Highlights of This Issue

The Delta-Notch pathway contributes to tumor angiogenesis, cell growth and differentiation, and stem cells self-renewal. Preclinically, Dll4 blockade causes dysfunctional vasculature and diminished perfusion. This phase I first-in-human study tested enoticumab, a novel anti-Dll4 monoclonal antibody in patients with refractory solid tumors. Enoticumab was associated with several reversible cardiovascular adverse events but otherwise was well tolerated. Antitumor activity was seen in patients with ovarian cancer, bronchoalveolar NSCLC with β-catenin mutation, and colorectal cancer with FAP syndrome. Given the negative feedback by Dll4/Notch on the VEGF/VEGFR axis, combination therapies with anti-VEGF agents are expected to provide increased efficacy, and should be tested in the clinic.

CD44 is associated with tumor development, progression, metastasis, and drug resistance in several tumor indications. Thus, blocking CD44 in tumor patients is regarded as a promising approach in anticancer therapies. However, CD44 represents a family of proteins with diverse functions originating from alternative splicing. Birzele and colleagues demonstrate how preclinical in vitro and in vivo characterization of CD44 isoform expression led to the identification of CD44s as a potential response prediction marker to anti-CD44 treatment (RG7356 antibody). This was confirmed in data from a phase I clinical trial where patients were treated with RG7356.

Transformed cells are dependent on methionine for growth and survival by mechanisms that are poorly understood. In this study, Strekalova and colleagues demonstrate that methionine deprivation exposes a targetable defect in triple-negative breast cancer cells, but not untransformed cells, by increasing cell surface expression of the proapoptotic TNF-related apoptosis-inducing ligand receptor-2 (TRAIL-R2), thereby enhancing their sensitivity to TRAIL-R2 agonists in vitro and in vivo. These findings indicate that metabolic stress exposes distinctive vulnerabilities in transformed cells that can be targeted with rationally selected therapies and provide the foundation for a clinical trial combining dietary methionine restriction and TRAIL-R2 agonists.

Papillary renal cell cancer (PRCC) is a subset of RCC with poor prognosis for patients with nonlocalized disease. Current treatment options, including the standard of care for RCC, provide only modest benefit. Recently, the molecular underpinnings of clinical PRCC have been evaluated describing a central role for MET. Schuller and colleagues used two independent patient-derived PRCC xenograft models, both harboring MET copy number gain similar to that seen in patients, for therapeutic testing. The authors demonstrate that targeted agents for MET inhibition, including AZD6094 (savolitinib, HMPL-504) induce tumor regressions and may be more efficacious than current therapeutic approaches warranting further clinical investigation.