MESH: Phase II trial of methotrexate as a synthetic lethal therapy for metastatic MSH2-deficient colorectal and other tumors.

Abstract

TPS338 Background: We have previously showed that MSH2-deficient tumor cells are exquisitely sensitive at submicromolar doses to treatment with the antifolate methotrexate. This synthetic lethal effect was associated with an increase in oxidative DNA damage and apoptosis (Martin SA et al., 2009. EMBO Molecular Medicine 1[6-7]:323-337). Based on these observations, we have initiated a clinical trial to assess the antitumor effects of low-dose methotrexate in MSH2-deficient cancer cells in the clinical setting. Methods: Eligible patients must have histological evidence of an MSH2-deficient metastatic cancer (defined by the absence of MSH2 on immunohistochemistry, or a loss-of-function germline mutation in MSH2). Patients must be refractory to standard palliative chemotherapy, or have other reasons why they cannot receive standard treatment. This trial originally opened to patients with colorectal cancer, but due to the low prevalence of MSH2 deficiency in the metastatic population, resulting in slow accrual...