Highlights of This Issue

Emerging technologies bring the promise of enhancing cancer detection and providing novel methods for monitoring tumor response. Liquid biopsy is one such emerging platform that allows tumor monitoring without the need for surgical interventions. The importance of liquid biopsy is more eminent when applied to surgically nonresectable tumors. Panditharatna and colleagues designed and developed a sensitive and specific assay for probing tumor-associated mutant DNA in liquid biopsies obtained from children diagnosed with brain cancers. The significance of this work is highlighted in its ability to correlate liquid biopsy data with MR imaging and provide its feasibility in the context of clinical trials.

The heterogeneity of pancreatic ductal adenocarcinoma (PDAC) is well-recognized molecularly and reflected clinically in variable disease presentations and treatment responses. Interrogating that biological heterogeneity for patients has been challenging, partly related to obtaining sufficient tumor samples. Koay and colleagues addressed this challenge by developing a classification of PDAC morphology on standard-of-care computed tomography (CT) scans, which are ubiquitous in clinics. They discovered two distinct imaging phenotypes that correlated with genetic aberrations, stromal content, and clinical outcomes. Thus, a CT-based biomarker could be used to separate PDAC into distinct subtypes, with implications for treatment selection, response evaluation, and early detection.

Prostate cancers show remarkable resistance to emerging immunotherapies, partly due to tolerogenic STAT3 signaling in tumor-associated myeloid cells. Moreira and colleagues developed an oligonucleotide strategy combining STAT3 knock-down with Toll-like Receptor-9 (TLR9) immune-stimulation in the microenvironment of bone-localized prostate tumors. Systemic administration of these oligonucleotides triggered immune-mediated eradication of two genetically different prostate tumor models in mice, which relied on both innate and adaptive CD8/CD4 T-cell–mediated immunity as verified immune cell depletion studies. The bifunctional oligonucleotide design, both immunostimulatory and tolerance-breaking, offers an opportunity for the therapy of immunologically “cold” tumors, such as prostate cancers.

MET-targeted therapies are clinically effective in MET exon 14 mutant non–small cell lung cancers (NSCLC); however, resistance inevitably develops. While several MET secondary mutations imparting resistance have been reported, Bahcall and colleagues describe one of the first examples of a resistance mechanism involving alternative signaling. The study characterizes acquired amplification of wild-type (WT) KRAS as a recurrent molecular mechanism behind crizotinib resistance in three cases of MET exon 14 mutant NSCLC, using in vitro assays and patient-derived xenografts. In these models, KRAS amplification uncouples MET from downstream effectors, induces expression of EGFR ligands, and confers hypersensitivity to ligand-dependent and independent activation. The auxiliary reliance on PI3K renders these models vulnerable to dual MET/PI3K inhibition as a promising therapeutic strategy.