Remediating Desmoplasia with EGFR-Targeted Photoactivable Multi-Inhibitor Liposomes Doubles Overall Survival in Pancreatic Cancer.

Abstract

Desmoplasia is characteristic of pancreatic ductal adenocarcinoma (PDAC), which exhibits 5-year survival rates of 3%. Desmoplasia presents physical and biochemical barriers that contribute to treatment resistance, yet depleting the stroma alone is unsuccessful and even detrimental to patient outcomes. This study is the first demonstration of targeted photoactivable multi-inhibitor liposomes (TPMILs) that induce both photodynamic and chemotherapeutic tumor insult, while simultaneously remediating desmoplasia in orthotopic PDAC. TPMILs targeted with cetuximab (anti-EGFR mAb) contain lipidated benzoporphyrin derivative (BPD-PC) photosensitizer and irinotecan. The desmoplastic tumors comprise human PDAC cells and patient-derived cancer-associated fibroblasts. Upon photoactivation, the TPMILs induce 90% tumor growth inhibition at only 8.1% of the patient equivalent dose of nanoliposomal irinotecan (nal-IRI). Without EGFR targeting, PMIL photoactivation is ineffective. TPMIL photoactivation is also sixfold more effective at inhibiting tumor growth than a cocktail of Visudyne-photodynamic therapy (PDT) and nal-IRI, and also doubles survival and extends progression-free survival by greater than fivefold. Second harmonic generation imaging reveals that TPMIL photoactivation reduces collagen density by >90% and increases collagen nonalignment by >103 -fold. Collagen nonalignment correlates with a reduction in tumor burden and survival. This single-construct phototoxic, chemotherapeutic, and desmoplasia-remediating regimen offers unprecedented opportunities to substantially extend survival in patients with otherwise dismal prognoses.

• Authors: Girgis Obaid, Shazia Bano, Hanna Thomsen, Susan Callaghan, Nimit Shah, Joseph W R Swain, Wendong Jin, Xiadong Ding, Colin G Cameron, Sherri A McFarland, Juwell Wu, Mark Vangel, Svetla Stoilova-McPhie, Jie Zhao, Mari Mino-Kenudson, Charles Lin, Tayyaba Hasan
• Journal: Advanced science (Weinheim, Baden-Wurttemberg, Germany) (Adv Sci (Weinh)) Vol. 9 Issue 24 Pg. e2104594 (08 2022) ISSN: 2198-3844 [Electronic] Germany
• PMID: 35748165 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.

Chemical References

• Liposomes
• Protein Kinase Inhibitors
• Irinotecan
• EGFR protein, human
• ErbB Receptors

Topics

• Carcinoma, Pancreatic Ductal (drug therapy)
• ErbB Receptors (therapeutic use)
• Humans
• Irinotecan (pharmacology, therapeutic use)
• Liposomes (therapeutic use)
• Pancreatic Neoplasms (drug therapy)
• Protein Kinase Inhibitors (therapeutic use)
• Pancreatic Neoplasms