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"Evaluating Tumor Heterogeneity Effects on Transport and Acute Therapeutic Outcomes of Photodynamic Therapy in Pancreatic Adenocarcinoma"

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer, yet 80% of the patients are not eligible for curative surgical resection due to the tumor invasion into surrounding major blood vessels. Alternative treatment options, from conventional chemotherapy to more novel approaches such as immunotherapy, mainly rely on systemic drug delivery and intratumoral distribution. While the tumor microenvironment has been established as a key factor that affects drug transport efficiency, it is a challenge to obtain transport-relevant tumor information in clinical settings to assess therapeutic outcomes. This thesis focused on understanding the PDAC tumor microenvironment parameters that could be a surrogate for drug uptake and using low-dose photodynamic therapy (PDT) to modulate such parameters to improve tumor drug distribution. Preclinical findings along with early evidence from clinical CT scans are presented.

The first aim of this thesis introduces an ex vivo imaging system that helps demonstrate the relationship between tumor stiffness heterogeneity and tumor collagen content, both of which are inversely correlated to drug uptake. This finding encourages the development of elastography as a feasible clinical imaging procedure that could predict treatment outcome. The second aim further improves the capability of this imaging system to visualize collagen distribution in fresh tissue samples by employing tumor staining and fluorescence imaging with ultraviolet excitation. The system is utilized in the third aim of this thesis which demonstrates that low-dose focal PDT treatment in PDAC mouse models could reduce desmoplasia and relieve stiffness heterogeneity. Such modulating effects of PDT makes this light treatment an effective neoadjuvant therapy to prime PDAC tumors for subsequent chemo or immunotherapy. Lastly, the fourth aim of this work shows that tumor priming effects could be quantified from CT scans of PDAC patients receiving PDT treatment by texture analysis, emphasizing the promise of PDT when used in combination with more conventional therapies.

Thesis Committee

• Brian Pogue, PhD (Chair)
• P. Jack Hoopes, PhD
• Kimberley Samkoe, PhD
• Petr Brůža, PhD
• Tayyaba Hasan, PhD (External)

Contact

For more information, contact Daryl Laware at daryl.a.laware@dartmouth.edu.