FOLR1-targeted Actinium-225-based Alpha-particle Therapy Eliminates Ovarian Cancer
Despite the advancement in therapies, ovarian cancer treatment is challenging due to poor prognosis and high relapse associated with acquired resistance. Targeting overexpression of FOLR1 in ovarian cancers has proven to be an attractive strategy. The recent FDA approval of FOLR1 targeted antibody drug conjugate has shown promising results albeit resistance with repeated use appears inevitable. Emerging targeted alpha-particle therapies, particularly Actinium-225 (225Ac), for treating refractory cancers have opened avenues for improved therapeutic options. The success of alpha-particle therapy relies on tumor specific delivery of the alpha emitters. Herein we describe the first example of FOLR1-targeted 225Ac alpha-particle therapy for treatment of ovarian cancer. Longitudinal PET imaging demonstrated high tumor-specific uptake of FOLR1 in SKOV3 xenografts. FOLR1-targeted 225Ac demonstrated high therapeutic efficacy achieving marked tumor regression, 80% survival and 40% complete response. The therapy resulted in tumor specific double stranded DNA damage, and no obvious toxicity was observed in normal tissues. Estimated human dosimetry showed high absorbed dose for tumor and minimal absorbed dose for healthy tissues establishing its safety. In totality, FOLR1-targeted 225Ac alpha-particle therapy is an efficacious and safe treatment with high feasibility for clinical translation to fight against ovarian cancer.