Highlights of This Issue Free

Phosphorylated p68 RNA helicase is overabundant in cancers such as triple-negative breast cancer (TNBC), promoting epthithelial-mesenchymal transformations through β-catenin and up-regulation of Snail1. Capasso and colleagues therefore designed an inhibitor for phosphorylated p68, which they call RX-5902, as a novel strategy to disrup. Wnt-independent β-catenin signaling. The anti-cancer activity of RX-5902 was verified in a range of TNBC cell lines, as well as in animal models derived from cell lines and patients (PDX). Due to its potent activity and previously determined tolerability in a phase I trial at the determined dose of 250 mg, RX-5902 is a promising new approach to treating TNBC patients.

Genomic sequencing of pancreatic ductal adenocarcinoma has begun to identify actionable alterations in patients, most notably in the DNA damage response (DDR) genes. These alterations render the cancer cells sensitive to DNA damaging agents like PARP inhibitors. In this review article, Armstrong and colleagues describe ATM, one of the most commonly mutated DDR genes. The elaborate on ATM's role in initiating DNA repair, describe the landscape of ATM deficiency in PDAC patients, and outline the clinical trials targeted at the ATM pathway.

B-cell maturation antigen (BCMA) is an ideal target for the treatment of multiple myeloma. Therefore, research has developed two approaches to targeting BCMA: CD3 bispecific antibodies and antibody-drug conjugates. In this study, Panowski and colleagues develop a CD3 bispecific and antibody-drug conjugate from the same antibody in order to compare their efficacy and safety. Both modalities were potent in the treating an orthotopic myeloma xenograft and primary patient cells. However, the CD3 bispecific antibody showed more consistent killing of primary patient cells and a more favorable toxicity profile in cynomolgus monkeys. Therefore, the researchers recommended the bispecific candidate for entry into their Phase I clinical trial.

Gaining local control is an important aspect in treating inflammatory breast cancer (IBC). Even though the PARP1 inhibitors AZD2281 (olaparib) and ABT-888 (veliparib) had very limited single agent efficacy in IBC, Michmerhuizen and colleagues demonstrate that they are potent radiosensitizers at sub-micromolar concentrations in this breast cancer subtype. This effect was due to the delayed repair of double-strand DNA breaks and was partially dependent on BRCA1 mutational status. The efficacy in vitro against IBC cell models and in vivo against cell line-derived xenografts provides rationale for opening phase II randomized trials of radiation and PARPi for women with IBC.