Selected Articles from This Issue

Abstract

Glioblastoma (GBM) is one of the most aggressive cancers and it is usually refractory to immunotherapies. EGFR variant III (EGFRvIII) is an EGFR mutation commonly present in GBM that generates a unique cell surface neoantigen in tumor cells. Here, Iurlaro and colleagues have designed and developed a novel T cell bispecific antibody (TCB) with specificity for EGFRvIII and CD3. The EGFRvIII-TCB promoted T cell activation and tumor cell killing in EGFRvIII-expressing patient-derived models, and induced tumor regression in GBM patient-derived xenografts (PDX). These results led to the clinical testing of the EGFRvIII-TCB for the treatment of EGFRvIII-expressing GBMs.Comparative oncology clinical trials, carried out in pet dogs with spontaneously occurring cancers, are increasingly recognized a valuable component of the anti-cancer drug discovery and development pathway. In this report, LeBlanc and colleagues conducted a clinical study of a novel orally bioavailable inhibitor of valosin-containing protein (VCP), CB-5339, in pet dogs with a variety of malignancies. This canine trial generated key pharmacokinetic and pharmacodynamic data, defined a tolerable dose and schedule, and discovered an efficacy signal in multiple myeloma. The data generated herein provided a foundation for future studies of this drug in humans with multiple myeloma as well as other tumor types.Glutamine metabolism has been considered an important mechanism for control of tumor growth and survival. Here, Yokoyama and colleagues describe the preclinical pharmacology and mechanism of action of the novel clinical stage glutamine antagonist, DRP-104 (sirpiglenastat). Broadly targeting all 10 glutamine metabolizing enzymes, DRP-104 leads to profound anti-tumor activity related to both direct effects on tumor metabolism as well as immune mediated activity via remodeling of the tumor microenvironment and induction of both innate and adaptive anti-tumor immunity. This unique activity shows promise for the treatment of various tumors including those resistant to immune checkpoint inhibitors.Prostate cancer is the second leading cause of cancer related deaths and most commonly diagnosed cancer in US males. Although androgen receptor-targeted therapies such as enzalutamide are initially effective for the treatment of advanced prostate cancer, resistance occurs frequently. Here, Ning and colleagues have demonstrated that Wnt5A/FZD2 signaling plays vital roles in conferring resistance to enzalutamide and the levels of their expression correlates with aggressive prostate cancer with shortened disease-free survival. Furthermore, a novel bioengineered BERA-Wnt5A siRNA construct significantly suppressed tumor growth and enhanced enzalutamide treatment, suggesting targeting Wnt5A could be developed as a potential therapy for advanced prostate cancer.