathways in lung cancer and identifying mechanisms by which tumors develop resistance to VEGF inhibitors using mouse cancer models.
2. Developing novel blood- and tumor-based surrogate biomarkers for assessing the biological activity of targeted agents, particularly inhibitors of VEGFR and other receptor tyrosine kinases.
3. Understanding how oncogenic pathways can lead to metastatic spread and resistance to anticancer therapies.
4. Develop predictive markers for identifying which patients are likely to respond or develop resistance to targeted agents.
Mechanisms regulating angiogenesis, metastatic spread, and resistance to VEGFR and EGFR inhibitors. Although VEGF and EGFR inhibitors have already demonstrated clinical benefits in patients, resistance unfortunately develops in almost all cases. A major goal of my laboratory is to understand the mechanisms by which this occurs, and use this information to develop combination regimens to combat antiangiogenic agents and EGFR inhibitors. For example, while most studies of drug resistance have focused on tumor cell mutations, we have found that resistance to VEGF inhibitors is primarily mediated by stromal pathways (Cascone et al, J Clin Investigation, 2011) including the EGFR and FGFR pathways, and that by blocking these stromal pathways, vascular remodeling and therapeutic resistance could be blocked. We have also identified a critical axis of EGFR→HIF→MET as a regulator of metastatic spread in NSCLC (Xu et al, Oncogene, 2010).
Blood-based biomarkers for angiogenesis inhibitors. The tumor microenvironment is influenced not only by tumor cells but a wide range of host-derived factors including the inflammatory system and the endogenous angiogenic response. Understanding the factors influencing tumor angiogenesis therefore takes a broader approach of assessing tumor cells, stroma, and host factors. We have used a number of different approaches for developing markers for predicting response and resistance to angiogenesis factors and other targeted agents. This includes profiling circulating cytokines and angiogenic factors (CAFs) which we have used to develop markers for several VEGF inhibitors, as well as circulating myeloid cells and endothelial cells (Nikolinakos et al, Can Res, 2010; Hanrahan et al, JCO, 2010; Kopetz et al, JCO, 2010; de Groot et al, CCR, 2011). This approach has also identified a potential role for the HGF/MET, FGFR, and myeloid recruitment pathways in driving tumor angiogenesis and drug resistance.
We also have a new platform for capturing circulating tumor cells (CTCs) and are investigating the use of CTCs as potential biomarkers.
Proteomic and gene expression markers for predicting drug response. We have taken a systems biology approach to develop proteomic, genomic, and gene expression profiles in NSCLC cell lines and tumors and have used this to identify key pathways or processes driving tumor progression and drug resistance. This includes extensive profiling of more than 100 cell lines and tumor specimens which we then correlate with clinical outcomes.
In collaboration with other members of the THNMO Department and the Biostatistics and Bioinformatics Departments, we are also conducting analysis of several clinical trials of targets agents that will permit us to test and potentially validate markers that are identified in our preclinical studies, and discover new markers and oncogenic pathways.
A tutorial in my laboratory would provide an opportunity for purely laboratory-based or translational projects that leverage the unparalleled set of clinical resources available. Molecular and cell biological techniques commonly used are gene expression profiling, proteomic profiling using reverse phase protein arrays and other approaches; flow cytometry, immunohistochemistry, and PCR, for both preclinical studies in mouse cancer models and analysis of clinical specimens. We also interact closely with the Biostatistics and Bioinformatics group and have joint meetings that permit trainees to gain more experience with high throughput molecular profiling (genomics, proteomics, methylomics, etc.), a critical set of skills for cutting edge systems-oriented discovery approaches).