Current Cancer Drug Targets - Volume 22, Issue 8, 2022

Immunotherapy can be considered a therapeutic revolution in oncology, with great impact on many tumor types, such as melanoma and non-small cell lung cancer. However, in metastatic colorectal cancer, the benefits in terms of prolonged tumor control and high response rate are limited to the rare subgroup of tumors with high mutation burden - mostly tumors that harbor microsatellite instability (MSI) or a deficient mismatch repair system (dMMR), or tumor microsatellite stability and damaging mutations in the exonuclease domains of POLE or POLD. The KEYNOTE-028 uncontrolled phase II trial demonstrated an impressive antitumor activity of pembrolizumab in patients with treatmentrefractory Lynch-associated tumors, including colorectal cancer. Nivolumab with or without ipilimumab confirmed the efficacy of immune checkpoint inhibitors in patients with previously treated dMMR / MSI metastatic colorectal cancer. The recent KEYNOTE-177 phase III trial demonstrated that pembrolizumab significantly reduced the relative risk of disease progression or death and improved progression-free survival in patients with treatment-naive dMMR / MSI metastatic colorectal cancer in comparison with first-line chemotherapy with or without biologics. Unfortunately, current pharmacological strategies with immunotherapy have not been successful for most patients with microsatellite stable metastatic colorectal cancer. In this review, we critically appraise the applicability of immune checkpoint inhibitors in dMMR/MSI metastatic colorectal cancer. We also discuss the recent negative trials of immunotherapy combinations in microsatellite stable tumors and more mature immunotherapy ongoing studies in the field of advanced colorectal cancer.

Background: The treatment options for GEP-NENs include various drugs and are based on grading, morphology, and location of the primary. Objective: The aim of our work is to investigate the clinical impact of new immune checkpoint inhibitors in order to define a new possible strategy of use within GEP-NENs. Methods: A scientific literature search from 2015 to January 2020 was performed using PubMed and Embase: reviews and prospective or retrospective studies with a minimum of twenty patients were selected; conference proceedings were included. Results: Several studies have been conducted to assess the role of immune checkpoint inhibitors in NENs, but nowadays, the current knowledge in this field is mainly based on phase I-II studies. Immunotherapy showed limited antitumor activity, but a higher response rate was reported in poor-differentiated neuroendocrine tumors. No specific biomarkers were identified for patient selection and response assessment. Conclusion: Immunotherapy appears as a powerful possibility to help our patients, but nowadays, we see many gaps in this field. We must balance therapeutic possibilities offered by precision oncology with an understanding of the limitations of the application of testing and treatment in clinical practice. Future efforts should focus on research of the best patients to a candidate for immunotherapy in terms of disease characteristics and previous treatments and how to select them with accurate biomarkers.

BTC is a rare and aggressive cancer disease, bearing an overall dismal prognosis with only finite therapy options. Only combination chemotherapy regimens achieve disease control, which is often only short-lived since the tumor tissue exhibits high resistance to chemotherapy. The emergence of immune checkpoint inhibitors in recent years has significantly improved the survival of cancer patients and thus, has been integrated into the therapeutic management of several solid tumors, including melanoma, colorectal carcinoma (CRC), hepatocellular carcinoma (HCC), triple- negative breast cancer (TNBC), and non-small-cell lung cancer (NSCLC). Investigation of the tumor biology of BTC and results of preliminary studies have shown that BTC may also be amenable to immunomodulation. In this review, we seek to give a comprehensive overview of the role, potential, and clinical significance of ICPI in the management of BTC.

Immunotherapy represents one of the biggest breakthroughs of the 21st century and redefined modern cancer treatment. Despite this new approach changing the treatment paradigm in various cancer entities, including lung and head-and-neck cancer, the efficacy of these treatment regimens varies in different patient subgroups, and so far, these treatment regimens have failed to meet the high expectations of gastroesophageal cancer patients. This review discusses new treatment approaches concerning immunotherapy in gastroesophageal cancer patients and sheds some light on ongoing trials and new treatment combinations.

Immunotherapy continues to redefine the solid tumor treatment landscape, with inhibitors of the PD-L1/PD-1 immune checkpoint having the most widespread impact. As the most common cancer diagnosed worldwide, there is significant interest in the development of immunotherapy for the treatment of breast cancer in both the early and metastatic settings. Recently reported results of several clinical trials have identified potential roles for immunotherapy agents alone or in combination with standard treatment for early and metastatic disease. While trials to date have been promising, immunotherapy has only been shown to benefit a select group of patients with breast cancer, defined by tumor subtype, PD-L1 expression, and line of therapy. With over 250 trials ongoing, emerging data will enable the further refinement of breast cancer immunotherapy strategies. The integration of multiple putative biomarkers and consideration of dynamic markers of early response or resistance may inform optimal patient selection for immunotherapy investigation and integration into clinical practice. This review will summarize the current evidence for immune-checkpoint blockade (ICB) in the treatment of early and metastatic breast cancer, highlighting current and potential future biomarkers of therapeutic response.

Chordoma is a rare, slow-growing sarcoma that is locally aggressive and typically resistant to conventional chemo- and radiotherapies. Despite its low incidence, chordoma remains a clinical challenge because therapeutic options for chordoma are limited, and little is known about the molecular mechanisms involved in resistance to therapies. Furthermore, there are currently no established predictive or prognostic biomarkers to follow disease progression or treatment. Whole-genome sequencing of chordoma tissues has demonstrated a low-frequency mutation rate compared to other cancers. This has generated interest in the role of epigenetic events in chordoma pathogenesis. In this review, we discuss the current understanding of the epigenetic drivers of chordoma and their potential applications in prognosis and the development of new therapies.

Background: Gastric cancer (GC) is the fourth most commonly found cancer and the second- highest cause of cancer-related death worldwide. TROP2 overexpression is closely related to many cancers, including gastrointestinal tumors. DSG2 is an important protein in cell adhesion, and its loss affects cell migration. Aims and Objective: This study aimed to explore the specific mechanism of TROP2 in promoting gastric cancer and provide a basis for the prevention and treatment of gastric cancer. Method: DSG2 was identified as an interacting protein of TROP2 in GC cells by coimmunoprecipitation and mass spectrometry. The regulated behavior of TROP2 on DSG2 expression was investigated with TROP2 over-expressure or knockdown. Cell-cell adhesion capacity mediated by DSG2 was evaluated by adhesion-related assays. Electron microscope observation was made for accessing GC tumor desmosome assembly. Proteins in EGFR/AKT and DSG2/PG/β-catenin pathways were evaluated by western blotting. Result: This study suggests that abundant expression of TROP2 in GC cells lessened DSG2 levels as well as desmosome adhesion, increased cell invasion and migration, and promoted malignant progression through EGFR/AKT and DSG2/PG/β-catenin pathways. Conclusion: TROP2 promotes cell invasion and migration in gastric cancer by decreasing DSG2 expression through EGFR/AKT and DSG2/PG/β-catenin pathways.