Graduation Date

Summer 8-13-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cancer Research

First Advisor

Michael A. Hollingsworth

Abstract

Since the 1980’s, legislatures have invested immense effort into strategies to capitalize on the United States’ global lead in basic and translational research. This is largely motivated by the discrepancy the US faces in converting its world leading research discoveries and innovations into commercial products, relative to other countries. This truncated productivity leaves the US out of substantial GDP growth and reduces public access to new innovations. Proponents of government and university owned patents reason that enhanced public private partnerships narrow the gap between the technology transfer of basic research discoveries and accessible commercial products.

With these concepts of technology transfer in mind, we set out to develop translationally relevant technologies to improve PDAC patient outcomes. First, we then partnered with pharmaceutical scientists and medicinal chemists to evaluate novel small molecule inhibitors and combined therapeutic approaches to treating PDAC. Second, we engineered a research tool, our Abdominal Imaging Window (AIW), which facilitates in vivo longitudinal deep tissue microscopy of pancreatic tumors and microenvironment throughout disease progression. Then, we collaborated with experts in the field of fluorescent imaging to develop tumor specific contrast agents that could be used in real time intraoperatively to improve surgical resection outcomes. Lastly, we investigated tools for strategic Science, Technology, Engineering, and Mathematics (STEM) outreach programing for not only recruiting future scientists, but for building a community of trust and understanding of scientific practices in the next generation.

In our investigation of novel combination therapeutics, we found that inhibition of CDK5 with small molecule inhibitor CP had the potential to reduce orthotopically implanted murine pancreatic adenocarcinomas of clinically relevant size to radiographically undetectable when used in combination with gemcitabine. These previously tumor bearing mice remained in remission and showed durable treatment free response of up to 40 days. Given this profound response, we pursued a multifaceted investigation into the effects of CDK5 inhibition on the tumor microenvironment, including the effects on perineural invasion and tumor associated neural migration.

To do so, we had to first engineer an Abdominal Imaging Window which would allow us to perform longitudinal intravital microscopy of tumor progression and neural invasion via multiphoton microscopy. These well tolerated AIWs provided macro and microscopic detail of PDAC progression longitudinally, and brought to the market a novel mechanism for performing upright microscopy in vivo.

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