Journal
CANCER RESEARCH
Volume 78, Issue 2, Pages 558-571Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-17-1700
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Funding
- Photopathology Center of the Wellman Center for Photomedicine, Massachusetts General Hospital
- Harvard Catalyst, The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH) [UL1 TR001102]
- Harvard University
- NIH [P01CA084203, R01CA156177, R01CA160998, K99CA194269, K99CA175292, R00CA175292]
- Massachusetts General Hospital Tosteson Fellowship [224889]
- National Institute for Health Research University College London Hospitals Biomedical Research Centre
- MRC [G0801588] Funding Source: UKRI
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Physiologic barriers to drug delivery and selection for drug resistance limit survival outcomes in cancer patients. In this study, we present preclinical evidence that a subtumoricidal photodynamic priming (PDP) strategy can relieve drug delivery barriers in the tumor microenvironment to safely widen the therapeutic window of a nanoformulated cytotoxic drug. In orthotopic xenograft models of pancreatic cancer, combining PDP with nanoliposomal irinotecan (nal-IRI) prevented tumor relapse, reduced metastasis, and increased both progression-free survival and 1-year disease-free survival. PDP enabled these durable improvements by targeting multiple tumor compartments to (i) increase intratumoral drug accumulation by > 10-fold, (ii) increase the duration of drug exposure above a critical therapeutic threshold, and (iii) attenuate surges in CD44 and CXCR4 expression, which mediate chemoresistance often observed after multicycle chemotherapy. Overall, our results offer preclinical proof of concept for the effectiveness of PDP to minimize risks of tumor relapse, progression, and drug resistance and to extend patient survival. (C) 2017 AACR.
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