Background and purpose: The mortality associated with acute pancreatitis (AP) is largely attributable to abnormalities that occur in distant organs and supportive care remains the only treatment for patients with these complications. Recently, prophylactic pharmacological blockade of poly(ADP-ribose) polymerase (PARP) enzymes has been shown to attenuate the severity of the disease. However, the clinical relevance of PARP inhibitors administered after the onset of AP remains uncertain. The aim of the present study was to investigate the therapeutic effects of PARP inhibitors in established AP. Experimental approach: Mice were fed a choline/methionine-deficient/ethionine-supplemented (CMDE) diet to induce AP. PARP inhibitors were given at 36 h after the onset of CMDE diet. Severity of pancreatitis was assessed by measurements of serum amylase, lipase, IL-1b and IL-6, and histological grading. Serum hepatic enzymes, myeloperoxidase (MPO) activity and morphological changes were measured as indicators of hepatic insult. Lung injury was evaluated by MPO activity and morphological changes. Survival rates of mice were monitored for 7 days. Key results: CMDE diet administration resulted in a significant increase in serum amylase, lipase, IL-1b, IL-6, alanine aminotransferase and aspartate aminotranferase levels, indicating AP and associated liver injury. Analysis of the histopathological changes in pancreas, liver and lung revealed extensive tissue damage. Treatment of mice with PARPinhibitors after the onset of AP was associated with a reduction in the severity of AP and, accordingly, with a reduced mortality rate. Conclusions and Implications: Our results support the therapeutic application of PARP inhibitors in the treatment of established AP.
<b><i>Background:</i></b> Lung cancer is the most common thoracic malignancy, representing the leading cause of cancer-related deaths worldwide with a 5-year survival rate of <10%. <b><i>Summary:</i></b> The emergence of targeted therapy and immunotherapy has changed the treatment paradigm of advanced non-small cell lung cancer (NSCLC). However, for those who are not eligible for such therapy or currently have no available standard treatment options, new precision treatment approaches are needed. Human trophoblast cell-surface antigen 2 (TROP2) is a transmembrane glycoprotein that is highly expressed on several epithelial tumours including NSCLC. TROP2 is recognized as a promising molecular target for therapeutic development in various types of TROP2-expressing malignancies. As a result, several TROP2-targeted therapeutics have recently been developed for clinical use, such as anti-TROP2 antibodies and TROP2-targeted antibody-drug conjugates. <b><i>Key Message:</i></b> This review explores the literature data on the role of TROP2 in cancer development and the potential use of emerging TROP2 antibody-drug conjugates in NSCLC treatment.
Human epidermal growth factor receptor 3 (HER3) is a member of the transmembrane receptor tyrosine kinase family. Upregulation of HER3 pathway has been implicated as a mechanism of resistance in solid tumors, particularly in estrogen receptor positive, HER2 positive breast cancer and epidermal growth factor (EGFR) mutant nonsmall cell lung cancer. Several studies suggest that HER3 overexpression represents a negative prognostic biomarker associated with poor survival. Preclinical and clinical studies of anti‐HER3 investigational therapies suggest that expression of the HER3 ligand, neuregulin, may predict response to treatment. Despite its emergence as a key cancer therapeutic target, HER3 cannot be targeted with traditional tyrosine kinase inhibitors therapy due to its weak kinase activity. Monoclonal and bispecific antibodies targeting HER3 have been developed and tested in early phase trials. Objective responses were limited when first‐generation HER3‐specific monoclonal antibodies were investigated as monotherapies in phase 1 and 2 clinical trials for nonsmall cell lung cancer (NSCLC) and metastatic breast cancer (MBC). MBC and NSCLC HER3 specific antibody‐drug conjugates have shown encouraging results in resistance in cancer cells, particularly in those that overexpress HER3. These agents have shown some promise in early phase trials in both NSCLC and MBC setting in heavily pretreated patients with varying degrees of response. It is unclear which subgroup of patients will truly benefit from targeting HER3 as these therapies are under investigation.
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