Dr. Kenneth Y. Tsai
The University of Texas MD Anderson Cancer Center
Departments of Immunology and Dermatology
- Skin cancer
- Targeted and personalized therapy for cancer
- Cancer immunology
Our research is focused on the mechanisms of skin cancer development and progression. For our studies, we utilize a combination of cell culture, in-vivo mouse models and human skin samples to explore four primary areas:
(1) The Immunology of Skin Cancer
The immune status of patients and model organisms dramatically impacts the development and progression of many cancers, in particular skin cancers such as squamous cell carcinoma (SCC). Organ transplant recipients are at extremely high risk for these cancers, which are not only more frequent, but more lethal in these immunosuppressed individuals. We are interested in answering the following questions: (1) How do immune cell subsets such as regulatory T-cells or cytotoxic T-cells contribute to tumor progression and tumor control?; (2) How do tumors escape immune destruction or adapt to immune pressure?
We are using a combination of mouse models and human SCC samples to explore the interactions of tumor cells and immune cell subsets relevant for tumor progression and tumor killing. By using gene expression and protein profiling, we have identified several transcription factor modules that may permit tumors to evade the host immune response.
(2) Interactions of MAP Kinase Pathways in Targeted Therapy for Melanoma
Metastatic melanoma is an incurable cancer that often arises in the skin, but recent developments in targeted therapy and immune therapy offer important survival benefits. We have recently discovered a novel and unexpected interaction between targeted therapies for melanoma (vemurafenib / PLX4720) and stress-activated MAP kinase pathways. This has important clinical implications for combining these therapies with other modalities that induce apoptosis and may also explain in part some of the adverse reactions to these drugs, including the development of squamous cell carcinomas. We are interested in answering the following questions: (1) What are the mechanisms by which these drugs impact apoptosis and autophagy pathways?; (2) How do the effects on these pathways affect response of tumor cells to therapy or explain adverse effects of these drugs?
We are using a combination of mouse models and human melanoma cell lines and tumor specimens to probe how the multiple pathways impacted by targeted therapies affect outcomes. We are in the process of identifying how multiple MAP kinase pathways interact to determine the efficacy of targeted therapies singly and in combination.
3) Therapeutic Implications of Tumor Heterogeneity
It is well established that tumors exhibit both genetic and non-genetic heterogeneity. One potential explanation for this has been advanced as the cancer stem cell hypothesis, which is validated for some cancers. Tumors exhibit heterogeneous responses to therapeutic interventions and an understanding of mechanisms that dictate this heterogeneity is critically important for improving therapies. We are interested in addressing the following questions: (1) How does tumor heterogeneity, as measured by the variance of protein expression, affect susceptibility to targeted therapies?; (2) Conversely, can sensitivity to targeted therapies be predicted by measuring the degree of heterogeneity within a tumor?
4) Exploration of Skin as a Surrogate Biomarker in Targeted Therapies for Cancer
Since the advent of imatinib, molecularly targeted therapy has revolutionized cancer treatment. There are now several rationally-designed antibody-based and small molecule inhibitors that have produced impressive clinical responses. Despite this, one fundamental problem is the inability to predict who will respond and who will not, a critical determinant of the ability to practice truly personalized medicine. How can the patients most likely to respond be identified and optimally treated with appropriate drugs? How can mechanisms of acquired resistance be predicted? Can off-target effects be predicted and managed proactively?
This presents an opportunity to establish skin as a surrogate biomarker of drug efficacy in vivo. We have been actively involved in the development of a novel proprietary reagent that enables the solubilization of tissue with preservation of protein and nucleic acids. We have already validated its safety and functionality in mouse skin and will soon establish safety and efficacy of sample recovery and skin solubilization in humans. Our plan is to establish this technology as a means of profiling epidermal cells in vivo. We are interested in addressing the following questions: (1) Can gene expression and phospho-protein profiles of skin be used as biomarkers for targeted therapies or drugs with narrow therapeutic indices?; (2) Can this non-invasive technology optimize drug dosing, safety, and monitoring?
The focus of these experimental areas spans basic cancer biology and translational research with direct therapeutic implications. A tutorial in the laboratory will provide the student with exposure to basic molecular biology, mouse models of cancer, exploration of translational projects involving cancer therapies, and study of human tumor specimens.