Metabolotheranostics of pancreatic cancer by targeting choline, glutamine, and glucose transporters with photoimmunotherapy

Altered choline, glutamine, and glucose metabolism form a triumvirate of metabolic reprogramming in most cancers that significantly influences growth, progression, and response to treatment. Photoimmunotherapy (PIT) is a highly target-specific treatment where a targeting antibody (Ab) is conjugated to a photosensitizing dye, IR700, that damages the target only when exposed to near-infrared (NIR) light irradiation. The requirement of an extracellular target has restricted PIT targeting to cell surface receptors and antigens. Here, for the first time, we exploited the extracellular domain of three metabolic transporters, CTL1 for choline, ASCT2 for glutamine, and GLUT1 for glucose for PIT, to demonstrate metabolotheranostics of cancer cells. We analyzed the TCGA database to establish increased expression of the three transporters in human pancreatic ductal adenocarcinoma (PDAC). For the PIT studies, we used two patient-derived PDAC cell lines selected for differences in transporter expression and demonstrated an expression-dependent reduction of cell viability following PIT. A single CTL1-PIT treatment of Pa04C tumors resulted in the eradication of four out of five established tumors. In PDAC, the PIT of metabolic transporters would be most effective in the intraoperative setting, where it could significantly impact cancer cells that may have invaded critical structures.