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Cells Apr 2020Osteosarcomas are the most frequent primary bone sarcomas, affecting mainly children, adolescents, and young adults, and with a second peak of incidence in elderly... (Review)
Review
Osteosarcomas are the most frequent primary bone sarcomas, affecting mainly children, adolescents, and young adults, and with a second peak of incidence in elderly individuals. The current therapeutic management, a combined regimen of poly-chemotherapy and surgery, still remains largely insufficient, as patient survival has not improved in recent decades. Osteosarcomas are very heterogeneous tumors, both at the intra- and inter-tumor level, with no identified driver mutation. Consequently, efforts to improve treatments using targeted therapies have faced this lack of specific osteosarcoma targets. Nevertheless, these tumors are inextricably linked to their local microenvironment, composed of bone, stromal, vascular and immune cells and the osteosarcoma microenvironment is now considered to be essential and supportive for growth and dissemination. This review describes the different actors of the osteosarcoma microenvironment and gives an overview of the past, current, and future strategies of therapy targeting this complex ecosystem, with a focus on the role of extracellular vesicles and on the emergence of multi-kinase inhibitors.
Topics: Animals; Bone Remodeling; Humans; Immune System; Mesenchymal Stem Cells; Molecular Targeted Therapy; Osteosarcoma; Tumor Microenvironment
PubMed: 32326444
DOI: 10.3390/cells9040976 -
Advanced Materials (Deerfield Beach,... May 2018White blood cells (WBCs) are a major component of immunity in response to pathogen invasion. Neutrophils are the most abundant WBCs in humans, playing a central role in... (Review)
Review
White blood cells (WBCs) are a major component of immunity in response to pathogen invasion. Neutrophils are the most abundant WBCs in humans, playing a central role in acute inflammation induced by pathogens. Adhesion to vasculature and tissue infiltration of neutrophils are key processes in acute inflammation. Many inflammatory/autoimmune disorders and cancer therapies have been found to be involved in activation and tissue infiltration of neutrophils. A promising strategy to develop novel targeted drug delivery systems is the targeting and exploitation of activated neutrophils. Herein, a new drug delivery platform based on neutrophils is reviewed. There are two types of drug delivery systems: neutrophils as carriers and neutrophil-membrane-derived nanovesicles. It is discussed how nanoparticles hijack neutrophils in vivo to deliver therapeutics across blood vessel barriers and how neutrophil-membrane-derived nanovesicles target inflamed vasculature. Finally, the potential applications of neutrophil-based drug delivery systems in treating inflammation and cancers are presented.
Topics: Drug Delivery Systems; Humans; Inflammation; Nanoparticles; Neoplasms; Neutrophils
PubMed: 29577477
DOI: 10.1002/adma.201706245 -
Expert Opinion on Investigational Drugs Nov 2019: Targeted therapies in cancer aim to inhibit specific molecular targets responsible for enhanced tumor growth. AKT/PKB (protein kinase B) is a serine threonine kinase... (Review)
Review
: Targeted therapies in cancer aim to inhibit specific molecular targets responsible for enhanced tumor growth. AKT/PKB (protein kinase B) is a serine threonine kinase involved in several critical cellular pathways, including survival, proliferation, invasion, apoptosis, and angiogenesis. Although phosphatidylinositol-3 kinase (PI3K) is the key regulator of AKT activation, numerous stimuli and kinases initiate pro-proliferative AKT signaling which results in the activation of AKT pathway to drive cellular growth and survival. Activating mutations and amplification of components of the AKT pathway are implicated in the pathogenesis of many cancers including breast and ovarian. Given its importance, AKT, it has been validated as a promising therapeutic target.: This article summarizes AKT's biological function and different classes of AKT inhibitors as anticancer agents. We also explore the efficacy of AKT inhibitors as monotherapies and in combination with cytotoxic and other targeted therapies.: The complex mechanism following AKT inhibition requires the addition of other therapies to prevent resistance and improve clinical response. Further studies are necessary to determine additional rational combinations that can enhance efficacy of AKT inhibitors, potentially by targeting compensatory mechanisms, and/or enhancing apoptosis. The identification of biomarkers of response is essential for the development of successful therapeutics.
Topics: Animals; Antineoplastic Agents; Apoptosis; Drug Development; Drug Resistance, Neoplasm; Humans; Molecular Targeted Therapy; Neoplasms; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt
PubMed: 31594388
DOI: 10.1080/13543784.2019.1676726 -
Cancer Discovery Jul 2021Synthetic lethality (SL) provides a conceptual framework for tackling targets that are not classically "druggable," including loss-of-function mutations in tumor... (Review)
Review
Synthetic lethality (SL) provides a conceptual framework for tackling targets that are not classically "druggable," including loss-of-function mutations in tumor suppressor genes required for carcinogenesis. Recent technological advances have led to an inflection point in our understanding of genetic interaction networks and ability to identify a wide array of novel SL drug targets. Here, we review concepts and lessons emerging from first-generation trials aimed at testing SL drugs, discuss how the nature of the targeted lesion can influence therapeutic outcomes, and highlight the need to develop clinical biomarkers distinct from those based on the paradigms developed to target activated oncogenes. SIGNIFICANCE: SL offers an approach for the targeting of loss of function of tumor suppressor and DNA repair genes, as well as of amplification and/or overexpression of genes that cannot be targeted directly. A next generation of tumor-specific alterations targetable through SL has emerged from high-throughput CRISPR technology, heralding not only new opportunities for drug development, but also important challenges in the development of optimal predictive biomarkers.
Topics: Drug Development; Genes, Tumor Suppressor; Humans; Molecular Targeted Therapy; Neoplasms; Synthetic Lethal Mutations
PubMed: 33795234
DOI: 10.1158/2159-8290.CD-20-1503 -
F1000Research 2018Brain metastases are the most common malignancy encountered in the central nervous system (CNS), with up to 30-40% of cancer patients developing brain metastases at some... (Review)
Review
Brain metastases are the most common malignancy encountered in the central nervous system (CNS), with up to 30-40% of cancer patients developing brain metastases at some point during the course of their disease. The management of brain metastasis is rapidly evolving and the roles of local therapies such as whole-brain radiation therapy, stereotactic radiosurgery, and resection along with systemic therapies are in flux. An emphasis on the neurocognitive side effects associated with treatment has gained prominence. Novel molecular studies have demonstrated important evolutionary patterns underpinning the development of brain metastasis and leptomeningeal disease, which may be key to unlocking new therapeutic strategies. This article provides a framework for incorporating the results of recent randomized radiotherapy clinical trials into practice, expounds upon the emphasis on cognition being an important driver in therapeutic selection, describes the importance of CNS-penetrating systemic therapies, and provides an overview of the novel molecular insights that will likely set the stage for future developments in this field.
Topics: Brain Neoplasms; Disease Management; Humans; Neoplasm Metastasis; Radiosurgery; Radiotherapy; Therapeutics
PubMed: 30473769
DOI: 10.12688/f1000research.15903.1 -
International Journal of Molecular... Feb 2021Around 77 new oncology drugs were approved by the FDA in the past five years; however, most cancers remain untreated. Small molecules and antibodies are dominant... (Review)
Review
Around 77 new oncology drugs were approved by the FDA in the past five years; however, most cancers remain untreated. Small molecules and antibodies are dominant therapeutic modalities in oncology. Antibody-drug conjugates, bispecific antibodies, peptides, cell, and gene-therapies are emerging to address the unmet patient need. Advancement in the discovery and development platforms, identification of novel targets, and emergence of new technologies have greatly expanded the treatment options for patients. Here, we provide an overview of various therapeutic modalities and the current treatment options in oncology, and an in-depth discussion of the therapeutics in the preclinical stage for the treatment of breast cancer, lung cancer, and multiple myeloma.
Topics: Antibodies, Monoclonal; Cell- and Tissue-Based Therapy; Genetic Therapy; Humans; Immunoconjugates; Immunotherapy; Medical Oncology; Molecular Targeted Therapy; Neoplasms; Small Molecule Libraries
PubMed: 33670524
DOI: 10.3390/ijms22042008 -
Cancer Cell Apr 2021Despite remarkable successes in the clinic, cancer targeted therapy development remains challenging and the failure rate is disappointingly high. This problem is partly... (Review)
Review
Despite remarkable successes in the clinic, cancer targeted therapy development remains challenging and the failure rate is disappointingly high. This problem is partly due to the misapplication of the targeted therapy paradigm to therapeutics targeting pan-essential genes, which can result in therapeutics whereby efficacy is attenuated by dose-limiting toxicity. Here we summarize the key features of successful chemotherapy and targeted therapy agents, and use case studies to outline recurrent challenges to drug development efforts targeting pan-essential genes. Finally, we suggest strategies to avoid previous pitfalls for ongoing and future development of pan-essential therapeutics.
Topics: Antineoplastic Agents; Drug Therapy; Genes, Essential; Humans; Molecular Targeted Therapy; Neoplasms; Treatment Outcome
PubMed: 33450197
DOI: 10.1016/j.ccell.2020.12.008 -
American Society of Clinical Oncology... Apr 2022Mantle cell lymphoma is a rare B-cell non-Hodgkin lymphoma that is clinically and biologically heterogeneous. Risk stratification at the time of diagnosis is critical....
Mantle cell lymphoma is a rare B-cell non-Hodgkin lymphoma that is clinically and biologically heterogeneous. Risk stratification at the time of diagnosis is critical. One of the most powerful prognostic indices is the Mantle Cell Lymphoma International Prognostic Index-Combined, which integrates an estimate of proliferation (Ki67 index) with the standard Mantle Cell Lymphoma International Prognostic Index clinical factors. In addition, the presence of mutation is associated with suboptimal response to intensive chemoimmunotherapy and particularly dismal survival outcomes. Given their excellent activity in the relapsed/refractory setting, increasingly, biologically targeted therapeutics-such as covalent Bruton tyrosine kinase inhibitors, lenalidomide, and venetoclax-are being incorporated into "chemotherapy-free" regimens and in combination with established chemoimmunotherapy backbones for treatment-naïve mantle cell lymphoma. In addition, risk-adapted treatment programs are increasingly being studied. These programs tailor treatment according to baseline prognostic factors (e.g., presence of mutation) and may incorporate biomarkers of response such as minimal residual disease assessment. Although still investigational, these studies present an opportunity to move beyond the biology-agnostic, historical fitness-based treatment selection paradigm and toward a more personalized, tailored treatment approach in mantle cell lymphoma. After Bruton tyrosine kinase inhibitor failure, many promising standard or investigational therapies exist, including CAR T-cell therapy (including brexucabtagene autoleucel and lisocabtagene maraleucel), bispecific antibody therapy targeting CD20-CD3, zilovertamab vedotin (an antibody-drug conjugate that targets ROR1), and the noncovalent Bruton tyrosine kinase inhibitor pirtobrutinib. These new therapies show promising efficacy, even among high-risk patients, and will likely translate to improvements in survival outcomes for patients with progressive mantle cell lymphoma following treatment with a Bruton tyrosine kinase inhibitor.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Humans; Immunoconjugates; Immunotherapy; Immunotherapy, Adoptive; Lymphoma, Mantle-Cell; Protein Kinase Inhibitors
PubMed: 35561299
DOI: 10.1200/EDBK_349509 -
Rheumatology (Oxford, England) Dec 2021In this review, the results of recent and ongoing clinical trials in patients with SLE are discussed. After many unsuccessful trials in the past decade, belimumab was... (Review)
Review
In this review, the results of recent and ongoing clinical trials in patients with SLE are discussed. After many unsuccessful trials in the past decade, belimumab was the first biologic specifically designed for SLE that met its primary end point. At the same time, studies on the pathophysiology of SLE have further elucidated the pathways involved in the disease, which has led to the identification of new possible therapeutics and has encouraged the initiation of new trials. These new drugs include biologics that target B cells, T cells and type 1 interferons, and small molecules that inhibit kinases. Other therapeutics aim to restore immunological balance by restoring tolerance. Results from phase II and even phase III trials are promising and it is likely that some of the therapeutics discussed will receive approval in the following years. Hopefully, this will allow for more tailor-made medicine for SLE patients in the future.
Topics: Biological Therapy; Humans; Lupus Erythematosus, Systemic
PubMed: 34951924
DOI: 10.1093/rheumatology/keab498 -
Arteriosclerosis, Thrombosis, and... Apr 2019Cardiovascular disease remains a leading cause of morbidity and mortality in people with types 1 or 2 diabetes mellitus. Although beneficial roles for strict control of... (Review)
Review
Cardiovascular disease remains a leading cause of morbidity and mortality in people with types 1 or 2 diabetes mellitus. Although beneficial roles for strict control of hyperglycemia have been suggested, such a strategy is not without liabilities. Specifically, the risk of hypoglycemia and its consequences remain an omnipresent threat with such approaches. The advent of the CVOT (Cardiovascular Outcomes Trials) for new antidiabetes mellitus treatments has uncovered unexpected benefits of cardiovascular protection in some of the new classes of agents, such as the GLP-1 RAs (glucagon-like peptide-1 receptor agonists) and the SGLT-2 (sodium-glucose cotransporter-2) inhibitors. Further, state-of-the-art approaches, such as antibodies to PCKSK9 (proprotein convertase subtilisin-kexin type 9); RNA therapeutics; agents targeting distinct components of the immune/inflammatory response; and novel small molecules that block the actions of RAGE (receptor for advanced glycation end products) signaling, also hold potential as new therapies for diabetes mellitus and cardiovascular disease. Finally, interventions such as weight loss, through bariatric surgery, may hold promise for benefit in diabetes and cardiovascular disease. In this Brief Review, some of the novel approaches and emerging targets for the treatment of diabetes mellitus and cardiovascular disease are discussed. Ultimately, identification of the optimal timing and combinations of such interventions, especially in the context of personalized approaches, together with emerging disease-modifying agents, holds great promise to reduce the burden that diabetes poses to the cardiovascular system.
Topics: Anti-Inflammatory Agents; Bariatric Surgery; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus; Humans; Hypoglycemia; Hypoglycemic Agents; Hypolipidemic Agents; Immunosuppressive Agents; MicroRNAs; Molecular Targeted Therapy; Outcome Assessment, Health Care; Precision Medicine; RNA, Long Noncoding; Therapies, Investigational; Weight Loss
PubMed: 30786741
DOI: 10.1161/ATVBAHA.119.310961