Gamma Secretase Inhibitors in Cancer: A Current Perspective on Clinical Performance.

Gamma secretase inhibitors (GSIs), initially developed as Alzheimer's therapies, have been repurposed as anticancer agents given their inhibition of Notch receptor cleavage. The success of GSIs in preclinical models has been ascribed to induction of cancer stem-like cell differentiation and apoptosis, while also impairing epithelial-to-mesenchymal transition and sensitizing cells to traditional chemoradiotherapies. The promise of these agents has yet to be realized in the clinic, however, as GSIs have failed to demonstrate clinical benefit in most solid tumors with the notable exceptions of CNS malignancies and desmoid tumors. Disappointing clinical performance to date reflects important questions that remain to be answered. For example, what is the net impact of these agents on antitumor immune responses, and will they require concurrent targeting of tumor-intrinsic compensatory pathways? Addressing these limitations in our current understanding of GSI mechanisms will undoubtedly facilitate their rational incorporation into combinatorial strategies and provide a valuable tool with which to combat Notch-dependent cancers. In the present review, we provide a current understanding of GSI mechanisms, discuss clinical performance to date, and suggest areas for future investigation that might maximize the utility of these agents. IMPLICATIONS FOR PRACTICE: The performance of gamma secretase inhibitors (GSIs) in clinical trials generally has not reflected their encouraging performance in preclinical studies. This review provides a current perspective on the clinical performance of GSIs across various solid tumor types alongside putative mechanisms of antitumor activity. Through exploration of outstanding gaps in knowledge as well as reasons for success in certain cancer types, the authors identify areas for future investigation that will likely enable incorporation of GSIs into rational combinatorial strategies for superior tumor control and patient outcomes.

HIV, Antiretroviral Therapy and Metabolic Alterations: A Review.

The introduction of antiretroviral therapy (ART) has caused some metabolic problems to people who suffer from HIV. ART probably is not the sole reason for these metabolic disorders. Most likely, HIV itself affects the metabolism as well. We conducted research to find the prevalence of the different types of metabolic disorders among HIV(+) patients. Female gender, high BMI, and older age are among the risk factors for the occurrence of metabolic disorders. Regarding dyslipidemia, hypertriglyceridemia and low high-density lipoproteins (HDLs) are the most common types of dyslipidemia in the studies we included. Protease inhibitors (PIs) are widely known as the most common class of antiretroviral drugs that cause metabolic disorders, and some studies in our review also demonstrated this knowledge. In our review, we concluded that HIV and ART concurrently alter the metabolism, but further research is required about this substantial topic.

Immune Checkpoint Inhibitors in Lung Cancer: Role of Biomarkers and Combination Therapies.

Lung cancer is the leading cause of cancer-related death worldwide, with a poor prognosis. Despite aggressive treatment, progression-free survival (PFS) and overall survival are limited. Recently, various kinds of immune checkpoint inhibitors (ICIs) have emerged for several cancers, targeting PD1, PDL1, and CTLA-4. ICIs have made a significant breakthrough in cancer and revolutionized the management of cancer including lung cancer. However, there are a lot of controversies regarding which group of patients is most suitable to be treated with ICIs in terms of monotherapy, combination, and predictive biomarkers. We reviewed various kinds of studies, such as meta-analysis, randomized control trials, multi-center cohort studies, and case-control studies from PubMed written in English from the last five years. ICIs have significant benefits in the overall survival compared with traditional chemotherapy. Patients with a higher level of PDL1 expression and high tumor mutational burden (TMB) have a higher response rate, and those with EGFR-/ALK- were better than those with EGFR+/ALK+. The patient who responded to immunotherapy completely can still maintain the efficacy after two years of treatment. Neoadjuvant immunotherapy in patients with resectable non-small cell lung cancer resulted in a 45% major pathology response (MPR) and 40% downstaging. Combined therapy (ICIs + chemotherapy) was better than chemotherapy alone, irrespective of PD-L1 expression. A combination of ICIs such as CTLA-4 and PD-1/PD-L1 improved PFS as well. Radiochemotherapy ahead of ICIs is promising as well. However, ICIs combined with EGFR/ALK-TKI (tyrosine kinase inhibitor) are not suggested for the time being. PDL1 expression, TMB, and EGFR/ALK mutations are promising predictive biomarkers. Gut microbiota, galectin-3, and intensity of CD8 cell infiltration are other potential predictive biomarkers. These are very important in the future management of lung cancers as they can prevent unnecessary toxicities and cost of treatment.