Author ORCID Identifier

https://orcid.org/0000-0003-1555-608X

Date of Graduation

12-2018

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Anirban Maitra

Committee Member

Russell Broaddus

Committee Member

Stephen Hahn

Committee Member

Nicholas Navin

Committee Member

Cullen Taniguchi

Committee Member

Eduardo Vilar-Sanchez

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest 5-year survival rates amongst solid tumors. As early detection of PDAC is unusual and typically incidental, most patients present with locally advanced and metastatic disease where effective therapeutic strategies remain a significant unmet need. Specifically, surrogate biomarkers for tumor monitoring of PDAC may lead to improved elucidation of clinical actionability and prognostic potential. On the other hand, tumor tissue is rarely sampled in patients presenting with de novo or recurrent metastatic PDAC, apart from a fine needle aspiration or a core needle biopsy performed for diagnosis. This precludes the opportunity for elucidating molecular underpinnings of cancer recurrence, chemoresistance, and therapeutic decision-making in advanced disease patients over the course of their therapy. For this reason, we aim to use so called “liquid biopsies” in the form of circulating nucleic acids and exosomes as a strategy that is amenable to longitudinal, relatively non-invasive sampling. Circulating tumor DNA and circulating exosomes contain genetic cargo representative of the neoplastic cells from which they are released and can serve as a reliable surrogate of the patient’s tumor DNA, enabling a new way of interrogating cancers. We demonstrate that serial quantitative measurements of these tumor nucleic acid sources in circulation can provide clinically relevant predictive and prognostic information in pancreatic cancer patients, including anticipation of impending disease progression and putative mechanisms of resistance to ongoing therapy. We also describe our ability to specifically capture tumor material in circulation following a comprehensive characterization of the pancreatic cancer exosomal “surfaceome”. By leveraging an immune-capture approach paired with ultrasensitive molecular barcoding techniques, we are able to increase our sensitivity of detection of rare molecules in circulation that are derived from the tumor. Ultimately, this has implications for stratification of patients into therapeutic “buckets” through a personalized approach that may lead to greater survival benefits in PDAC.

Keywords

pancreatic cancer, liquid biopsies, precision medicine, exosomes, circulating tumor DNA, digital PCR

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