Selected Articles from This Issue

Antibody Drug Conjugates (ADCs) are poised to become a major pillar in cancer care. Extending the success of monoclonal antibodies, ADCs additionally comprise cytotoxic payloads attached in multiple ways. Alternative, smaller formats have not gained mainstream traction due to inferior efficacy owing to a shorter half-life. Stamati and colleagues describe the application of scFv antibody fragments carrying a high number of payloads which out-perform conventional ADCs. Using certain frameworks, developable (antibody fragment) FDCs become viable with cures at 0.6 mg/kg, dosed weekly like ADCs. Penetration and rapid payload tumor delivery is evident providing new options to treat solid tumors.This study addresses the urgent need for targeted therapies in triple-negative breast cancer (TNBC), an aggressive and treatment-resistant subtype. It identified HBS-101 as a first-in-class small-molecule inhibitor of Midkine (MDK), a cytokine overexpressed in various cancers. HBS-101 binds directly to MDK, disrupting its receptor interactions and downstream oncogenic signaling. The compound significantly reduced tumor growth, invasion, and brain metastases in TNBC models, while showing oral bioavailability, blood-brain barrier penetration, and minimal toxicity. These findings establish HBS-101 as a promising therapeutic candidate for MDK-driven cancers, offering new hope for patients with advanced or metastatic TNBC.Metastatic castration-resistant prostate cancer remains challenging due to the development of treatment resistance and limited therapeutic options. In this study, Busenbender and colleagues developed PeS-9, a novel 1,4-naphthoquinone-glucose conjugate targeting GLUT-1-overexpressing prostate cancer cells. PeS-9 demonstrated activity and selectivity in vitro and in vivo. The drug targeted mitochondria, induced ROS-mediated DNA damage, and androgen receptor degradation. Importantly, PeS-9 showed synergistic effects with the PARP inhibitor olaparib and inhibited tumor growth and metastasis in a mouse model without severe side effects. This study highlights PeS-9 as a promising drug candidate and underlines the feasibility of GLUT-1 targeting in prostate cancer therapy.The ataxia telangiectasia and RAD3-related (ATR) kinase functions with ataxia telangiectasia–mutated (ATM) kinase as a modulator of DNA damage response (DDR). Varadarajan and colleagues assessed the antitumor effects of the ATR inhibitor elimusertib (BAY-1895344) in patient-derived xenograft models and demonstrated antitumor activity in models with DDR alterations including ATM loss, including in models with both intrinsic and acquired PARP inhibitor resistance. Further work is needed to better refine patient selection for ATR-based therapies and optimize combination therapies.