Selected Articles from This Issue

Abstract

Ataxia telangiectasia mutated (ATM) kinase controls key cell cycle checkpoints and the repair of DNA double strand breaks and has been considered an attractive intervention point in DNA damage response for cancer therapy. Here, Zimmermann et al. introduce two novel ATM inhibitors. These highly potent and selective small molecules effectively suppress the ATM pathway, enhance antitumor effect of radiation and topoisomerase I inhibitors and synergize with PARP inhibitors in cancer cells and animal models of human cancer. They represent new molecular tools with potential for combination with key cancer therapies.ERα antagonists and degraders are highly effective in the treatment of the majority of ERα+ breast cancers but resistance mechanisms, including ERα mutations that facilitate ligand-independent activation, blunt the effectiveness of these therapies. Here, Furman et al. report on the development H3B-6545, a novel covalent inhibitor of ERa which demonstrates superiority over standard-of-care fulvestrant in both ERWT and ERαMUT breast tumor models. Consistent with these preclinical findings, ongoing clinical trials of H3B-6545 are demonstrating preliminary activity in ER+, HER2− metastatic breast cancer patients with both ERαWT and ERαY537S mutations.Pancreatic cancer is a devastating malignancy with a 5-year survival rate of only 9%. Glypican-1 (GPC1) is a cell surface proteoglycan that is upregulated in pancreatic cancer. Here, Ho and colleagues have constructed a GPC1-targeted immunotoxin derived from a bacterial toxin. Small molecule screening has been performed to identify irinotecan that shows synergistic efficacy with the immunotoxin. The GPC1-targeted immunotoxin inhibits pancreatic tumor growth via degradation of internalized GPC1, downregulation of Wnt signaling, and inhibition of protein synthesis. The anti-GPC1 immunotoxin in combination with irinotecan thus provides a potential new treatment for patients with pancreatic tumors.Despite the approval of immune checkpoints in small cell lung cancer (SCLC), it remains a rapidly progressing and fatal form of cancer. Recently, antibody drug conjugates (ADCs) have gained clinical traction in breast, bladder, and hematologic cancers. Here, Wiedemeyer and colleagues develop ABBV-011, a novel SEZ6-targeted, calicheamicin-based ADC that contains a non-cleavable linker which eliminates toxic metabolites associated with first generation calicheamicin ADCs. In mice, ABBV-011 potently regresses patient-derived xenografts of SCLC. ABBV-011 is being tested in a Phase 1 study and has potential as a first-in-class ADC therapy for SCLC.