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Signal Transduction and Targeted Therapy Dec 2020Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and the second most common form of acute leukemia in children. Despite this, very little... (Review)
Review
Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and the second most common form of acute leukemia in children. Despite this, very little improvement in survival rates has been achieved over the past few decades. This is partially due to the heterogeneity of AML and the need for more targeted therapeutics than the traditional cytotoxic chemotherapies that have been a mainstay in therapy for the past 50 years. In the past 20 years, research has been diversifying the approach to treating AML by investigating molecular pathways uniquely relevant to AML cell proliferation and survival. Here we review the development of novel therapeutics in targeting apoptosis, receptor tyrosine kinase (RTK) signaling, hedgehog (HH) pathway, mitochondrial function, DNA repair, and c-Myc signaling. There has been an impressive effort into better understanding the diversity of AML cell characteristics and here we highlight important preclinical studies that have supported therapeutic development and continue to promote new ways to target AML cells. In addition, we describe clinical investigations that have led to FDA approval of new targeted AML therapies and ongoing clinical trials of novel therapies targeting AML survival pathways. We also describe the complexity of targeting leukemia stem cells (LSCs) as an approach to addressing relapse and remission in AML and targetable pathways that are unique to LSC survival. This comprehensive review details what we currently understand about the signaling pathways that support AML cell survival and the exceptional ways in which we disrupt them.
Topics: Antineoplastic Agents; Cell Proliferation; Drug Delivery Systems; Humans; Leukemia, Myeloid, Acute; Signal Transduction
PubMed: 33335095
DOI: 10.1038/s41392-020-00361-x -
Signal Transduction and Targeted Therapy Feb 2021Despite great success in cancer immunotherapy, immune checkpoint-targeting drugs are not the most popular weapon in the armory of cancer therapy. Accumulating evidence... (Review)
Review
Despite great success in cancer immunotherapy, immune checkpoint-targeting drugs are not the most popular weapon in the armory of cancer therapy. Accumulating evidence suggests that the tumor immune microenvironment plays a critical role in anti-cancer immunity, which may result in immune checkpoint blockade therapy being ineffective, in addition to other novel immunotherapies in cancer patients. In the present review, we discuss the deficiencies of current cancer immunotherapies. More importantly, we highlight the critical role of tumor immune microenvironment regulators in tumor immune surveillance, immunological evasion, and the potential for their further translation into clinical practice. Based on their general targetability in clinical therapy, we believe that tumor immune microenvironment regulators are promising cancer immunotherapeutic targets. Targeting the tumor immune microenvironment, alone or in combination with immune checkpoint-targeting drugs, might benefit cancer patients in the future.
Topics: Humans; Immune Checkpoint Inhibitors; Immunotherapy; Neoplasms; Tumor Microenvironment
PubMed: 33608497
DOI: 10.1038/s41392-020-00449-4 -
Nature Biotechnology Mar 2017After nearly 40 years of development, oligonucleotide therapeutics are nearing meaningful clinical productivity. One of the key advantages of oligonucleotide drugs is... (Review)
Review
After nearly 40 years of development, oligonucleotide therapeutics are nearing meaningful clinical productivity. One of the key advantages of oligonucleotide drugs is that their delivery and potency are derived primarily from the chemical structure of the oligonucleotide whereas their target is defined by the base sequence. Thus, as oligonucleotides with a particular chemical design show appropriate distribution and safety profiles for clinical gene silencing in a particular tissue, this will open the door to the rapid development of additional drugs targeting other disease-associated genes in the same tissue. To achieve clinical productivity, the chemical architecture of the oligonucleotide needs to be optimized with a combination of sugar, backbone, nucleobase, and 3'- and 5'-terminal modifications. A portfolio of chemistries can be used to confer drug-like properties onto the oligonucleotide as a whole, with minor chemical changes often translating into major improvements in clinical efficacy. One outstanding challenge in oligonucleotide chemical development is the optimization of chemical architectures to ensure long-term safety. There are multiple designs that enable effective targeting of the liver, but a second challenge is to develop architectures that enable robust clinical efficacy in additional tissues.
Topics: Animals; Drug Design; Humans; Molecular Targeted Therapy; Oligonucleotides, Antisense; RNA; RNAi Therapeutics
PubMed: 28244990
DOI: 10.1038/nbt.3765 -
Cancer Cell Jan 2022Functional precision medicine is a strategy whereby live tumor cells from affected individuals are directly perturbed with drugs to provide immediately translatable,... (Review)
Review
Functional precision medicine is a strategy whereby live tumor cells from affected individuals are directly perturbed with drugs to provide immediately translatable, personalized information to guide therapy. The heterogeneity of human cancer has led to the realization that personalized approaches are needed to improve treatment outcomes. Precision oncology has traditionally used static features of the tumor to dictate which therapies should be used. Static features can include expression of key targets or genomic analysis of mutations to identify therapeutically targetable "drivers." Although a surprisingly small proportion of individuals derive clinical benefit from the static approach, functional precision medicine can provide additional information regarding tumor vulnerabilities. We discuss emerging technologies for functional precision medicine as well as limitations and challenges in using these assays in the clinical trials that will be necessary to determine whether functional precision medicine can improve outcomes and eventually become a standard tool in clinical oncology.
Topics: Biomarkers, Tumor; Humans; Medical Oncology; Mutation; Neoplasms; Pharmaceutical Preparations; Precision Medicine
PubMed: 34951956
DOI: 10.1016/j.ccell.2021.12.004 -
Frontiers in Endocrinology 2020The rising global prevalence of obesity, metabolic syndrome, and type 2 diabetes has driven a sharp increase in non-alcoholic fatty liver disease (NAFLD), characterized... (Review)
Review
The rising global prevalence of obesity, metabolic syndrome, and type 2 diabetes has driven a sharp increase in non-alcoholic fatty liver disease (NAFLD), characterized by excessive fat accumulation in the liver. Approximately one-sixth of the NAFLD population progresses to non-alcoholic steatohepatitis (NASH) with liver inflammation, hepatocyte injury and cell death, liver fibrosis and cirrhosis. NASH is one of the leading causes of liver transplant, and an increasingly common cause of hepatocellular carcinoma (HCC), underscoring the need for intervention. The complex pathophysiology of NASH, and a predicted prevalence of 3-5% of the adult population worldwide, has prompted drug development programs aimed at multiple targets across all stages of the disease. Currently, there are no approved therapeutics. Liver-related morbidity and mortality are highest in more advanced fibrotic NASH, which has led to an early focus on anti-fibrotic approaches to prevent progression to cirrhosis and HCC. Due to limited clinical efficacy, anti-fibrotic approaches have been superseded by mechanisms that target the underlying driver of NASH pathogenesis, namely steatosis, which drives hepatocyte injury and downstream inflammation and fibrosis. Among this wave of therapeutic mechanisms targeting the underlying pathogenesis of NASH, the hormone fibroblast growth factor 21 (FGF21) holds considerable promise; it decreases liver fat and hepatocyte injury while suppressing inflammation and fibrosis across multiple preclinical studies. In this review, we summarize preclinical and clinical data from studies with FGF21 and FGF21 analogs, in the context of the pathophysiology of NASH and underlying metabolic diseases.
Topics: Animals; Fibroblast Growth Factors; Humans; Metabolic Diseases; Molecular Targeted Therapy; Non-alcoholic Fatty Liver Disease
PubMed: 33381084
DOI: 10.3389/fendo.2020.601290 -
International Journal of Molecular... Aug 2023Diabetes mellitus is a chronic multifaceted disease with multiple potential complications, the treatment of which can only delay and prolong the terminal stage of the... (Review)
Review
Diabetes mellitus is a chronic multifaceted disease with multiple potential complications, the treatment of which can only delay and prolong the terminal stage of the disease, i.e., type 2 diabetes mellitus (T2DM). The World Health Organization predicts that diabetes will be the seventh leading cause of death by 2030. Although many antidiabetic medicines have been successfully developed in recent years, such as GLP-1 receptor agonists and SGLT-2 inhibitors, single-target drugs are gradually failing to meet the therapeutic requirements owing to the individual variability, diversity of pathogenesis, and organismal resistance. Therefore, there remains a need to investigate the pathogenesis of T2DM in more depth, identify multiple therapeutic targets, and provide improved glycemic control solutions. This review presents an overview of the mechanisms of action and the development of the latest therapeutic agents targeting T2DM in recent years. It also discusses emerging target-based therapies and new potential therapeutic targets that have emerged within the last three years. The aim of our review is to provide a theoretical basis for further advancement in targeted therapies for T2DM.
Topics: Humans; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Drug Delivery Systems; Glycemic Control; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 37686185
DOI: 10.3390/ijms241713381 -
Journal of Extracellular Vesicles Feb 2021Natural extracellular vesicles (EVs) are ideal drug carriers due to their remarkable biocompatibility. Their delivery specificity can be achieved by the conjugation of...
Natural extracellular vesicles (EVs) are ideal drug carriers due to their remarkable biocompatibility. Their delivery specificity can be achieved by the conjugation of targeting ligands. However, existing methods to engineer target-specific EVs are tedious or inefficient, having to compromise between harsh chemical treatments and transient interactions. Here, we describe a novel method for the covalent conjugation of EVs with high copy numbers of targeting moieties using protein ligases. Conjugation of EVs with either an epidermal growth factor receptor (EGFR)-targeting peptide or anti-EGFR nanobody facilitates their accumulation in EGFR-positive cancer cells, both and . Systemic delivery of paclitaxel by EGFR-targeting EVs at a low dose significantly increases drug efficacy in a xenografted mouse model of EGFR-positive lung cancer. The method is also applicable to the conjugation of EVs with peptides and nanobodies targeting other receptors, such as HER2 and SIRP alpha, and the conjugated EVs can deliver RNA in addition to small molecules, supporting the versatile application of EVs in cancer therapies. This simple, yet efficient and versatile method for the stable surface modification of EVs bypasses the need for genetic and chemical modifications, thus facilitating safe and specific delivery of therapeutic payloads to target cells.
Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Drug Carriers; Drug Delivery Systems; ErbB Receptors; Erythrocytes; Extracellular Vesicles; Humans; Lung Neoplasms; Mice; Paclitaxel; Peptides; Single-Domain Antibodies; Xenograft Model Antitumor Assays
PubMed: 33643546
DOI: 10.1002/jev2.12057 -
Current Opinion in Oncology Sep 2022T-cell-engaging antibodies or T-cell engagers (TCEs) can connect a patient's cytotoxic T cells with cancer cells, leading to potent redirected lysis. Until very... (Review)
Review
PURPOSE OF REVIEW
T-cell-engaging antibodies or T-cell engagers (TCEs) can connect a patient's cytotoxic T cells with cancer cells, leading to potent redirected lysis. Until very recently, only one TCE was approved, the CD19/CD3-bispecific blinatumomab. Many new TCEs in late-stage clinical development target various hematopoietic lineage markers like CD20, BCMA, or CD123. Although very compelling single-agent activity of TCEs was observed with various blood-borne cancers, therapy of solid tumor indications has thus far been less successful.
RECENT FINDINGS
The approval in 2022 of the gp100 peptide-major histocompatibility complex (MHC)/CD3 bispecific TCE tebentafusp in uveal melanoma confirms that TCEs can also efficiently work against solid tumors. TCEs targeting peptide-MHC complexes will expand the target space for solid tumor therapy to intracellular targets. Likewise, early clinical trial data from TCEs targeting DLL3 in small cell lunger cancer showed promising antitumor activity. Various technologies for conditional activation of TCEs in the tumor microenvironment (TME) may expand the scope of conventional surface targets that suffer from a narrow therapeutic window. Finally, pharmacological enhancements for TCE therapies by engagement of certain costimulatory receptors and cytokines, or blockade of checkpoints, are showing promise.
SUMMARY
Targeting peptide-MHC complexes, conditional TCE technologies, and concepts enhancing TCE-activated T cells are paving the way towards overcoming challenges associated with solid tumor therapy.
Topics: Antibodies, Bispecific; Antigens, CD19; CD3 Complex; Humans; Immunotherapy; Intracellular Signaling Peptides and Proteins; Melanoma; Membrane Proteins; Recombinant Fusion Proteins; T-Lymphocytes; Tumor Microenvironment
PubMed: 35880455
DOI: 10.1097/CCO.0000000000000869 -
International Journal of Molecular... Apr 2019Telomerase, an enzyme responsible for the synthesis of telomeres, is activated in many cancer cells and is involved in the maintenance of telomeres. The activity of... (Review)
Review
Telomerase, an enzyme responsible for the synthesis of telomeres, is activated in many cancer cells and is involved in the maintenance of telomeres. The activity of telomerase allows cancer cells to replicate and proliferate in an uncontrolled manner, to infiltrate tissue, and to metastasize to distant organs. Studies to date have examined the mechanisms involved in the survival of cancer cells as targets for cancer therapeutics. These efforts led to the development of telomerase inhibitors as anticancer drugs, drugs targeting telomere DNA, viral vectors carrying a promoter for human telomerase reverse transcriptase (hTERT) genome, and immunotherapy targeting hTERT. Among these novel therapeutics, this review focuses on immunotherapy targeting hTERT and discusses the current evidence and future perspectives.
Topics: Animals; Antigens, Neoplasm; Antineoplastic Agents; Cancer Vaccines; Cell- and Tissue-Based Therapy; Dendritic Cells; Genetic Therapy; Humans; Immunotherapy; Molecular Targeted Therapy; Neoplasms; Telomerase; Vaccines, DNA
PubMed: 31013796
DOI: 10.3390/ijms20081823 -
Retina (Philadelphia, Pa.) May 2017Geographic atrophy (GA) is an advanced, vision-threatening form of age-related macular degeneration (AMD) affecting approximately five million individuals worldwide. To... (Review)
Review
PURPOSE
Geographic atrophy (GA) is an advanced, vision-threatening form of age-related macular degeneration (AMD) affecting approximately five million individuals worldwide. To date, there are no approved therapeutics for GA treatment; however, several are in clinical trials. This review focuses on the pathophysiology of GA, particularly the role of complement cascade dysregulation and emerging therapies targeting the complement cascade.
METHODS
Primary literature search on PubMed for GA, complement cascade in age-related macular degeneration. ClinicalTrials.gov was searched for natural history studies in GA and clinical trials of drugs targeting the complement cascade for GA.
RESULTS
Cumulative damage to the retina by aging, environmental stress, and other factors triggers inflammation via multiple pathways, including the complement cascade. When regulatory components in these pathways are compromised, as with several GA-linked genetic risk factors in the complement cascade, chronic inflammation can ultimately lead to the retinal cell death characteristic of GA. Complement inhibition has been identified as a key candidate for therapeutic intervention, and drugs targeting the complement pathway are currently in clinical trials.
CONCLUSION
The complement cascade is a strategic target for GA therapy. Further research, including on natural history and genetics, is crucial to expand the understanding of GA pathophysiology and identify effective therapeutic targets.
Topics: Aging; Antibodies, Monoclonal, Humanized; Clinical Trials as Topic; Complement System Proteins; Environment; Geographic Atrophy; Humans; Macular Degeneration; Molecular Targeted Therapy
PubMed: 27902638
DOI: 10.1097/IAE.0000000000001392