Overexpressed cell-surface receptors play a crucial role as biomarkers in immunodiagnostics and immunotherapy. Epithelial cell adhesion molecule (EpCAM) is a 40 kDa cell-membrane glycoprotein associated with cell differentiation, survival, migration, and proliferation. The structure, biological functions, and role of EpCAM in tumorigenesis have been extensively studied, including its involvement in metastasis, tumor cellular signaling, and pro-proliferating pathways. It is differentially overexpressed on the surface of several tumor types, with substantial evidence suggesting a positive correlation with poor disease prognosis and overall survival. Consequently, it has emerged as a significant target for immunotherapy development, with some of them already entering clinical evaluation and one having been approved by the U.S. Food and Drug Administration to date. Pre-clinical and clinical studies evaluating anti-EpCAM immunotherapies have reported diverse outcomes necessitating critical assessment in considering future therapy development. EpCAM-targeting immunotherapies including monoclonal antibodies, adoptive cell transfer therapy, immunocytokines, recombinant immunotoxin, and bispecific T-cell engagers have been studied as monotherapy or in combination with other treatments resulting in improved outcomes. Depending on disease status, EpCAM-targeting therapies are studied in adjuvant and neoadjuvant settings by integrating the clinical features of patients and treatment intent. However, the wide range of adverse events reported in various unsuccessful clinical studies has implications for future clinical trial designs, patient stratification, and endpoint criteria measures. This review examines the efficacy and toxicity profiles of anti-EpCAM immunotherapeutic approaches that have undergone clinical investigations for the treatment of antigen-positive malignancies and provides perspectives to guide future research and development strategies toward precision medicine.

Ovarian cysts are fluid-filled sacs located in or on the surface of the ovaries. They can affect women of all ages but are most commonly seen in those of reproductive age and postmenopausal women. The two primary types of ovarian cysts are functional and pathological. Due to their asymptomatic nature, ovarian cysts are frequently diagnosed at later stages, potentially limiting therapeutic options and negatively affecting patient outcomes. Early detection requires diagnostic modalities that can differentiate between benign and malignant ovarian lesions. One promising approach is the use of immunocytochemistry (ICC) in the diagnosis of ovarian cysts, a rapidly evolving method in ovarian pathology. ICC utilizes antibodies to detect and visualize specific cellular antigens (proteins) in cytology specimens, serving as an ancillary diagnostic technique for establishing empirical diagnoses, predicting biomarkers, and assessing prognosis. A standard ICC protocol entails sample preparation, fixation, permeabilization, blocking, immunolabeling, counter-staining, and microscopic imaging of stained cells. Specific biomarkers play a significant role in distinguishing between benign and malignant ovarian cysts. Commonly used biomarkers include Cancer antigen 125, Ki-67, p53, HE4, and WT1. Future directions in this field are likely to focus on multiplex ICC, the discovery of novel biomarkers, the integration of artificial intelligence with other diagnostic modalities, and improving the standardization of ICC practice. Integrating these biomarkers into ovarian pathology will enable accurate diagnosis with reduced turnaround times, overcoming the limitations of hematoxylin and eosin staining methods.

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have transformed the therapeutic landscape for hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, demonstrating significant efficacy in both early and advanced stages of the disease. Combined with endocrine therapy, these inhibitors have dramatically improved survival outcomes. However, resistance to CDK4/6 inhibitors inevitably develops, posing a significant challenge in clinical management. Resistance to CDK4/6 inhibitors can develop through inherent and acquired fashions, and their mechanisms are explored in this comprehensive review. Inherent resistance arises from pre-existing genetic or signaling pathway alterations that diminish cancer cell sensitivity to CDK4/6 inhibitors. Acquired resistance, on the other hand, develops over time through mechanisms, such as the activation of alternative signaling pathways or changes in the tumor microenvironment. The review also examines potential biomarkers for predicting resistance, especially circulating tumor DNA markers, and discusses strategies to overcome resistance. These include combination therapies targeting multiple pathways simultaneously, sequential approaches to delay the onset of resistance, and the development of next-generation CDK4/6 inhibitors with improved efficacy and reduced resistance potential. Understanding resistance mechanisms and developing effective countermeasures are crucial for optimizing patient outcomes and extending the clinical benefits of CDK4/6 inhibitors in cancer therapy. Leveraging these insights will enable clinicians to personalize treatment strategies, ultimately enhancing the long-term effectiveness of CDK4/6 inhibitors in managing breast cancer.

WD repeat domain 4 (WDR4) is an essential member of the WD-repeat protein family, known for its regulatory roles in cellular processes critical to cancer development, including RNA modification, protein stability, cell cycle progression, and apoptosis. Studies have shown that WDR4 plays a pivotal role in tumorigenesis across various cancer types, with a particular focus on breast cancer in this study, where its overexpression is closely associated with aggressive tumor characteristics and poorer patient outcomes. As a scaffold protein, WDR4 is involved in N7-methylguanosine tRNA methylation and ubiquitin-mediated protein degradation, thereby regulating RNA stability, protein synthesis, and cell survival. This review provides a comprehensive analysis of WDR4’s molecular mechanisms, its oncogenic functions across different cancer types, and its interactions with other key factors in the tumor microenvironment, further exploring its potential role in tumor progression. As research on WDR4 progresses, we not only gain a deeper understanding of its complex role in tumor biology but also uncover new therapeutic avenues. In particular, the potential of WDR4 as a biomarker and therapeutic target is increasingly recognized. Despite the challenges faced in its clinical application, such as the difficulty in developing targeted therapies and managing side effects, the future prospects of WDR4 in cancer diagnosis and treatment remain promising, and it is expected to emerge as an effective therapeutic target in the near future.

Pancreatic cancer is a malignant tumor associated with a high mortality rate. This research presents a systems biology approach to explore the mechanisms of pancreatic ductal adenocarcinoma (PDAC), aiming to identify significant biomarkers that can serve as drug targets. We propose a systematic drug repurposing strategy that incorporates a deep neural network (DNN)-based drug-target interaction (DTI) model along with drug design specifications to develop a potential multi-molecule drug for PDAC treatment. We first established candidate protein-protein interaction networks and gene regulatory networks using big data mining techniques. Real PDAC and non-PDAC genome-wide genetic and epigenetic networks (GWGENs) were systematically identified using their corresponding microarray data through system identification and system order detection methods. The top 6,000 core GWGENs of PDAC and non-PDAC were extracted using the Principal Network Projection method. Subsequently, we annotated the core GWGENs using the Kyoto Encyclopedia of Genes and Genomes pathways to construct their respective core signaling pathways. By comparing upstream microenvironmental factors, core signaling pathways, and downstream aberrant cellular functions between PDAC and non-PDAC, we investigated the carcinogenic mechanisms of PDAC. Notably, c-MYC, forkhead box O3, and tumor suppressor p53 were identified as significant biomarkers for potential drug targets. Furthermore, the DNN-based DTI model predicted the interaction probabilities between candidate molecular drugs and these biomarkers. Based on drug design specifications such as regulatory ability, sensitivity, and toxicity, suitable multi-molecular potential drugs were selected. Ultimately, gemcitabine and MK-2206 were identified as a promising multi-molecular drug combination for PDAC treatment.

Recent research highlights the significant roles of microRNAs (miRNAs) in various diseases, particularly cancer, where they serve as diagnostic and prognostic markers. This study focuses on colorectal cancer (CRC) by examining the expression of six specific miRNAs, miR-20a, miR-21, miR-29a, miR-31, miR-92a, and miR-224, in 81 tumor samples compared to matched normal tissues. We assessed the expression levels of six target genes, SMAD4, PTEN, TGFBRII, BCL2, KLF4, and RASA1, using reverse transcription quantitative polymerase chain reaction and immunohistochemistry. Our results indicated a significant upregulation of miR-20a, miR-21, miR-29a, and miR-31 in tumor samples, alongside a decrease in TGFBRII mRNA expression. Correlation analyses demonstrated that high levels of miR-20a were inversely related to both mRNA and protein levels of PTEN. Elevated expressions of miR-21 and miR-224 were associated with lower mRNA and protein levels of TGFBRII. Furthermore, increased levels of miR-29a and miR-31 showed an inverse relationship with mRNA and protein levels of RASA1. These findings suggest a strong link between upregulated miRNAs and downregulated target genes, indicating their significant roles in CRC carcinogenesis. Notably, the upregulation of miR-20a, miR-21, miR-29a, and miR-31 may serve as effective biomarkers for differentiating CRC from normal mucosa, potentially enhancing screening strategies in the general population.

Decades of efforts to target the “undruggable” Kirsten rat sarcoma viral oncogene homolog (KRAS) oncoprotein yielded promising results in 2021 with the approval of Sotorasib, a KRAS(G12C) inhibitor for non-small cell lung cancer patients with the KRAS(G12C) variant. Before Sotorasib’s approval, developing KRAS(G12C) covalent inhibitors faced challenges, particularly their inability to preserve the KRAS protein in the GDP-bound state, which hindered clinical trial progression. Considering the importance of developing inhibitors targeting KRAS(G12C), we aimed to identify compounds analogous to Sotorasib, resulting in the discovery of a total of 174 Sotorasib scaffold-compounds. We then performed covalent docking-based virtual screening to examine the binding affinity of Sotorasib-like compounds to KRAS(G12C). Four compounds showed comparable binding energies according to Glide score to Sotorasib for targeting KRAS(G12C). Subsequently, molecular dynamics (MD) simulations were conducted for these four compounds, spanning 100 ns, 300 ns, and 500 ns durations, to identify the most stable complex with the lowest root-mean-square deviation (RMSD), similar to the KRAS(G12C)-Sotorasib reference complex. Additional dynamic cross-correlation matrix and PCA were performed as post-MD analyses to investigate the movements of two switches and the flexible regions of KRAS(G12C)-Sotorasib and -C02b complexes. As a result, among these four compounds, KRAS(G12C)-C02b was found as the optimal candidate. Further investigations beyond this study may provide more insight into C02b’s inhibitory effect on KRAS(G12C), offering a deeper understanding of its potential as a therapeutic agent.

Homoharringtonine (HHT) has been used in leukemia therapy since the 1970s. Its inhibitory effects on solid tumors have attracted increasing interest and have been actively explored in recent years. This study investigates the therapeutic effects and pharmacological mechanisms of HHT on pancreatic cancer, focusing on mitochondrial energy metabolism and macrophage sensitivity to HHT. HHT significantly inhibited the proliferation and colony formation of pancreatic cancer cell lines PANC-1 and Pan02 in vitro and suppressed tumorigenic potential in vivo. The mechanistic study revealed that HHT induced a significant elevation of reactive oxygen species (ROS) levels in pancreatic cancer cells over time, as evidenced by the enhanced dichlorodihydrofluorescein diacetate fluorescence and an elevated NAD+/NADH ratio. This resulted in mitochondrial respiratory dysfunction, including reductions in basal respiration, maximal respiration, and adenosine triphosphate production. In addition, HHT caused cell cycle arrest and disrupted the cytoskeleton, thereby inhibiting cell division and proliferation. The anti-tumor effects of HHT were further evaluated using a subcutaneous pancreatic tumor-bearing mouse model, showing that HHT inhibited the proliferation of pancreatic tumor cells in vivo, which led to reduced tumor mass. Moreover, HHT significantly reduced the viability of macrophages both in vitro and in vivo, leading to the depletion of tumor-associated macrophages in the tumor microenvironment (TME), thereby alleviating immune suppression. In conclusion, HHT effectively inhibits pancreatic cancer progression through upregulating cellular ROS levels over time, thereby disrupting mitochondrial respiratory capacity in tumor cells and reducing macrophage populations, contributing to TME reprogramming and immune restoration.

Despite the demonstrated safety and efficacy of pyrotinib and capecitabine in treating human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, their efficacy in recurrent breast cancer in which the HER2 status has changed to negative remains unexplored. Here, we report a case of a 38-year-old female diagnosed with invasive ductal adenocarcinoma of the left breast, staged as mcT2N0M0. Fluorescence in situ hybridization (FISH) confirmed that the tumor was hormone receptor (HR) positive with low HER2 expression (2+) and a HER2/CEP17 ratio of 3.56. Following neoadjuvant targeted therapy and chemotherapy, she underwent a modified radical mastectomy. Post-surgical histopathological examination revealed a non-pathological complete response, classified as ypT1cypN1M0. The tumor remained HR positive with low HER2 expression (2+), but the FISH result was negative (HER2/CEP17 ratio of 1.65). For 1 year, she was administered dual-targeted therapy with goserelin and exemestane. Sequential therapy with neratinib was initiated; however, it was discontinued due to grade IV diarrhea. Despite ongoing endocrine therapy, she experienced tumor recurrence on the left chest wall. A biopsy of the recurrent lesion revealed it to be HR positive with low HER2 expression (2+) and a negative FISH result (HER2/CEP17 ratio of 1.33). The recurrent lesion responded to combination therapy consisting of pyrotinib and capecitabine, with tolerable adverse events. This case highlights the potential advantages of combining pyrotinib and capecitabine when the HER2 status changes to negative following systemic therapy.

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide and the third most common cancer in Thailand. Approximately 2% - 5% of CRC cases are associated with inherited cancer syndromes, whereas the majority is sporadic. Herein, we have reported the case of a 32-year-old male with poorly differentiated middle rectal adenocarcinoma (T4bN1M1, Stage IV) that was refractory to fluoropyrimidine-based chemotherapy. Genetic profiling revealed a homozygous c.934-2A>G mutation in the MUTYH gene, which disrupted the DNA repair. Despite palliative radiation (30 Gy in 10 fractions) and systemic therapies (capecitabine plus oxaliplatin + panitumumab and fluorouracil, leucovorin, and irinotecan + bevacizumab), the disease progressed rapidly. Third-line therapy with Irinotecan plus oxaliplatin demonstrated initial success (partial response). Eventually, disease progression ensued. This report highlights the challenges of managing CRC caused by biallelic MUTYH mutations and emphasizes the importance of comprehensive genomic profiling for guiding therapeutic decisions. A review of similar cases in the literature is also presented.

Polypoid melanoma (PM) is a variant of nodular melanoma characterized by exophytic growth, an irregular surface, and a cauliflower-like appearance. Its reported incidence varies widely, ranging from 2% to 43%, and it is associated with a poor prognosis. This study presents a case of this rare melanoma subtype, along with its demographic characteristics, as reported in the international literature. PM is recognized as an independent risk factor in the evolving landscape of melanoma and requires tailored management strategies. Dermatologists and surgical oncologists should maintain a high level of suspicion to improve patient outcomes.