Darvishi et al. Page 1632

The oncogenic transcription factor C/EBPβ is an emerging therapeutic target for many cancers. Rotolo and colleagues present data describing ST101, a peptide antagonist that prevents C/EBPβ dimerization and enhances its proteasome-dependent degradation. ST101 attenuates C/EBPβ target gene expression, resulting in tumor-specific cytotoxicity in glioblastoma, breast, melanoma, prostate, and lung cancer cells, while normal human epithelial cells are not impacted. In vivo xenograft models indicate that ST101 induces potent tumor growth inhibition or regression, both as a single agent and in combination studies. These data identify ST101 as a promising therapeutic against C/EBPβ-dependent cancers.

Blessing et al. Page 1663

Sarcomas are malignant mesenchymal tumors for which radical resection is standard of care for localized disease. However, complete resection is often not achieved and locoregional recurrence rates are as high as 84%. Although classically chemoresistant, including paclitaxel (PTX), Blessing and colleagues demonstrate prolonged cell-cycle arrest, mitotic catastrophe, subsequent apoptosis, and irreversible cell death in CS-1 as well as patient-derived liposarcoma and leiomyosarcoma when exposed to supratherapeutic PTX levels achievable via unique biocompatible, drug-eluting polymer films implanted during tumor resection.  Re-evaluation of chemotherapeutics traditionally thought to be ineffective is warranted in the setting of enhanced supratherapeutic drug delivery platforms in vivo.

Wang et al. Page 1710

Despite the promise of immune checkpoint inhibitors (ICIs) in tumor therapy, clinical trial outcomes report toxicities, including immune-related adverse effects (irAEs). Studies suggest that irAEs from ICI may be dose-dependent. By using a gene-based approach, Wang and colleagues report the potential of a systemic low-dose single-chain antibody (scFv) therapy against PD-L1 in conferring antitumor immunity in mice models of breast and colorectal cancers. The therapy effects of a one-time application of gene-based scFv therapy was comparable to multiple infusions of an anti-PD-L1 monoclonal antibody. Further validation of this approach on T cell homeostasis may offer an alternative for ICI therapy.

Thomas et al. Page 1722

The combination of DNA-damaging agents, like inhibitors of topoisomerase I, with inhibitors of the DNA damage response (DDR) have utility for treating DDR-deficient cancers. However, their combined toxicity has severely limited their use. Thomas, Santi, and co-workers investigated the use of a long-acting topoisomerase inhibitor, PLX038, with PARP inhibitors. PLX038 monotherapy and in combination with a PARP inhibitor potently inhibited the growth of an ATM-deficient xenograft. A clinical trial of PLX038 and rucaparib was initiated and during the dose escalation phase, a patient with an ATM deficiency showed a durable, complete response after only the first cycle of treatment.