Photodynamic priming and VDR activation modulate tumor-stroma interactions and permeability for durable control and enhanced treatment tolerability (Conference Presentation)

Cancer patients often must confront the decision of whether to continue high dose chemotherapy at the expense of cumulative toxicities and high cost. Strategies to reduce the toxicity of these high dose regimens, while also retaining efficacy, have not been prioritized yet are sorely needed to preserve the performance status of these vulnerable patients. Here, we introduce a dual pronged approach to modulate the microenvironment of desmoplastic pancreatic tumors and enable significant dose de-escalation of the FDA approved frontline chemotherapeutic nanoliposomal irinotecan (nal-IRI) without compromising long-term tumor control. We demonstrate that light-based photodynamic priming (PDP) coupled with vitamin D receptor (VDR) activation targets cancer-associated microvasculature and fibroblasts to increase intratumoral nal-IRI and suppress pro-tumorigenic CXCL12/CXCR7 crosstalk. Combined optical and biochemical alteration of the tumor microenvironment enhances the efficacy of nal-IRI to enable a 75% dose de-escalation, resulting in improved tolerability with retained efficacy. Strategies aimed at modifying the tumor landscape to increase susceptibility represents a promising and relatively underexplored approach to enable dose de-escalation of toxic chemotherapeutics, and may simultaneously improve patient outcomes and quality-of-life.