Primary Appointment

Dual/Joint/Adjunct Appointment

I  am  a  dermatologist  and  dermatopathologist  with  primary  research  interests  in  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  enable  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.  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 ?

Last updated: 3/13/2013