Highlights of This Issue

Abstract

Simultaneous blockade of MAPK and PI3K pathway signaling in tumors can preempt adaptive resistance and achieve synergistic cell killing. Clinical application of this approach, however, has proven elusive due to an increased prevalence of dose-limiting toxicity. Dreaden and colleagues address this unmet need by developing a tumor-targeting nanoscale drug formulation based layer-by-layer (LbL) self-assembly that horizontally blocks MAPK and PI3K signaling in mouse models of breast carcinoma. The authors observed further enhanced drug synergy following co-encapsulation, tumor-targeted drug delivery, and disease stabilization following systemic administration—importantly—in the absence of hepatic and renal toxicity observed with the free drug combination.Peripheral neuropathy is a common adverse effect of chemotherapy that can lead to possible cessation of therapy with no effective treatments or genetic markers to predict those at risk. Using an integrative genome-wide approach that included cell-based and patient data led to the identification of genes contributing to paclitaxel induced peripheral neuropathy in Asians and common to Europeans and Asians. Two genes, AIPL1 and BCR, were functionally validated in a stem cell-derived neuronal cell model. This approach may help prioritize target genes associated with peripheral neuropathy, leading to the development of future neuroprotective agents and personalized cancer treatments.The human papillomavirus (HPV) oncoproteins are attractive targets for cancer immunotherapy, but evidence that human T cells directed against these antigens can target HPV+ tumors is limited. Draper and colleagues identified from the TIL of a patient with metastatic anal cancer a high avidity T-cell receptor (TCR) targeting HPV-16 E6. They found that T cells genetically engineered to express this TCR were capable of recognizing HPV-16+ oropharyngeal and cervical cancer cell lines. This research provides the preclinical basis for a clinical trial of TCR genetically engineered T cells targeting HPV-16 E6 that is now active.Tumor development is a dynamic process with genetic heterogeneity observed both in space and time. To investigate the genomic landscape of pheochromocytoma, Crona and colleagues investigated 136 tumor samples from 94 patients and describe genetic heterogeneity at all levels: between patients, between different tumor lesions of the individual patient, and within tumor lesions. Of particular notice are the observed pregnant differences between paired primary and metastatic tumor lesions. Clonal classification allowed for reconstructing the life history of individual tumors identifying somatic mutations as well as specific copy number losses as early events in pheochromocytoma tumorigenesis.