Laboratory of Molecular Design
Molecular Predictors of Therapeutic Efficacy and Toxicity of EGFR Antagonists in Colorectal Cancer

     Administration of EGFR antagonists to cancer patients is associated with significant dose-limiting toxicities, most notably affecting the skin and the gastrointestinal tract. It is unclear whether the incidence and severity of skin toxicity associated with EGFR blockade in patients reflects therapeutic efficacy at disease sites. To resolve this issue and to increase the therapeutic window of EGFR antagonists in the clinic requires the identification of molecular pathways that determine efficacy and/or toxicity of EGFR antagonists. In a mouse model, we have found, with ImClone collaborators, that cetuximab, an EGFR antagonistic antibody, causes changes in the expression of inflammatory mediators (IL-1/TNF-a) in the dermal/epidermal unit, as well as in the serum of treated mice. These results are consistent with sterile inflammation caused by cetuximab. In addition, co-administration of the cytokine antagonists etanercept and anakinra not only decreased the severity of skin inflammation, but also reduced efficacy of cetuximab to inhibit growth of human colorectal cancer xenografts in mice. These results call for a concerted investigation of how inflammatory mechanisms of toxicity and efficacy are related in subjects treated with EGFR antagonists. We propose three independent lines of investigation to distinguish these interconnected phenomena. Specific Aim 1: Determine biomarkers that drive human skin inflammation caused by EGFR blockade. Hypothesis: Skin toxicity caused by EGFR antagonists triggers molecular changes that overlap with treatment response at tumor sites. Approach: We will identify inflammatory markers in human skin punch organ cultures treated with EGFR antagonists. Specific Aim 2: Compare molecular biomarkers observed in skin with those induced by EGFR blockade in human colorectal cancer xenografts in mice. Hypothesis: Minimally invasive PET imaging of proliferative and inflammatory mRNAs can can simultaneously report tumor response and local inflammatory responses. Approach: We will PET image proliferative and inflammatory mRNAs identified in Aim 1, in two groups of mice bearing colorectal cancer xenografts. After imaging, proliferative and inflammatory mRNAs and proteins will be determined in tumors from Group 1. Mice in Group 2 will be imaged before and after treatment with EGFR antagonists, followed by analysis of tumor proliferative and inflammatory mRNAs and proteins. Specific Aim 3: Investigate changes in circulating inflammatory biomarkers with colorectal cancer response in patients treated with EGFR antagonists. Hypothesis: Longitudinal observation of inflammatory markers in patientsí plasma will predict tumor response to and toxicity of EGFR antagonist therapy. Approach: Based on results already obtained in mice treated with EGFR antagonists we will determine systemic changes in inflammatory markers in plasma of colorectal cancer patients treated with EGFR antagonists. We will determine whether therapeutic efficacy correlates with inflammatory markers in plasma.