Methods For Treating Cancer Using Combination Therapies

Abstract

Described are methods, uses, and kits for utilizing a targeted ligand conjugate in combination with a thiol inhibitor or a system x c − inhibitor for the treatment of cancer or inflammation. Also described are in vitro assays utilizing a targeted ligand conjugate in combination with a thiol inhibitor or a system x c − inhibitor.

1 . An in vitro assay for identifying a ligand conjugate suitable for co-administration to a patient with a thiol inhibitor, the assay comprising:
 a) adding the ligand conjugate to the culture medium of a first sample of cultured cells, wherein the ligand conjugate comprises a disulfide linkage;   b) adding the thiol inhibitor to the culture medium of the first sample of cultured cells to provide a test sample;   c) adding the ligand conjugate to the culture medium of a second sample of cultured cells to provide a control sample;   d) measuring the non-ligand-specific activity of the ligand conjugate or the nonspecific uptake of the drug in the test sample;   e) measuring the non-ligand-specific activity of the ligand conjugate or the nonspecific uptake of the drug in the control sample; and   f) determining that the ligand conjugate is suitable for co-administration to the patient with the thiol inhibitor if the non-ligand-specific activity of the ligand conjugate and/or the nonspecific uptake of the drug are decreased in the test sample relative to the control sample,   wherein the ligand conjugate is of the formula BLD X , wherein B is a cell surface receptor targeting ligand, D is an independently selected drug, x is an integer selected from 1, 2, 3, 4 and 5; and L is a releasable polyvalent linker comprising a thiol reactive linkage; or a pharmaceutically acceptable salt thereof,   wherein B is a PSMA binding ligand, and   wherein the PSMA binding ligand is