Recurrent platinum-resistant ovarian cancer represents a significant therapeutic challenge, characterized by poor responses to standard chemotherapy and limited survival outcomes. This chapter comprehensively reviews the biological mechanisms underlying platinum resistance, including alterations in DNA repair pathways, intracellular drug transport, evasion of apoptosis, tumor microenvironment adaptations, and cancer stem cell dynamics. Emerging therapies targeting these mechanisms are discussed in detail, along with promising strategies that combine these therapies. Clinical trial data are discussed to highlight advances in overcoming platinum resistance and the potential for biomarker-driven treatment approaches. The chapter emphasizes the importance of targeting tumor heterogeneity and resistance mechanisms through novel therapies and personalized strategies to improve outcomes in patients with recurrent platinum-resistant ovarian cancer.

Circulating mRNA has emerged as a promising biomarker in head and neck cancer (HNC). These molecules provide real-time insight into the inflammatory tumour microenvironment and systemic immune modulation. Understanding inflammation-related circulating mRNAs can help link tumour biology with clinical outcomes.

Renal medullary carcinoma (RMC) is a rare but highly aggressive kidney cancer that resists conventional therapies. To identify therapeutic targets, this study employs histopathologic, genomic, and transcriptomic profiling of 25 RMC samples. TROP2, EPCAM, CLDN6, and CDH6 are significantly overexpressed compared with other renal and solid tumors. Pathway analyses indicate Hippo pathway upregulation and a tumor microenvironment rich in fibroblasts and neutrophils. We subsequently explore treatment of four heavily pretreated patients, all with high TROP2 expression, using sacituzumab govitecan, a TROP2-targeted antibody-drug conjugate. Of these four patients, one patient achieves a partial response with symptom improvement, two patients maintain stable disease, and the median progression-free survival reaches 2.9 months. This study represents the most extensive molecular characterization of RMC to date, identifying TROP2 and other potential therapeutic targets. Sacituzumab govitecan demonstrates potential clinical benefit, warranting further evaluation in prospective trials to confirm its efficacy and explore additional targets identified herein.

As crucial post-transcriptional regulators, microRNAs (miRNAs) serve as valuable biomarkers for disease diagnosis and precision medicine. Current detection technologies (e.g., Luminex xMAP), however, suffer from technical limitations including elevated coefficient of variation and suboptimal sensitivity. To address these challenges, we developed an innovative imaging-based detection system leveraging DNA self-assembly and fluorescence barcoding technologies. Our system demonstrates two breakthrough features: (1) Programmable DNA assemblies facilitate highly specific target recognition with built-in signal amplification, achieving enhanced sensitivity through magnetic bead-mediated target enrichment; and (2) A rationally designed four-color fluorescent encoding system can generate 33 unique barcode combinations, from which we select 10 barcode combinations that allow multiplexed detection of 10 miRNAs in a single-tube reaction vessel. Validation studies using breast cancer cell lines (MCF-7) confirmed the system's robust performance in complex biological matrices. Our platform offers distinct advantages of streamlined workflow, cost-effectiveness and superior reproducibility, and is expected to provide a new technical means for early tumor screening and precision medicine.

Lorlatinib has demonstrated significant efficacy for treating anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC); however, its safety profile-particularly regarding immune-related adverse events-remains incompletely characterized. We describe a case of ALK-positive NSCLC complicated by autoimmune thyroiditis during lorlatinib therapy. The temporal link between lorlatinib exposure, the emergence of thyroid autoantibodies, and their resolution following drug withdrawal raises the possibility that lorlatinib may influence autoimmune responses.

Hepatoblastoma is a primary malignant liver tumor in children, thought to arise from abnormal liver development during the fetal period. Approximately 90 % of cases harbor activating mutations in CTNNB1, which encodes β-catenin, while other genetic mutations are rare. Recent studies have shown that CTNNB1 mutations are frequently accompanied by increased expression of the transcriptional coactivator YAP, which promotes cell proliferation and suppresses apoptosis. Based on these findings, we established a hepatoblastoma model by introducing constitutively active forms of CTNNB1 and YAP into human induced pluripotent stem cell (iPSC)-derived hepatoblasts. Cells transduced with both genes showed distinct morphological changes and upregulation of CTNNB1, YAP, and their downstream target genes. RNA-seq followed by Gene Set Enrichment Analysis (GSEA) revealed that the gene expression profile of these cells closely matches that of hepatoblastoma patients. Utilizing this model, we identified Prostate-Associated Gene 4 (PAGE4) as a novel candidate gene involved in hepatoblastoma progression. Furthermore, immunohistochemistry of hepatoblastoma specimens confirmed that PAGE4 is indeed expressed at higher levels compared to normal liver tissue. Functional analysis in hepatoblastoma cell lines demonstrated that PAGE4 plays a role in promoting cell proliferation and resistance to apoptosis. Since PAGE4 is a known cancer/testis antigen with tumor-specific expression, our findings highlight it as a novel and promising therapeutic target for hepatoblastoma, particularly in the context of cancer immunotherapy.

GLI1-altered mesenchymal tumors are a group of soft tissue tumors that have emerged as a new entity, in large part, as a result of increased next-generation sequencing (NGS)-based DNA and RNA sequencing of tumors. Over the last decade, multiple case reports and small series have reported such tumors involving multiple sites (including soft tissue, head and neck and viscera). They appear to have rather distinctive morphology and can either show GLI1-gene fusions or GLI1-gene amplifications. Although cases with metastasis are increasingly recognized, definite morphologic indicators of metastasis have not yet been identified. In this review, we focus on GLI1-altered mesenchymal tumors of the head and neck, with an emphasis on clinicopathologic features, molecular findings and approach to the diagnosis.

Circ-CCDC66 (circular-Coiled-coil domain-containing protein 66) has been implicated in therapy resistance in colorectal and gastric cancers, but its role in breast cancer remains poorly understood.

Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy with a heterogeneous prognosis. To date, there are no reliable circulating biomarker to predict clinical outcomes in ACC. Agouti-related peptide (AgRP), an orexigenic hypothalamic neuropeptide, is also produced by the adrenal gland. However, its expression in adrenal tumours remains unexplored.

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is an autosomal dominant syndrome characterized by polyposis localized in the gastric body and fundus with a strong tendency for adenocarcinoma. The genetic mutations that accumulate during the progression from normal mucosa through polyp to carcinoma in GAPPS remain unclear. We investigated the evolutionary process from normal mucosa to polyp and carcinoma in GAPPS. Through comprehensive mutational and transcriptome analyses, we aimed to provide insights into the biology of this disease. Whole-exome sequencing and RNA sequencing were performed on carcinoma, polyp, and normal mucosa samples from multiple sites from seven patients with GAPPS (n = 54 samples). We comprehensively investigated genomic alterations (including copy number alterations and somatic mutations), clonal architecture, and transcriptome dynamics during carcinogenesis. Genomic evolutionary analysis showed that in GAPPS, somatic mutations of APC occur in carcinoma and polyp while mutations of KRAS additionally occur in carcinoma. We also found the co-occurrence of APC and KRAS mutations in carcinoma recurrently both across cases and within subclones of the same case. The co-occurrence of APC/KRAS mutations may contribute to the carcinogenesis of GAPPS. Our study provides detailed information on the genomic and transcriptomic landscape in GAPPS carcinogenesis, conferring valuable insights into its underlying mechanisms.

Pediatric acute-myeloid-leukemia (pAML) is an aggressive malignancy and the second most common blood cancer in children. In spite of significant advances in the frontline therapeutic approaches, approximately 50% of pAML patients show poor prognosis and relapse. Though drugs show positive response against the cancer cells initially, however, it becomes resistant in the long run of treatment, requiring the use of alternative drugs. Therefore, this study aimed to discover pAML-causing druggable molecular signatures highlighting their pathogenetic processes and alternative therapeutic agents. To address these issues, at first, we performed an integrated single-cell RNA sequencing (scRNA-seq) profile analysis of two datasets with accession IDs GSE154109 and GSE235923, which revealed 6 pAML-related key cell types (Erythroid cells, GdT-cells, Naive B-cells, Naive CD4 T-cells, Non-Classical Monocytes, and T-regs) and 198 common differentially expressed genes (cDEGs) between pAML and healthy groups. The protein-protein interaction (PPI) analysis yielded top-ranked eight cDEGs (JUN, MDM2, FOS, SOD2, FBXW7, CHD3, MCL1, and MAP2K1) as common key genes (cKGs) across the key cell types. Disease-cKGs enrichment analysis further confirmed the relevance of these genes to pAML and other leukemic diseases. Regulatory network analysis identified top four transcription factors (FOXC1, GATA2, RELA, and TP53) and three microRNAs (hsa-let-7a-5p, hsa-let-7e-5p, hsa-miR-15a-5p) that regulate these cKGs. Gene ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis results reflected their potential roles in pAML pathogenesis. Pathway perturbation analysis through gene-set enrichment analysis (GSEA) tool identified significantly perturbed pathways, highlighting how they are altered in pAML environment and how the cKGs are linked in the process. Subsequently, three potential therapeutic candidates (IRINOTECAN HYDROCHLORIDE, IMATINIB and IBRUTINIB) were disclosed through an integrative strategy combining molecular docking, drug-likeness, ADME/T, and DFT analyses. Molecular dynamics (MD) simulation studies for the top three drug-target complexes indicated the stability of complexes. Thus, the findings potentially offer valuable insights for pAML pathogenesis and effective therapeutic candidates for pAML patients.

Radiotherapy is a primary treatment for intermediate and advanced cervical cancer (CC). Resistance to radiotherapy is a principal reason for treatment failure in synchronous applications, yet the molecular mechanisms remain poorly understood. Identifying reliable prognostic markers to predict and evaluate patient outcomes is essential for advancing therapeutic strategies. This study aims to address this need by developing a prognostic prediction model for concurrent radiotherapy in CC, utilizing both single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing data.

Basal cell nevus syndrome (Gorlin syndrome) is a rare genetic condition characterized by multiple basal cell carcinomas, often arising before age 20.  Most cases result from a mutation in the patched 1 gene-part of the sonic hedgehog pathway. Rarely, this condition is related to a suppressor of fused gene mutation, which occurs downstream from Smoothened, and is unresponsive to Smoothened inhibitors including vismodegib and sonidegib. Notably, basal cell nevus syndrome, secondary to a suppressor of fused gene mutation, is associated with a higher incidence of childhood medulloblastoma with implications for the patient and offspring.  A 72-year-old man with pearly papules coalescing into plaques across the nose and cheeks presented. The lesions had appeared as a teenager, and the patient reported his sister had similar lesions. Five biopsies, reviewed by three dermatopathologists, were consistent with basal cell carcinoma. Genetic testing was negative for patched 1 and patched 2 mutations but positive for a heterozygous suppressor of fused mutation. Patients with basal cell nevus syndrome should be treated with surgical excision, counseled on sun protection, screened and monitored for complications, and treated with vismodegib (if associated with patched 1 mutation) or itraconazole (if associated with suppressor of fused mutation).

Clear cell renal cell carcinoma (ccRCC) is the most common type of RCC. Apoptosis, pyroptosis, and necroptosis are key regulatory processes in carcinogenesis. Accumulating evidence indicated significant crosstalk among three forms of cell death, which is termed as the PANoptosis. However, the connection between PANoptosis and ccRCC remains uncertain. Here, we utilized the TCGA and GEO database to explore distinct PANoptosis patterns based on 62 PANoptosis genes and investigated the clinical, biological, and immune cell infiltration characteristics of PANoptosis patterns. Then, we identified prognosis-related genes from PANoptosis patterns and developed a scoring system that effectively predicts clinical outcomes of ccRCC patients. We also explored the expression of key regulators to confirm these identifications. Immunological analyses revealed a positive correlation between risk score and M0 type macrophages, activated mast cells, follicular helper T cells, and regulatory T cells. Finally, the risk model demonstrated the ability to predict drug sensitivity for ccRCC, such as sorafenib, rapamycin and pazopanib. In conclusion, our findings offer novel insights into the role of PANoptosis in ccRCC and identify potential targets for controlling ccRCC.

Diffuse large B-cell lymphoma (DLBCL) is characterized by molecular complexity and heterogeneity. The SET oncoprotein is overexpressed in B-cell chronic lymphocytic leukemia and non-Hodgkin lymphoma. Acting as an intrinsic inhibitor of the tumor suppressor protein phosphatase 2A (PP2A), targeting SET has shown anti-cancer activity. In this study, we investigated the molecular mechanism of SET antagonism in DLBCL. Overexpression of SET resulted in decreased phosphatase activities of PP2A and SHP-1, while activating Lyn. Conversely, SET inhibition, either through antagonists or siRNA, led to the activation of PP2A and SHP-1, resulting in the inactivation of Lyn. Analysis of public datasets revealed upregulation of Lyn in late-stage DLBCL samples, which was associated with a worse outcome. Ectopic expression of Lyn enhanced the cell viability and migratory capacity of DLBCL cells. Notably, Lyn inhibited PP2A and SHP-1 phosphatase activities, suggesting the existence of a SET/PP2A/SHP-1/Lyn feedback loop. Immunohistochemically, SHP-1 levels were negatively correlated with pLyn/Lyn levels in DLBCL tissues. Overall, these results suggest that SET antagonism to inactivate Lyn represents an attractive approach for DLBCL treatment.

EZH2 functions as an oncogene in various cancers. However, the role of EZH2 in diffuse large B cell lymphoma (DLBCL) is scarcely reported. This study investigates the potential of EZH2 in DLBCL and the underlying mechanisms. mRNA levels were detected using reverse transcription-quantitative PCR. Protein expression was detected using Western blot. Cell viability was detected using CCK-8 assay. Cell proliferation was detected using methylcellulose colony formation. Cell migration and invasion was detected using transwell. We found that EZH2 is upregulated in DLBCL. EZH2 deficiency effectively enhances the chemosensitivity of DLBCL cells to Glofitamab, manifested by promoting Glofitamab-mediated inhibition in the proliferation, migration, and invasion of DLBCL cells. EZH2 deficiency enhances the apoptosis of DLBCL cells. Mechanistically, EZH2 mediates histone methylation of TP53INP1, resulting in its downregulation in DLBCL. TP53INP1 knockdown antagonizes the effects of EZH2 deficiency and contributes to the aggressiveness of DLBCL cells. In summary, EZH2 inhibits the progression of DLBCL via driving H3K27me3 methylation of TP53INP1. Targeting EZH2 may be a promising strategy for DLBCL.

Statins, commonly prescribed for hypercholesterolemia, have demonstrated a range of anticancer properties, including the induction of apoptosis and ferroptosis, modulation of autophagy, and reprogramming of the tumor microenvironment. These effects position statins as promising candidates for drug repurposing in oncology. However, integrating statins into cancer care will require a precision medicine approach. Despite the increasing volume of preclinical data supporting statin anticancer effects, clinical evaluation remains limited. To date, only a small number of clinical trials have investigated statins in oncology, and these have primarily focused on moderate-intensity regimens. Emerging evidence suggests that certain statins may be more effective than others as anticancer agents, with their therapeutic activity shown to be both dose- and time-dependent. This review highlights key considerations for formulating a precision cancer medicine framework for statins. These include the chemical properties and pharmacokinetics of different statins, interpatient genetic variability affecting statin response, biomarkers of statin sensitivity, the need to achieve therapeutically relevant concentrations in tumor tissue, potential synergies with existing chemotherapeutic agents, and recent advances in targeted statin delivery technologies.

The Wilms' Tumor 1 (WT1) gene has attracted significant attention in oncological research owing to its involvement in the pathogenesis of a variety of malignancies. Initially identified in association with Wilms' tumor, a pediatric renal carcinoma, WT1 is now recognized for its broader implications in the etiology of multiple cancers, including leukemia, ovarian cancer, and lung cancer. This review offers a comprehensive analysis of the historical development of WT1 research, explores its mechanisms in cancer progression, and assesses its potential as a therapeutic target, with an emphasis on its clinical implications for cancer treatment strategies.

The Notch pathway regulates the homeostasis and tumorigenesis of gastrointestinal epithelium. Given its roles in cancer stem cell capacity and cancer immunity, we hypothesized that Notch activation can predict poor prognosis and resistance to immune checkpoint inhibitors (ICIs) in gastrointestinal adenocarcinoma (GIAC). The mRNA expression and genomic alterations of Notch pathway were characterized in esophagus (ESAD), stomach (STAD), colon (COAD), or rectum (READ) adenocarcinomas from The Cancer Genome Atlas (TCGA) dataset. The prognostic model (mRNA-score) was constructed using the TCGA dataset (the training set) and was validated in 3 independent sets (GSE19417 [ESAD], GSE84437 [STAD], and GSE40967 [COAD]). The associations of the mRNA-score with drug sensitivity, immune cell infiltration, and immunotherapy efficacy were, respectively, analyzed using the Genomics of Drug Sensitivity in Cancer (GDSC) database, the TCGA dataset, and multiple clinical cohorts including GSE165252, PRJEB25780, IMvigor210, and CheckMate-009/010/025. Notch pathway genes exhibited conserved genomic/transcriptomic features across four GIAC subtypes. Three pan-GIAC clusters were determined by unsupervised clustering, and the cluster with higher expression of the Notch pathway genes had shorter overall survival (OS), immunosuppressive microenvironment, and higher scores of the signatures concerning angiogenesis, cell cycle, PI3K-AKT-mTOR, TGF-β, glycolysis, etc. A prognostic algorithm (mRNA-score) was constructed, which was correlated with poor OS in the training set (TCGA, P < 0.001) and three validation sets (GSE19417, P = 0.025; GSE84437, P = 0.001, GSE40967, P = 0.007). A high mRNA-score was linked with more "resting"/ "anti-inflammatory" rather than "activated"/ "pro-inflammatory" tumor-infiltrating immune cells and ICI resistance in GIACs (GSE165252, P = 0.047; PRJEB25780, P = 0.047) and other solid tumors such as urothelial carcinoma and clear cell renal cell carcinoma. Our findings demonstrate the utility of the Notch pathway in predicting prognosis and ICI resistance. Further studies are warranted to explore the efficacy of Notch inhibitors as immunotherapeutic adjuvants to overcome ICI resistance.

Gastric cancer (GC) represents a highly aggressive malignancy within the gastrointestinal tract. The expression of miR-3662 exhibits specificity across different tumor types, but its precise biological role in GC pathogenesis remains poorly understood. Based on the results of bioinformatics analysis, we observed that miR-3662 was significantly overexpressed in GC. Subsequently, we investigated the biological role of miR-3662 in regulating the malignant phenotype of GC cells. Bioinformatics prediction combined with dual-luciferase assay confirmed that CAB39L is a direct target of miR-3662. Functional gain- and loss-of-function experiments were conducted to explore the impact of the miR-3662/CAB39L axis on the malignant characteristics of GC cells, as well as its influence on the activation of the AMPK signaling pathway and the expression of key glycolytic proteins. The results demonstrated that miR-3662 overexpression enhanced the proliferation, invasion, and migration of AGS cells, upregulated the expression of PFKP and LDHA, while suppressing apoptosis and reducing AMPK phosphorylation. Conversely, silencing miR-3662 exhibited opposing effects in HGC-27 cells. CAB39L expression was found to be downregulated in GC tissues. Upregulation of CAB39L inhibited GC cell proliferation, invasion, and migration, decreased the expression of PFKP and LDHA, and increased both apoptosis and AMPK activation. Furthermore, overexpression of CAB39L partially counteracted the promoting effects of high levels of miR-3662 on the malignant biological phenotype of GC cells. In conclusion, this study reveals that miR-3662 acts as a carcinogenic regulator in GC by targeting CAB39L, with the underlying mechanism potentially involving the modulation of AMPK activation to enhance cellular glycolysis.