Current Drug Targets - Volume 22, Issue 9, 2021

The microsatellite instable phenotype resulting from errors in DNA mismatch repair proteins accounts for as far as 15 to 20% of non-hereditary colon cancers but is scarce in rectal cancer. It has been shown that the increased existence of tumor-specific neoantigens in hypermutated tumors is correlated with higher tumor-infiltrating lymphocytes (TILs) and overexpression of immune checkpoint receptors and ligands, mainly PD-1 and PD-L1. In particular, the data gained up to now gives evidence that neoantigen recognition constitutes a dominant component in the course of immunotherapies. This review's primary objective is to describe current approvals and summarize present knowledge about the outcomes of immuno-oncology treatment of microsatellite instable colorectal cancer (CRC). The secondary objective is to give a narrative report about testing methodologies, prognostics, and the predictive value of microsatellite instability. For this purpose, a literature review was performed, focusing on published clinical trial results, ongoing clinical trials and timelines, testing methods, and prognostic and predictive value of MSI. Following four recent FDA approvals of immunotherapy of MSI-high CRC, further work should be warranted by pathology societies towards standardization and rising concordance and reproducibility across the IHC/MSI testing landscape in order to facilitate professionals to offer better survival options for patients with CRC.

Background: Colorectal cancer (CRC) is considered one of the most predominant and deadly cancer globally. Nowadays, the main clinical management for this cancer includes chemotherapy and surgery; however, these treatments result in the occurrence of drug resistance and severe side effects, and thus it is a crucial requirement to discover an alternative and potential therapy for CRC treatment. Numerous therapeutic cancers were initially recognized from natural metabolites utilized in traditional medicine, and several recent types of research have shown that many natural products own potential effects against CRC and may assist the action of chemotherapy for the treatment of CRC. It has been indicated that most patients are well tolerated by natural compounds without showing any toxicity signs even at high doses. Conventional chemotherapeutics interaction with natural medicinal compounds presents a new feature in cancer exploration and treatment. Most of the natural compounds overwhelm malignant cell propagation by apoptosis initiation of CRC cells and arresting of the cell cycle (especially at G, S, and G2/M phase) that result in inhibition of tumor growth. Objective: This mini-review aimed to focus on natural compounds (alkaloids, flavonoids, polysaccharides, polyphenols, terpenoids, lactones, quinones, etc.) that were identified to have anti- CRC activity in vitro on CRC cell lines and/or in vivo experiments on animal models. Conclusion: Most of the studied active natural compounds possess anti-CRC activity via different mechanisms and pathways in vitro and in vivo that might be used as assistance by clinicians to support chemotherapy therapeutic strategy and treatment doses for cancer patients.

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer related deaths in the world with an estimated number of 1.8 million new cases and about 881,000 deaths worldwide in 2018. The epidemiology of CRC varies significantly between different regions in the world as well as between different age, gender and racial groups. Multiple factors are involved in this variation, including risk factor exposure, demographic variations in addition to genetic susceptibility and genetic mutations and their effect on the prognosis and treatment response. In this mini-review, we discuss the recent epidemiological trend including the incidence and mortality of colorectal cancer worldwide and the factors affecting these trends.

Circulating tumour DNA (ctDNA) is a novel tool that has been investigated in several types of tumours, including colorectal cancer (CRC). In fact, the techniques based on liquid biopsies are proposed as appealing non-invasive alternatives to tissue biopsy, adding more insights into tumour molecular profile, heterogeneity and for cancer detection and monitoring. Additionally, some analysis showed that in CRC patients, ctDNA seems to act as a biomarker able to predict the outcome (prognostic role) and the response to treatments (predictive role). In particular, in the early stage CRC (stage I-III), it could represent a time marker of adjuvant therapy as well as a marker of minimal residual disease and recurrence risk in addition to the already recognized risk factors. In metastatic CRC, the analysis of molecular tumour profile by ctDNA has shown to have high concordance with the tissue biopsy at diagnosis. Additionally, some studies demonstrated that ctDNA level during the treatment was linked with the early response to treatment and prognosis. Finally, the quantitative analysis of ctDNA and copy number alterations may be useful in order to detect resistance to therapy at the time of progression of disease and to help in finding new therapeutic targets.

Immunotherapy has revolutionized the treatment landscape in a number of solid tumors. In colorectal cancer, evidence suggests that microsatellite high (MSI-H) tumors are the most responsive to immune checkpoint blockade due to increased neo-antigen load and a favorable tumor microenvironment. Indeed, Pembrolizumab now represents a first-line option in such patients. However, MSI-H tumors represent the minority and a proportion of patients’ progress despite initially responding. Trials are investigating different immunotherapy combinatorial strategies to enhance immune response in less immunogenic colorectal tumors. Such strategies include dual immune checkpoint blockade, combining immune checkpoint inhibitors with other treatment modalities such as radiotherapy, chemotherapy or other biological or targeted agents. Moreover, there is an increasing drive to identify biomarkers to better select patients most likely to respond to immunotherapy and understand intrinsic and acquired resistance mechanisms. Apart from MSI-H tumors, there is a strong rationale to suggest that tumors with alterations in DNA polymerase epsilon and DNA polymerase delta are also likely to respond to immunotherapy and trials in this subpopulation are underway. Other strategies such as priming O6-methylguanineDNA methyltransferase silenced tumors with alkylating agents to make them receptive to immune checkpoint blockade are also being investigated. Here we discuss different colorectal subpopulations together with their likelihood of response to immune checkpoint blockade and strategies to overcome barriers to a successful clinical outcome. We summarize evidence from published clinical trials and provide an overview of trials in progress whilst discussing newer immunotherapy strategies such as adoptive cell therapies and cancer vaccines.

Background: Anti-EGFR monoclonal antibodies (mAbs) have become a relevant solution for the treatment of patients with metastatic colorectal cancer. Current anti-EGFR monoclonal antibodies face a series of problems, including resistance and non-durable response, and RAS and BRAF mutations serve as exclusion criteria for treatment with anti-EGFR mAbs. Advances in molecular tumor profiling and information on subsequent pathways responsible for disease progression and drug resistance helped develop a new generation of anti-EGFR mAbs. These second-generation mAbs have been developed to overcome existing resistance mechanisms and to limit common side effects. For the moment, existing literature suggests that these novel anti-EGFR mAbs are far from finding their way to clinical practice soon. Objective: In this review, we summarize and evaluate current data regarding ongoing research and completed clinical trials for different second-generation anti-EGFR monoclonal antibodies. Conclusion: Anti-EGFR mAbs exhibit efficacy in advanced colorectal cancer, but second-generation mAbs failed to prove their benefit in the treatment of metastatic colorectal cancer. Understanding the biological basis of primary and acquired drug resistance could allow scientists to design better clinical trials and develop improved second-generation mAbs.

Background: Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. Currently, colonoscopy remains the gold standard diagnostic test for CRC detection. Nonetheless, this technique is invasive and expensive. Remarkable ongoing strategies are focusing on the development of affordable methods to diagnose CRC at earlier stages. The introduction of suitable noninvasive, sensitive and specified diagnostic tests for early CRC detection by employing biomarker analysis seems to be a fundamental need to reduce the numbers of unnecessary colonoscopies. In this review, we provide an overview of single- and multi-panel biomarkers (Genomic markers, transcriptome markers, proteomic markers, inflammatory markers, and microbiome markers) encompassing noninvasive tests in blood and stool for early CRC detection. Methods: A bibliographic search using PubMed/Medline, Web of Science, and EBSCOhost databases was performed to find relevant published studies over the last 6 years. Forty-three pertinent studies were included in this review. Results: The primary outcome highlights the sensitivity and specificity of single diagnostic biomarkers studied in blood or stool. The secondary outcome reveals the sensitivity and specificity of the biomarkers panel (combinations) in blood or stool. While some markers show better performance, others are not suitable for screening purposes. Conclusion: There is a need to adjust experimental and analytical tests that can interfere with a robust result to replace or supplement those markers that are currently in use. Nevertheless, robust verification and validation with large clinical cohorts are needed for successful noninvasive tests that can fulfill the role of colonoscopy.

In this narrative-review, we report the most recent data from the literature of anti-vascular endothelial growth factor treatment for myopic choroidal neovascularization (mCNV). Myopic CNV is the most frequent sight-threatening complication of pathologic myopia. The natural course of mCNV can result in expanding macular atrophy and /or fibrosis, leading to irreversible visual loss after 5 years. Retinal multimodal imaging is mandatory for early diagnosis and monitoring of the disease during treatment. Intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is recommended as the first-line treatment option for mCNV. Prompt treatment of active mCNV with intravitreal anti-VEGF therapy has been demonstrated to be effective in terms of visual outcome improvements reducing the occurrence of late-stage complications.

Pathological bone loss diseases (osteolysis, Paget’s diseases) are commonly caused by the excessive differentiation and activity of osteoclasts. The Rho GTPases family members Rac1/2 (Rac1 and Rac2) have been reported for their special role in exerting multiple cellular functions during osteoclastic differentiation, which includes the most prominent function on dynamic actin cytoskeleton rearranging. Besides that, the increasing studies demonstrated that the regulating effects of Rac1/2 on the osteoclastic cytoskeletal organization are through the GEFs member Dock5. Although the amount of relevant studies on this topic is still limited, several excellent studies have been reported that extensively explored the molecular mechanisms involved in Rac1/2 and Dock5 during the osteoclastogenesis regulation, as well as their role as the therapeutic target in bone loss diseases. Herein, in this review, we aim to focus on recent advances studies for extensively understanding the role of Rho GTPases Rac1/2 and Dock5 in osteoclastogenesis, as well as their role as a potential therapeutic target in regulating osteoclastogenesis.

Autism is a highly inherited and extremely complex disorder in which results from various cases indicate chromosome anomalies, unusual single-gene mutations, and multiplicative effects of particular gene variants, characterized primarily by impaired speech and social interaction and restricted behavior. The precise etiology of Autism Spectrum Disorder (ASD) is currently unclear. The extracellular signal-regulated kinase (ERK) signaling mechanism affects neurogenesis and neuronal plasticity during the development of the central nervous mechanism. In this regard, the pathway of ERK has recently gained significant interest in the pathogenesis of ASD. The mutation occurs in a few ERK components. Besides, the ERK pathway dysfunction lies in the upstream of modified translation and contributes to synapse pathology in syndromic types of autism. In this review, we highlight the ERK pathway as a target for neurodevelopmental disorder autism. In addition, we summarize the regulation of the ERK pathway with ERK inhibitors in neurological disorders. In conclusion, a better understanding of the ERK signaling pathway provides a range of therapeutic options for autism spectrum disorder.

Due to an editorial oversight, we would like to apologize for an error that occurred in the both print and online version of an editorial entitled “Can Medical Therapy Fix Sexual Dysfunction after Major Pelvic and Prostate Surgery and does it Work for Kidney Stones? Chemotherapy before Cystectomy, New Schemes for which Patients?. It was published without the co-authors’ names in the journal “Current Drug Targets” 2021; 22(1): 2 [1]. The original editorial can be found online at https://doi.org/10.2174/138945012201201231123209 REFERENCE [1] Petros S, Ioannis M, Ioannis V, Luca C, Can medical therapy fix sexual dysfunction after major pelvic and prostate surgery and does it work for kidney stones? chemotherapy before cystectomy, new schemes for which patients? Curr Drug Targets 2021; 22(1): 1.