Selected Articles from This Issue

Abstract

α-FR is overexpressed in a variety of solid tumors, including high-grade serous ovarian cancer, triple-negative breast cancer, and non–small cell lung cancer. CT900 is a small molecule thymidylate synthase (TS) inhibitor that binds to and is taken up by α-FR. Banerjee and colleagues report results from the first clinical trial to show reproducible single agent responses caused by a small molecule in α-FR-overexpressing cancers. The toxicity profile did not show classical TS inhibitor toxicity such as myelosuppression suggesting differential α-FR mediated uptake in tumor tissue. This trial is proof of concept for developing α-FR targeting small molecules, which are selectively taken up in α-FR-overexpressing tumors for patient benefit and are an alternate approach to antibody drug conjugates that already target α-FR.Immune checkpoint inhibitors (ICI) have modest efficacy in patients with mucosal melanoma. Although PD-1/PD-L1 monotherapy has limited benefit, combined therapy with CTLA4 and PD-1 inhibitors improves response rates but increases toxicity. VEGF is highly expressed in melanoma and contributes to progression. Combined treatment with ICI and VEGF inhibitors has shown positive outcomes across various cancer types. Here, Mao and colleagues present the results of a phase II study evaluating the PD-L1 inhibitor atezolizumab and the VEGF inhibitor bevacizumab as first-line therapy in Chinese patients with advanced mucosal melanoma. Over a median follow-up of 13.4 months, the objective response rate was 45.0% in 40 evaluable patients. Atezolizumab in combination with bevacizumab showed promising efficacy and manageable safety. This study sheds light on the dual strategy of VEGF and PD-L1 inhibition in patients with this rare melanoma subtype, for whom prognosis is otherwise generally poor.Defining the immune mechanisms responsible for early control of tumors is critical for guiding treatment strategies. Ferguson and colleagues applied imaging mass cytometry to map the immune landscape and identify differences in immune populations and their specific interactions between high-risk primary cSCC tumors that did not progress and those that developed metastases. The study also reveals that the immunosuppressive state alters the cellular composition of primary tumors. The ability to predict metastatic tumor progression at the time of initial diagnosis of primary cSCC will aid personalized medical care and better disease surveillance.Using publicly available genome-wide genetic dependency maps, Grubb and colleagues sought lineage-enriched anticancer targets. In kidney cancer, this strategy identified BCL2L1 which encodes the antiapoptotic BCL-XL protein as a candidate. Relying on cell-based apoptosis assays, in vivo studies, and clinical validations, as well as using genetic and pharmacological approaches, these studies revealed that a tumor's mesenchymal cell state conferred BCL-XL dependence. The findings identify BCL-XL as a novel target in kidney cancer and present potential biomarkers to stratify renal tumors based on their reliance on BCL-XL.