Adil Farooq

Hepatocellular carcinoma (HCC), the most prevalent primary liver cancer, continues to pose a significant global health burden due to its high mortality rate. In addition to genetic alterations, epigenetic aberrations, including DNA methylation, histone modifications, chromatin remodeling, and noncoding RNA (ncRNA) dysregulation, play critical roles in HCC initiation and progression. Notably, miR-375 and miR-483-5p are among the most dysregulated miRNAs in HCC, with their altered expression levels closely associated with tumor stage and patient survival. These epigenetic modifications offer promising therapeutic avenues due to their reversibility and dynamic nature. Furthermore, specific epigenetic signatures such as CDH1 promoter hypermethylation and HOTAIR overexpression are being explored as potential biomarkers for early detection and treatment response. In this chapter, we review recent advances in the epigenetic landscape of HCC and discuss their diagnostic and therapeutic implications, highlighting their potential to improve patient outcomes through personalized medicine approaches.

Background and Objectives: Metformin, a staple in diabetes care, has recently emerged as a candidate chemotherapeutic agent. In vitro studies suggest that metformin inhibits cancer growth by altering cellular metabolism and enhancing immune responses. Clinical observations further indicate that it suppresses key tumor-promoting pathways such as mTOR and STAT3. This review critically evaluates the therapeutic potential of metformin in oncology through the lens of precision medicine. This review integrates evidence from molecular mechanisms, clinical studies, biomarker-driven trial designs, and the regulatory challenges that continue to delay its approval for oncologic use. Methods: A structured literature search (2015–2025) identified 63 relevant studies, including preclinical, clinical, and translational research. Conclusions: Although metformin shows consistent anticancer effects in laboratory and animal models, its clinical benefits in patients are variable. This inconsistency is likely due to tumor heterogeneity and a lack of biomarker-based patient selection in trials. Targeting these shortcomings through biomarker-enriched, tumor-specific clinical trials is essential to define metformin’s role as a repurposed agent in precision oncology.

Background: Oncolytic virus (OV) therapy couples direct tumor lysis with systemic immune priming, yet clinical benefit remains heterogeneous and the predictive biomarker landscape is poorly defined. We undertook a systematic review and meta-analysis to quantify the efficacy and safety of OV therapy in solid tumors and to synthesize current evidence on response-modulating biomarkers. Methods: Following PRISMA 2020 guidelines, MEDLINE, Embase, Cochrane CENTRAL, ProQuest and Scopus were searched from inception to May 2025. Phase II–III randomized trials of genetically engineered or naturally occurring OV reporting objective response rate (ORR), progression-free survival (PFS), overall survival (OS) or biomarker data were eligible. Hazard ratios (HRs) or odds ratios (OR) were pooled with random-effects models; heterogeneity was assessed with I2 statistics. Qualitative synthesis integrated genomic, immunologic and microbiome biomarkers. Results: Thirty-six trials encompassing around 4190 patients across different tumor types met inclusion criteria. Compared with standard therapy, OV-based regimens significantly improved ORR nearly three-fold (pooled OR = 2.77, 95% CI 1.85–4.16), prolonged PFS by 11% (HR = 0.89, 95% CI 0.80–0.99) and reduced mortality by 16% (OS HR = 0.84, 95% CI 0.72–0.97; I2 = 59%). Benefits were most pronounced in melanoma (ORR 26–49%; OS HR 0.57–0.79) and in high-dose vaccinia virus for hepatocellular carcinoma (HR = 0.39). Grade ≥ 3 adverse events were not increased versus control (risk ratio 1.05, 95% CI 0.89–1.24); common toxicities were transient flu-like symptoms and injection-site reactions. Biomarker synthesis revealed that high tumor mutational burden, interferon-pathway loss-of-function mutations, baseline CD8+ T-cell infiltration, post-OV upregulation of IFN-γ/PD-L1, and favorable gut microbial signatures correlated with response, whereas intact antiviral signaling, immune-excluded microenvironments and myeloid dominance predicted resistance. Conclusions: OV therapy confers clinically meaningful improvements in tumor response, PFS and OS with a favorable safety profile. Integrating composite genomic–immune–microbiome biomarkers into trial design is critical to refine patient selection and realize precision viro-immunotherapy. Future research should prioritize biomarker-enriched, rational combination strategies to overcome resistance and extend benefit beyond melanoma.

Protein–protein interactions (PPIs) are critical for cellular signaling, apoptosis regulation, and immune function in the body, and dysregulation is a hallmark of cancer. The large, dynamic, and shallow nature of PPI interfaces rendered them “undruggable” by conventional small molecules in the past. Recent advances in structural biology, chemical innovation, and artificial intelligence have revolutionized the landscape of PPI-directed drug discovery. This review summarizes the mechanistic roles of PPIs in oncogenesis, critically discusses novel therapeutic interventions, such as small molecules, peptidomimetics, stapled peptides, proteolysis-targeting chimeras (PROTACs), molecular glues, and AI-based drug optimization strategies, altering the druggable proteome in oncology. Therapeutics with clinically well-validated action, including Venetoclax and AMG 510, and next-generation candidates demonstrate the translational applications of these approaches. Some of the key challenges, such as interface complexity, specificity, bioavailability, and resistance, are addressed together with countermeasures like rational design, combination therapies, enhanced delivery systems, and biomarker-based patient selection. To this end, the incorporation of multi-omics data and artificial-intelligence (AI)-driven modeling technologies is revolutionizing the personalized cancer therapeutics development space. Collectively, these advances mark a paradigm shift: PPIs, once considered inaccessible, are now at the forefront of precision oncology, offering new hope for patients with previously intractable malignancies.