SESORRS endoscopy for the staging and evaluation of colorectal cancer

Colorectal cancer (CRC) is the third most common cancer and a leading cause of death worldwide. The degree of CRC invasion into the large intestinal wall is associated with patient prognosis. White light endoscopy (WLE) is used to evaluate lesions of interest within the colon, however WLE provides only morphological information, often failing to efficiently evaluate the required resection margin or extent of tumor invasion. There is a significant need to develop an endoscopic approach that can address these challenges. We believe this could be achieved using spatially offset Raman spectroscopy (SORS) in combination with surface enhanced resonance Raman scattering (SERRS) contrast agents (CAs). The combination of the two approaches is referred to as surface enhanced spatially offset resonance Raman spectroscopy (SESORRS). In the proposed preclinical study, I will test the hypothesis that SESORRS endoscopy could improve existing practices for the detection, staging and surgical resection of CRC. During the K99 mentored phase, I will build and validate the efficiency of a SORS endoscope using ex vivo phantoms (SA1.1, SA1.2). Using Apcfl/+ and Apcfl/+;KrasG12D/+ mouse models of CRC, we will evaluate the efficiency of SESORRS endoscopy to detect and stage CRC in vivo. Results will be correlated with MRI, PET, and ex vivo histology (SA2.1). The biodistribution and pharmacokinetic profiles of radiolabeled SERRS CAs will be evaluated using PET imaging (SA2.2). As an independent investigator, I will determine the optimal dose of SERRS CAs required for SORS endoscopic imaging of CRC (SA2.3). In SA3 I will determine and validate the advantage of using molecularly targeted-SERRS CAs over non-targeted SERRS CAs, together with the ability of SESORRS endoscopy to assist in the surgical resection of lesions of interest by detecting residual tumor cells on the surface, and beneath, the resection bed. If successful, SESORRS endoscopy could be very useful in the screening, diagnosis, and treatment of CRC. This project will enable us to predict the potential success of clinical SESORRS endoscopy and increase the likelihood of achieving eventual clinical translation. I have a unique set of expertise in SERRS, SORS and SESORRS imaging and believe I am highly qualified to lead, and conduct, the proposed project here at the Dana-Farber Cancer Institute. I also have identified the following key areas which require additional training in order to support my transition to independence: (1) mouse models of CRC; (2) understanding the cancer biology of CRC and the influence of genetic mutations on CRC invasion; (3) radiochemistry and PET imaging and; (4) requirements for clinical translation. I have deliberately chosen and carefully assembled a world-class committee of mentors and advisors including my primary mentor Dr. Kevin Haigis, as well as Dr. Conor L. Evans and Dr. Norman Nishioka who will serve as co-mentors. My mentors are in full support of my research and career goals. I am committed to this award and strongly believe that it will help me gain the necessary training required to enable my long-term career goal of being an established investigator in the field of molecular imaging.