Recently, precision medicine has enabled biomarker-driven treatment to be administered in a pan-tumor setting, so-called tissue-agnostic therapy. This represents a paradigm shift in cancer care from conventional cancer type-specific to biomarker-centric care, where patients are selected for this type of therapy based on molecular aberrations that occur across cancer types, regardless of tumor site or histology. This approach is particularly important because it offers new treatment options for patients with rare cancers or for whom there are no adequate treatments. Therefore drug development with the goal of tissue agnosticism can accelerate drug approval and address unmet medical needs. Herein, we discuss our opinions on the hallmarks of tissue-agnostic treatments and propose strategies for early drug discovery based on these hallmarks.

Epigenetic dysregulation characterized by aberrant DNA hypermethylation is a hallmark of cancer, and it can be targeted by hypomethylating agents (HMAs). Recently, we described the superior therapeutic efficacy of a novel HMA, namely, NTX-301, when used as a monotherapy and in combination with venetoclax in the treatment of acute myeloid leukemia. Following a previous study, we further explored the therapeutic properties of NTX-301 based on experimental investigations and integrative data analyses. Comprehensive sensitivity profiling revealed that NTX-301 primarily exerted anticancer effects against blood cancers and exhibited improved potency against a wide range of solid cancers. Subsequent assays showed that the superior efficacy of NTX-301 depended on its strong effects on cell cycle arrest, apoptosis, and differentiation. Due to its superior efficacy, low doses of NTX-301 achieved sufficiently substantial tumor regression in vivo. Multiomics analyses revealed the mechanisms of action (MoAs) of NTX-301 and linked these MoAs to markers of sensitivity to NTX-301 and to the demethylation activity of NTX-301 with high concordance. In conclusion, our findings provide a rationale for currently ongoing clinical trials of NTX-301 and will help guide the development of novel therapeutic options for cancer patients.

The role of TRIM51 as a multipurpose biomarker in melanoma Byungho Lim