Abstract
NF2 is an important tumor suppressor and regulator of physical stresses and loss of NF2 cause NF2-related cancers (NF2 syndrome and mesothelioma). However, there is no proper treatment for these diseases until now. This study by Cho and colleagues revealed that loss of NF2 induces a disturbance in the balance of TβR and facilitates TβR1-mediated oncogenic signaling, which could be blocked by TEW7197, a specific TβR1 kinase inhibitor. These findings support TEW7197 would be efficacious drug candidate for NF2-related diseases.Targeting tumor lactate homeostasis is considered to be an attractive approach for cancer therapy. In a cell based screen, Quanz and colleagues have discovered a novel specific and orally available inhibitor (BAY-8002) of the lactate transporter MCT1. BAY-8002 showed potent inhibition of lactate transport in cancer cells and tumor growth inhibition in vivo. The investigation of resistant cells as well as response to treatment in a large cell panel provide new insight into the metabolic plasticity of tumor cells. Furthermore, the results suggest stratification markers to be potentially pursued in the clinical development of MCT1 inhibitors.The receptor tyrosine kinase (RTK) AXL is overexpressed in many human cancers including head and neck squamous cell carcinoma, triple-negative breast cancer, and non-small cell lung cancer. McDaniel, Cummings and colleagues identified a mechanism of resistance to AXL-targeting agents mediated by MERTK, a related RTK. Endogenous MERTK expression increased after treatment with AXL inhibitors and ectopic overexpression conferred resistance to AXL-targeting agents. Moreover, MERTK inhibitors overcame resistance to AXL inhibition and significantly reduced tumor cell expansion and tumor growth. The synergistic interactions between AXL and MERTK inhibitors suggest that therapeutic co-targeting strategies could be very effective in these malignancies.Delivery of therapeutics to pancreatic ductal adenocarcinomas (PDAC) is challenging due to the physical stromal barriers surrounding these tumors. Lo and colleagues applied tumor-penetrating nanocomplexes (TPNs) to breach the stroma and effectively deliver therapeutic siRNA to PDAC. These particles are self-assembled nanostructures comprised of tandem peptides containing both a tumor-penetrating iRGD domain and a cell-penetrating domain, PEGylated derivatives of these tandem peptides, and siRNA. TPNs delivering anti-Kras siRNA exhibited tumor-penetrating ability in 3D organoids and autochthonous tumors, and slowed PDAC growth in vivo. The modular construction of the TPN platform allows for facile adaptation for future genetic targets.
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