Redaporfin Development for Photodynamic Therapy and its Combination with Glycolysis Inhibitors

Photodynamic therapy (PDT) remains an underutilized treatment modality in oncology. Many efforts have been dedicated to the development of better photosensitizers, better formulations and delivery methods, rigorous planning of light dose distribution in tissues, mechanistic insight, improvement of treatment protocols and combinations with other therapeutic agents. Hopefully, progress in all these fields will eventually expand the use of PDT. Here we offer a brief review of our own contribution to the development of a photosensitizer for PDT – redaporfin – currently in Phase II clinical trials, and present data on its combination with two glycolysis inhibitors: 2‐deoxyglucose and 3‐bromopyruvate. We show that 3‐bromopyruvate is more cytotoxic to a carcinoma cell line (CT26) than to a normal fibroblast (3T3) cell line, and that this selectivity is maintained in the in vitro combination with redaporfin‐PDT. This combination was investigated in BALB/c mice with large subcutaneous CT26 tumors and it is shown that the cure rate in the combination is higher (33% cures) than in PDT (11% cures) or in 3‐bromopyruvate (no cures) alone. The combination of redaporfin‐PDT with 3‐bromopyruvate illustrates the potential of combination therapies and how PDT benefits can be enhanced by systemic drugs with complementary targets. Redaporfin (Rdp) is a photostable bacteriochlorin photosensitizer in Phase II clinical trials for advanced head & neck cancer, whose development is briefly reviewed in this work. Recognizing that multidisciplinary approaches and combination therapies are usually preferred in oncology, we present the combination of Rdp with two glycolysis inhibitors, 2‐deoxygluose (2DG) and 3‐bromopyruvate (3BP), to take advantage of hyper aerobic glycolysis of cancer cells. We show that Rdp‐PDT in combination with 3BP increases survival of mice with subcutaneous CT26 tumors relative to monotherapies with the same doses.