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Towards personalized neoadjuvant therapy in colorectal cancer: optical methods to assess cellular-level and vascular-level resistance to chemoradiotherapy

Timothy J. Muldoon, MD, PhD

Cancer of the gastrointestinal epithelium accounts for over 150,000 new cancer cases in the United States each year. Locally advanced (Stage II and III) distal rectal tumors receive neoadjuvant chemoradiotherapy (CRT) prior to surgical resection. Pathologic complete response to neoadjuvant therapy (pCR) is seen in only a minority of cases (<25%), but has been associated with significantly improved clinical outcomes, including disease-free survival. Prediction of which patients will respond to neoadjuvant therapy remains challenging. We are developing optical methods to quantify two potential modes of resistance to neoadjuvant therapy in patients with colorectal tumors: cellular-level resistance to cytotoxic agents and limited perfusion in solid tumors. First, we are studying the use of in vitro patient tumor-derived organoid culture and live-cell metabolic imaging to quantify the heterogeneous drug sensitivity of specific tumors. Secondly, we have developed a hybrid multiscale spectroscopy probe to rapidly assess in vivo intratumoral hemodynamic changes in response to therapy. These methods are currently being validated in preclinical models, and will be deployed in a clinical pilot study following patients with known colorectal tumors receiving neoadjuvant therapy. Our goal is to develop and translate to the clinic novel optical tools which can provide therapeutic guidance tailored to the patient-specific tumor phenotype. These tools will allow physicians to better select cytotoxic agents, rapidly assess response to therapy, and identify potential alternative strategies during neoadjuvant therapy. This new paradigm could increase the likelihood of achieving pCR in patients with locally advanced colorectal tumors.

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