Selected Articles from This Issue

Abstract

Medulloblastoma is the most common malignant pediatric brain tumor, and despite advances in clinical approaches, currently available treatment regimens still fail children with MYC- and MYCN-driven tumors. Jonchere and colleagues conducted high throughput combination drug screens using an actively explored CDK4/6 inhibitor, ribociclib, as an anchor (the bedrock drug used in all combinations). Bromodomain and extra terminal (BET) and PI3K/mTOR inhibitors increased the ability of ribociclib to inhibit tumor cell proliferation in vitro and deplete target signaling genes in vivo. Highlighting the difficulty of translating in vitro findings in vivo, combination treatment did not significantly improve survival in tumor-bearing mice, preventing its translation to the clinic.There is an unmet medical need in several cancer indications that express the tumor associated antigen 5T4. In this paper, Nelson and colleagues describe the development of a novel bispecific antibody that stimulates 4-1BB function when co-engaged with the 5T4 expressed on tumor cells. The study shows how the design, binding epitope and molecular properties of ALG.APV-527 translates into very potent activity both in vitro and in vivo, while being well tolerated in a non-human primate toxicology study. The data demonstrates that ALG.APV-527 activates key immune cell populations such as T cells and NK cells within the tumor microenvironment while providing a wide therapeutic window, which supports clinical testing in 5T4-expressing solid malignancies.In patients with large and high-grade soft tissue sarcomas (STS), radiation therapy (RT) improves local control, but approximately 50% of patients develop lung metastases and succumb to the disease within 18 months. Therefore, alternative therapeutic approaches are urgently needed. Here, Patel and colleagues implemented the preclinical arm of a co-clinical trial in parallel with SU2C-SARC032 using a mouse model of STS, demonstrating that anti-programmed cell death protein-1 (PD-1) treatment with RT and surgery improves disease-free survival compared to surgery alone by improving local control. Furthermore, neoadjuvant RT improves local recurrence-free and metastasis-free survival compared to surgery with or without anti-PD-1 treatment.Understanding KRASG12C-inhibitor resistance is an important clinical need in KRASG12CMT CRC. In this study, Van Schaeybroeck and colleagues report a systems biology approach to identify effective KRASG12C inhibitor-based targeted therapy combinations for KRASG12CMT CRC. They identified Bcl-xL and KRASG12C-inhibition as a strategy with robust in vitro and in vivo efficacy in KRASG12CMT CRC models. Thus, this combination may represent a novel therapeutic avenue for KRASG12CMT CRC patients. KRASG12C-amplification was identified as a cause of acquired resistance to KRASG12C-inhibitor AZ'1569, and both KRASG12C-amplification and AZ'1569-resistance were reversible upon drug withdrawal, supporting the use of drug holidays in the case of KRAS amplification in patients.