Next generation of immune checkpoint inhibitors and beyond

Journal of Hematology & Oncology, Journal Year: 2021, Volume and Issue: 14(1)

Published: March 19, 2021

The immune system is the core defense against cancer development and progression. Failure of to recognize eliminate malignant cells plays an important role in pathogenesis cancer. Tumor evade recognition, part, due immunosuppressive features tumor microenvironment. Immunotherapy augments host generate antitumor effect. Immune checkpoints are pathways with inhibitory or stimulatory that maintain self-tolerance assist response. most well-described nature include cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), ligand-1 (PD-L1). Molecules block these enhance immunologic activity tumors have been developed become standard care treatment many malignancies. Only a small percentage patients meaningful responses treatments, however. New molecules being explored attempt improve application checkpoint inhibition therapy. In this review, we aim elucidate novel pathways, potential therapeutic under development, outline particular advantages challenges use each one them.

Language: Английский

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Vimentin Is at the Heart of Epithelial Mesenchymal Transition (EMT) Mediated Metastasis

Cancers, Journal Year: 2021, Volume and Issue: 13(19), P. 4985 - 4985

Published: Oct. 5, 2021

Epithelial-mesenchymal transition (EMT) is a reversible plethora of molecular events where epithelial cells gain the phenotype mesenchymal to invade surrounding tissues. EMT physiological event during embryogenesis (type I) but also happens fibrosis II) and cancer metastasis III). It multifaceted phenomenon governed by activation genes associated with cell migration, extracellular matrix degradation, DNA repair, angiogenesis. The employ acquire ability migrate, resist therapeutic agents escape immunity. One key biomarkers vimentin, type III intermediate filament that normally expressed in upregulated metastasis. This review highlights pivotal role vimentin explains its as downstream well an upstream regulator this highly complex process. areas require further research exploring EMT. As cytoskeletal protein, filaments support mechanical integrity migratory machinery, generation directional force, focal adhesion modulation attachment. viscoelastic scaffold, it gives stress-bearing flexible organelles. However, modulates for inducers such Snail, Slug, Twist ZEB1/2, epigenetic factors. In addition, suppresses cellular differentiation upregulates their pluripotent potential inducing self-renewability, thus increasing stemness stem cells, facilitating tumour spread making them more resistant treatments. Several missense frameshift mutations reported human cancers may contribute towards metastatic spread. Therefore, we propose should be target using technologies will curb growth reduced mortality morbidity.

Language: Английский

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Anticancer drug resistance: An update and perspective

Drug Resistance Updates, Journal Year: 2021, Volume and Issue: 59, P. 100796 - 100796

Published: Dec. 1, 2021

Driver mutations promote initiation and progression of cancer. Pharmacological treatment can inhibit the action mutant protein; however, drug resistance almost invariably emerges. Multiple studies revealed that cancer is based upon a plethora distinct mechanisms. Drug occur in same protein or different proteins; as well pathway parallel pathways, bypassing intercepted signaling. The dilemma clinical oncologist facing not all genomic alterations tumor microenvironment facilitate cell proliferation are known, neither likely to metastasis. For example, common KRas

Language: Английский

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Cabozantinib for radioiodine-refractory differentiated thyroid cancer (COSMIC-311): a randomised, double-blind, placebo-controlled, phase 3 trial

The Lancet Oncology, Journal Year: 2021, Volume and Issue: 22(8), P. 1126 - 1138

Published: July 5, 2021

Language: Английский

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Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Sept. 17, 2022

Abstract Protein tyrosine kinases (PTKs) are a class of proteins with kinase activity that phosphorylate residues critical molecules in signaling pathways. Their basal function is essential for maintaining normal cell growth and differentiation. However, aberrant activation PTKs caused by various factors can deviate from the expected trajectory to an abnormal state, leading carcinogenesis. Inhibiting PTK could inhibit tumor growth. Therefore, inhibitors (TKIs), target-specific PTKs, have been used treating malignant tumors play significant role targeted therapy cancer. Currently, drug resistance main reason limiting TKIs efficacy The increasing studies indicated microenvironment, death resistance, metabolism, epigenetic modification metabolism were deeply involved development TKI besides PTK-related pathways gene mutations. Accordingly, it great significance study underlying mechanisms find solutions reverse improving Herein, we reviewed potential approaches overcome aiming provide theoretical basis TKIs.

Language: Английский

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Recent advances in non-small cell lung cancer targeted therapy; an update review

Cancer Cell International, Journal Year: 2023, Volume and Issue: 23(1)

Published: Aug. 11, 2023

Abstract Lung cancer continues to be the leading cause of cancer-related death worldwide. In last decade, significant advancements in diagnosis and treatment lung cancer, particularly NSCLC, have been achieved with help molecular translational research. Among hopeful breakthroughs therapeutic approaches, advances targeted therapy brought most successful outcomes NSCLC treatment. therapy, antagonists target specific genes, proteins, or microenvironment tumors supporting growth survival. Indeed, can managed by blocking genes related tumor cell progression without causing noticeable damage normal cells. Currently, efforts focused on improving aspects regarding encouraging quality life patients. Treatment for is changing rapidly due pace scientific Accordingly, this updated study aimed discuss antigens comprehensively therapy-related agents NSCLC. The current also summarized available clinical trial studies

Language: Английский

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Mutant p53 Gain-of-Function: Role in Cancer Development, Progression, and Therapeutic Approaches

Frontiers in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 8

Published: Feb. 11, 2021

Frequent p53 mutations (mutp53) not only abolish tumor suppressor capacities but confer various gain-of-function (GOF) activities that impacts molecules and pathways now regarded as central for development progression. Although the complete impact of GOF is still far from being fully understood, effects on proliferation, migration, metabolic reprogramming, immune evasion, among others, certainly constitute major driving forces human tumors harboring them. In this review we discuss molecular mechanisms driven by mutp53 GOF. We present novel mechanistic insights their over key functional processes involved in cancer. analyze new impacting such system stemness. particular, increased lipogenic activity through mevalonate pathway (MVA) alteration homeostasis due to interactions between AMP-activated protein kinase (AMPK) Sterol regulatory element-binding 1 (SREBP1) anabolic favor reprograming. address, detail, reprogramming Warburg effect observed cancer cells a consequence, loss-of-function p53, rather an crucial imbalance glycolysis oxidative phosphorylation. Additionally, transcriptional activation targets, resulting interaction with NF-kB, HIF-1α, or SREBP1, are presented discussed. Finally, perspectives targeting chemo-resistance stress fact status currently constitutes one most relevant criteria understand role autophagy survival mechanism cancer, propose therapeutic approaches could promote reduction exercised

Language: Английский

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Acquired resistance to third-generation EGFR-TKIs and emerging next-generation EGFR inhibitors

The Innovation, Journal Year: 2021, Volume and Issue: 2(2), P. 100103 - 100103

Published: April 3, 2021

The discovery that mutations in the EGFR gene are detected up to 50% of lung adenocarcinoma patients, along with development highly efficacious epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), has revolutionized treatment this frequently occurring malignancy. Indeed, clinical success these TKIs constitutes a critical milestone targeted cancer therapy. Three generations EGFR-TKIs currently approved for mutation-positive non-small cell (NSCLC). first-generation include erlotinib, gefitinib, lapatinib, and icotinib; second-generation ErbB family blockers afatinib, neratinib, dacomitinib; whereas osimertinib, by FDA on 2015, is third-generation TKI targeting harboring specific mutations. Compared first- TKIs, display significant advantage terms patient survival. For example, median overall survival NSCLC patients receiving osimertinib reached 38.6 months. Unfortunately, however, like other therapies, new mutations, as well additional drug-resistance mechanisms emerge rapidly after treatment, posing formidable obstacles therapeutics aimed at surmounting chemoresistance. In review, we summarize molecular underlying resistance ongoing efforts address overcome We also discuss current status fourth-generation inhibitors, which great value overcoming appear have greater therapeutic benefits clinic.

Language: Английский

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Progress and Prospect of Immunotherapy for Triple-Negative Breast Cancer

Frontiers in Oncology, Journal Year: 2022, Volume and Issue: 12

Published: June 20, 2022

Breast cancer is the most commonly diagnosed (estimated 2.3 million new cases in 2020) and leading cause of death 685,000 deaths women globally. cancers have been categorized into four major molecular subtypes based on immunohistochemistry (IHC) expression classic hormone growth factor receptors including estrogen receptor (ER), progesterone (PR), human epidermal 2 (HER2), as well a proliferation marker Ki-67 protein expression. Triple-negative breast (TNBC), subtype lacking ER, PR, HER2 expression, associated with high metastatic potential poor prognosis. TNBC accounts for approximately only 15%-20% diagnoses; it responsible cancer-related due to lack targeted treatment options this patient population, currently, systemic chemotherapy, radiation, surgical excision remain modalities these patients TNBC. Although general do not robust response immunotherapy, subset has demonstrated tumor mutation burden tumor-infiltrating lymphocytes, resembling features observed melanoma or lung cancers, which can benefit from immune checkpoint inhibitors (ICIs). Therefore, immunogenic nature aggressive disease presented an opportunity development TNBC-targeting immunotherapies. The recent US Food Drug Administration approval atezolizumab combination chemotherapeutic agent nab-paclitaxel PD-L1-positive unresectable, locally advanced, led era immunotherapy treatment. In addition, becomes active research area, both biology field oncology field. review, we will extend our coverage discoveries preclinical early results clinical trials molecule-based therapy cytokines, monoclonal antibodies, antibody-drug conjugates, bi-specific tri-specific ICIs, neoantigen vaccines; oncolytic virus-based therapies adoptive cell transfer-based TIL, chimeric antigen receptor-T (CAR-T), CAR-NK, CAR-M, T-cell receptor-T. end, list series challenges opportunities prospectively reveal novel technologies such high-throughput single-cell sequencing CRISPR gene editing-based screening generate knowledges immunotherapy.

Language: Английский

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T Cell Metabolism in Infection

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: March 14, 2022

T lymphocytes (T cells) are divided into two functionally different subgroups the CD4+ helper cells (Th) and CD8+ cytotoxic (CTL). Adequate CD4 CD8 cell activation to proliferation, clonal expansion effector function is crucial for efficient clearance of infection by pathogens. Failure do so may lead exhaustion. Upon antigen presenting cells, undergo metabolic reprograming that support functions. In this review we will discuss how dictates functionality during viral infections using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) human immunodeficiency virus (HIV) as examples. Moreover, briefly programs bacterial exemplified Mycobacterium tuberculosis (MT) infection.

Language: Английский

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