Selected Articles from This Issue

CD47 is a cell surface glycoprotein that is expressed on normal human tissues and serves as a marker of self. Tumor cells have co-opted CD47 overexpression to evade immune surveillance, making blockade of CD47 an attractive strategy in oncology. However, clinical development of CD47-targeted agents has been complicated by its robust normal tissue expression. SGN-CD47M is a novel protease-activated anti-CD47 antibody that incorporates a functional IgG1 backbone whose binding and function is restricted to the tumor microenvironment. SGN-CD47M may have enhanced antitumor activity and improved tolerability relative to existing therapies that target CD47.Pancreatic cancer is one of the most aggressive types of cancer with one of the lowest 5-year survival rates among all cancers. TROP2 is a promising therapeutic target in pancreatic cancer correlated with metastasis and poor prognosis. Here, Papacharisi and colleagues describe new TROP2 targeting ADCs containing the highly potent payload amanitin with a new mode of action with excellent antitumor efficacy in refractory pancreatic cancer and TNBC models. Taken together, the high in vivo efficacy, favorable PK profiles, and good tolerability supported a high therapeutic window, demonstrating the therapeutic potential of these novel TROP2 targeting ADCs for the treatment of pancreatic cancer.KT‐253 is a highly potent and selective heterobifunctional degrader of the MDM2 oncoprotein, a key E3 ligase that modulates the most common tumor suppressor, p53. While MDM2 small molecule inhibitors have been developed to stabilize and upregulate p53 expression, they have been found to induce a feedback loop that increases MDM2 levels, which can repress p53 and therefore limit their efficacy. In preclinical studies, Chutake and colleagues highlight the therapeutic potential of MDM2 degradation to overcome the MDM2 feedback loop, thereby robustly activating the p53 pathway and inducing apoptosis in a range of p53 wild‐type hematologic and solid tumor models.Androgen receptor (AR) signaling is a key driver of prostate cancer; AR pathway inhibitors are standard treatments for patients with this disease, but many tumors develop resistance, and patients experience disease progression. Here, Snyder and colleagues report preclinical evaluation of bavdegalutamide, a PROteolysis TArgeting Chimera (PROTAC) that harnesses the ubiquitin-proteasome system to induce AR degradation. Bavdegalutamide showed substantial AR degradation and tumor growth inhibition in prostate cancer animal models, including those with AR pathway inhibitor resistance. Bavdegalutamide, the first PROTAC to enter human clinical trials, was evaluated in a phase I/II study in patients with metastatic castration-resistant prostate cancer.