Highlights of This Issue

BRCA2 plays a central role in homologous recombination by loading RAD51 on DNA double strand breaks. Ovarian cancer (OC) patients who carry BRCA2 germline mutation and are treated with platinum had prolonged survival. Through two independent cohorts, Labidi-Galy and colleagues investigated the correlation between BRCA2 genotype and OC patients’ survival, according to the location of mutations in the functional domains of the protein. They observed that among BRCA2 carriers, those having mutations located in the RAD51-binding domain (exon 11) have prolonged progression-free survival, platinum-free interval, and overall survival. These results have implications for personalized therapy in BRCA carriers.

Chemotherapy resistance represents a significant barrier to acute myeloid leukemia (AML) therapy. Lee and colleagues demonstrate that double negative T cells (DNT) from healthy individuals can be expanded ex vivo to therapeutic levels under GMP conditions and can be cryopreserved. Expanded human DNTs target a large array of primary AML cells, including chemotherapy-resistant patient samples in vitro and significantly reduce the leukemia load in patient-derived xenograft models in a DNT donor unrestricted manner. Importantly, allogeneic DNTs do not attack normal human cells or cause xenogeneic GVHD. Collectively, healthy donor-derived allogeneic DNTs provide a potential new cellular therapy that is safe and effective to treat patients with chemotherapy-resistant AML.

Small cell lung cancer (SCLC) is incurable in most cases, and the absence of distinct kinase addictions has precluded effective targeted therapies. BCL-2 has emerged as an effective drug target in SCLC, but clinical trials with the BCL-2/BCL-xL inhibitor, navitoclax, were complicated by its ability to inhibit BCL-xL, which resulted in dose-dependent thrombocytopenia in SCLC patients. Lochmann and colleagues demonstrate that inhibiting only BCL-2 with the FDA-approved BCL-2 pure inhibitor, venetoclax, is sufficient to induce anti-SCLC activity in a subset of high BCL-2-expressing cell lines and patient-derived xenograft models, suggesting venetoclax as a promising therapeutic in SCLC patients with high-BCL2.

Richardson and colleagues sought to determine whether the canonical EMT marker, vimentin, has a functional role in lung adenocarcinoma metastasis. A novel, genetically engineered mouse model was created that lacks vimentin in a clinically-relevant metastatic lung cancer background. The model revealed that vimentin is necessary for efficient metastasis via heterotypic tumor cell-cancer-associated fibroblast (CAF) interactions. The 3D in vitro studies show that vimentin-positive CAFs are required to lead tumor cell invasion, supporting a vimentin-dependent model of collective invasion. Similar interactions and expression are observed in human lung adenocarcinoma, suggesting that vimentin targeting could reduce metastasis by inhibiting collective invasion.