Photodynamic Therapy Using Hippo Pathway Inhibitor Verteporfin: A Potential Dual Mechanistic Approach in Treatment of Soft Tissue Sarcomas

SIMPLE SUMMARY: Advanced sarcomas have yet to undergo improved outcomes seen in other cancer subtypes. Verteporfin has the potential to show landmark change in sarcoma due to its anti-proliferative properties: inhibition of the Hippo pathway and as photodynamic therapy. The effect of verteporfin on the Hippo pathway is reviewed specifically in the setting of sarcoma due to increased activation of this pathway in multiple subtypes. Role and efficacy of photodynamic therapy in other malignancies is also reviewed, with additional discussion of preclinical studies demonstrating synergistic effects of photodynamic therapy within current sarcoma standard of care treatment. Future investigations of the feasibility of incorporating verteporfin into sarcoma treatment are discussed. ABSTRACT: Sarcoma is a widely varied and devastating oncological subtype, with overall five-year survival of 65% that drops to 16% with the presence of metastatic disease at diagnosis. Standard of care for localized sarcomas is predicated on local control with wide-local resection and radiation therapy, or, less commonly, chemotherapy, depending on tumor subtype. Verteporfin has the potential to be incorporated into this standard of care due to its unique molecular properties: inhibition of the upregulated Hippo pathway that frequently drives soft tissue sarcoma and photodynamic therapy-mediated necrosis due to oxidative damage. The initial anti-proliferative effect of verteporfin is mediated via binding and dissociation of YAP/TEAD proteins from the nucleus, ultimately leading to decreased cell proliferation as demonstrated in multiple in vitro studies. This effect has the potential to be compounded with use of photodynamic therapy to directly induce cellular necrosis with use of a clinical laser. Photodynamic therapy has been incorporated into multiple malignancies and has the potential to be incorporated into sarcoma treatment.