Selected Articles from This Issue

The phosphoinositide 3-kinase (PI3K) signaling pathway plays an important role in many tumor types, but development of PI3K inhibitors is challenging because of toxicity risks associated with inhibiting multiple PI3K isoforms. AZD8186 is a potent, selective inhibitor of PI3Kβ. In a phase I open-label study Choudhury and colleagues evaluated the safety, tolerability, and recommended phase II dose of AZD8186 monotherapy and in combination with abiraterone acetate or vistusertib. Eligible patients had advanced prostate cancer, triple-negative breast cancer, or squamous non-small-cell lung cancer, and patients with other solid tumor types were eligible if they were PTEN-deficient/mutated or PIK3CB-mutated/amplified. As monotherapy and in combination, AZD8186 was well tolerated, with few dose-limiting toxicities reported. Both monotherapy and combination therapy showed preliminary evidence of antitumor activity, which merits further assessment in subsequent studies.

FGFR alterations occur in ∼8% of gliomas, with most detected in FGFR1 and FGFR3. Although FGFR fusions have proven oncogenic potential in gliomas, less is known about the role of FGFR mutations or amplification. Lassman and colleagues describe a phase II study of infigratinib, a selective FGFR1–3 oral tyrosine kinase inhibitor, in patients with FGFR-altered recurrent gliomas. Durable disease control (>1 year) was observed with infigratinib in a subset of patients with activating FGFR1 or FGFR3 mutations or FGFR3 fusions. Further trials with refined biomarker inclusion criteria are warranted.

Cancer targeted near infrared (NIR) fluorescent probes offer the promise of accurate tumor delineation during surgeries and the detection of cancer specific molecular expression in vivo. However, nonspecific probe accumulation reduces specificity, precluding the clinical adoption of imaging agents. By exploiting fluorescence lifetime contrast, Pal and colleagues present the first clinical demonstration of tumor imaging with cellular specificity using a systemically injected contrast agent in humans. Because fluorescence lifetimes can be measured through thick biological tissue with NIR light, the results have direct clinical relevance for improving tumor resection accuracy during surgeries and for the noninvasive quantification of EGFR expression in humans.

Diffuse midline gliomas (DMGs) are incurable brain tumors in children. DMGs upregulate the antiapoptotic protein BCL-2 following radiation therapy (RT), which may limit therapeutic efficacy and promote recurrence. In this study, Madhavan and colleagues, concurrently inhibit BCL-2 using the FDA-approved drug venetoclax, demonstrating that the combination leads to increased ROS production and cell apoptosis. Combined venetoclax and RT in orthotopic mouse models of DMG shows a potent synergy leading to prolonged xenograft survival. Together, these results suggest that venetoclax combined with radiotherapy warrants further study in clinical trials for children with DMGs.