Mechanism-Centric Approaches for Biomarker Detection and Precision Therapeutics in Cancer

Biomarker discovery is at the heart of personalized treatment planning and cancer precision therapeutics, encompassing disease classification and prognosis, prediction of treatment response, and therapeutic targeting. However, many biomarkers represent passenger rather than driver alterations, limiting their utilization as functional units for therapeutic targeting. We suggest that identification of driver biomarkers through mechanism-centric approaches, which take into account upstream and downstream regulatory mechanisms, is fundamental to the discovery of functionally meaningful markers. Here, we examine computational approaches that identify mechanism-centric biomarkers elucidated from gene co-expression networks, regulatory networks (e.g., transcriptional regulation), protein–protein interaction (PPI) networks, and molecular pathways. We discuss their objectives, advantages over gene-centric approaches, and known limitations. Future directions highlight the importance of input and model interpretability, method and data integration, and the role of recently introduced technological advantages, such as single-cell sequencing, which are central for effective biomarker discovery and time-cautious precision therapeutics.

Tumor-macrophage crosstalk: how to listen

The tumor microenvironment contains many cellular components influencing tumor behaviors, such as metastasis, angiogenesis and chemo-resistance. Tumor-associated macrophages (TAMs) are one of such components that can also manipulate the overall prognosis and patient survival. Analysis of tumor-macrophage crosstalk is crucial as tumor cells can polarize circulatory monocytes into TAMs. Such trans-polarization of macrophages support tumor mediated evasion and suppression of immune response. Additionally, such TAMs significantly influence tumor growth and proliferation, making them a potential candidate for precision therapeutics. However, the failure of macrophage-dependent therapies at clinical trials emphasizes the fault in current perception and research modality. This review discussed this field’s progress regarding emerging model systems with a focused view on the in vitro platforms. The inadequacy of currently available models and their implications on existing studies also analyzed. The need for a conceptual and experimental leap toward a human-relevant in vitro custom-built platform for studying tumor-macrophage crosstalk is acknowledged.

PHOTACs enable optical control of protein degradation

PROTACs (PROteolysis TArgeting Chimeras) are bifunctional molecules that target proteins for ubiquitylation by an E3 ligase complex and subsequent degradation by the proteasome. They have emerged as powerful tools to control the levels of specific cellular proteins. We now introduce photoswitchable PROTACs that can be activated with the spatiotemporal precision that light provides. These trifunctional molecules, which we named PHOTACs (PHOtochemically TArgeting Chimeras), consist of a ligand for an E3 ligase, a photoswitch, and a ligand for a protein of interest. We demonstrate this concept by using PHOTACs that target either BET family proteins (BRD2,3,4) or FKBP12. Our lead compounds display little or no activity in the dark but can be reversibly activated with different wavelengths of light. Our modular approach provides a method for the optical control of protein levels with photopharmacology and could lead to new types of precision therapeutics that avoid undesired systemic toxicity.