FLT PET in colorectal cancer

Abstract

Biomarkers that predict response to targeted therapy in oncology are an essential component of personalized medicine. With an increasing reliance on molecularly targeted therapies, there remains an equally critical challenge to develop and validate specific biomarkers that reflect target inhibition, pathway inactivation, and predict overall clinical response. Most biomarkers utilized in oncology studies require tissue sampling which is highly susceptible to sampling error due and bias from heterogeneity. These limitations highlight a critical need to accelerate the translation of novel imaging approaches that are capable of reporting cellular and molecular responses of tumor cells to therapy. Presently, a major impediment to the clinical translation of novel imaging methodology is a lack of understanding of how targeted therapy can affect uptake of molecular probes and a lack appropriate validation studies conducted within relevant biological contexts. This dissertation seeks to elucidate molecular determinants that affect 3’-deoxy-3’[18F]-fluorothymidine ([18F]-FLT) PET imaging as a biomarker of response to targeted therapeutics in colorectal cancer (CRC) in both pre-clinical models and in patients. Using pre-clinical mouse models, [18F]-FLT PET was shown to measure TK1 protein levels in a tumor, was blind to utilization of the de novo pathway of thymidine synthesis, and may not correlate with Ki67 IHC measures of total cellular proliferation in a prognostic setting. Also is preclinical mouse models of CRC, [18F]-FLT was shown to serve as an early PET biomarker that may be sensitive to activation of pro-survival mechanisms that may predict tumors that are more likely to resist treatment and ultimately may be more prone to recurrence. In the clinical setting, [18F]-FLT PET was shown to correlate with treatment response in KRAS mutant rectal cancers after EGFR targeted therapy and chemoradiotherapy. Each of these components advance the understanding the strengths and weaknesses of [18F]-FLT and how [18F]-FLT PET can best be utilized in clinical practice