Objective: Hepatocellular carcinoma (HCC) is frequently diagnosed in patients with late-stage disease who are ineligible for curative surgical therapies. The majority of patients become resistant to sorafenib, the only approved first-line therapy for advanced cancer, underscoring the need for newer, more effective drugs. The purpose of this study is to expedite identification of novel drugs against sorafenib resistant (SR)-HCC. Methods: We employed a transcriptomics-based drug repurposing method termed connectivity mapping using gene signatures from in vitro-derived SR Huh7 HCC cells. For proof of concept validation, we focused on drugs that were FDA-approved or under clinical investigation and prioritized two anti-neoplastic agents (dasatinib and fostamatinib) with targets associated with HCC. We also prospectively validated predicted gene expression changes in drug-treated SR Huh7 cells as well as identified and validated the targets of Fostamatinib in HCC. Results: Dasatinib specifically reduced the viability of SR-HCC cells that correlated with up-regulated activity of SRC family kinases, its targets, in our SR-HCC model. However, fostamatinib was able to inhibit both parental and SR HCC cells in vitro and in xenograft models. Ingenuity pathway analysis of fostamatinib gene expression signature from LINCS predicted JAK/STAT, PI3K/AKT, ERK/MAPK pathways as potential targets of fostamatinib that were validated by Western blot analysis. Fostamatinib treatment reversed the expression of genes that were deregulated in SR HCC. Conclusion: We provide proof of concept evidence for the validity of this drug repurposing approach for SR-HCC with implications for personalized medicine.

Macrophages, key players in the myeloid series, are vital for innate immunity, inflammation, pathogen elimination, host defense, and tissue repair. Their polarization can produce M1 and M2 phenotypes. At locations of tissue damage, M1 macrophages are triggered by TLR agonists or IFN-γ, leading to the production of pro-inflammatory cytokines such as IL-1β, TNF-α, IFN-γ, and IL-12, as well as reactive oxygen species (ROS). In contrast, M2 macrophages that IL-4 and IL-13 have stimulated produce TGF-β, IL-6, and IL-10, which are anti-inflammatory cytokines. Additionally, these cells transform arginine into ornithine, which stimulates the production of collagen and cell division, which are essential for wound healing, neoangiogenesis, and tissue remodeling. The regulation of damage, inflammation, and tissue repair depends on macrophages’ capacity to dynamically alter their phenotype in response to external stimuli, including signals from pathogens, dying cells, and activated lymphocytes. M2 macrophages sustain tumor microenvironments, encourage endothelium development, and progress malignancy in neoplastic tissues. This chapter delves into the complex interplay of macrophage polarization, metabolism, and the advancement of illness. It emphasizes the molecular pathways, activation states, and potential therapeutic applications in conditions such as inflammation, cancer, cardiovascular diseases, and other afflictions.