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Expert Review of Proteomics Jun 2016The advent of biologic drugs like infliximab, Etanercept, rituximab and tocilizumab has greatly improved the treatment of rheumatoid arthritis, however, increased risk... (Review)
Review
INTRODUCTION
The advent of biologic drugs like infliximab, Etanercept, rituximab and tocilizumab has greatly improved the treatment of rheumatoid arthritis, however, increased risk of infection and high cost still remain unmet needs. A new generation of targeted therapeutics is being developed to target payload drug specifically to arthritic tissue; to concentrate the drug in the disease area and limit the off target systemic exposure. This might also reduce total effective dose.
AREAS COVERED
This article summarizes the properties and progress of targeted therapies that have been published on PubMed, and addresses their clinical potential. Expert commentary: Incredible progress with targeted therapies has already been made in the short time since the principle was first proven in animal models in 2007 when targeting payload drug to overexpressed oncofetal domain of fibronectin in inflamed arthritic joints.
Topics: Animals; Antibodies, Monoclonal, Humanized; Arthritis, Rheumatoid; Etanercept; Humans; Molecular Targeted Therapy
PubMed: 27258782
DOI: 10.1080/14789450.2016.1188008 -
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 Healthcare Materials Jul 2018In order to overcome the main disadvantages of conventional cancer therapies, which prove to be inadequate because of their lack of selectivity, the development of... (Review)
Review
In order to overcome the main disadvantages of conventional cancer therapies, which prove to be inadequate because of their lack of selectivity, the development of targeted delivery systems is one of the main focuses in anticancer research. It is repeatedly shown that decorating the surface of nanocarriers with high-affinity targeting ligands, such as peptides or small molecules, is an effective way to selectively deliver therapeutics by enhancing their specific cellular uptake via the binding between a specific receptor and the nanosystems. Nowadays, the need of finding new potential biological targets with a high endocytic efficiency as well as a low tendency to mutate is urgent and, in this context, mannose and mannose-6-phosphate receptors appear promising to target anticancer drugs to cells where their expression is upregulated. Moreover, they open the path to encouraging applications in immune-based and gene therapies as well as in theragnostic purposes. In this work, the potential of mannose- and mannose-6-phosphate-targeted delivery systems in cancer therapy is discussed, emphasizing their broad application both in direct treatments against cancer cells with conventional chemotherapeutics or by gene therapy and also their encouraging capabilities in immunotherapy and diagnostics purposes.
Topics: Animals; Antineoplastic Agents; Drug Carriers; Drug Delivery Systems; Humans; Immunotherapy; Mannose; Mannosephosphates; Nanomedicine; Neoplasms; Receptor, IGF Type 2
PubMed: 29719138
DOI: 10.1002/adhm.201701398 -
Journal of Hepatology Feb 2020Intrahepatic cholangiocarcinoma (iCCA) is a highly lethal hepatobiliary neoplasm whose incidence is increasing. Largely neglected for decades as a rare malignancy and... (Review)
Review
Intrahepatic cholangiocarcinoma (iCCA) is a highly lethal hepatobiliary neoplasm whose incidence is increasing. Largely neglected for decades as a rare malignancy and frequently misdiagnosed as carcinoma of unknown primary, considerable clinical and investigative attention has recently been focused on iCCA worldwide. The established standard of care includes first-line (gemcitabine and cisplatin), second-line (FOLFOX) and adjuvant (capecitabine) systemic chemotherapy. Compared to hepatocellular carcinoma, iCCA is genetically distinct with several targetable genetic aberrations identified to date. Indeed, FGFR2 and NTRK fusions, and IDH1 and BRAF targetable mutations have been comprehensively characterised and clinical data is emerging on targeting these oncogenic drivers pharmacologically. Also, the role of immunotherapy has been examined and is an area of intense investigation. Herein, in a timely and topical manner, we will review these advances and highlight future directions of research.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Chemotherapy, Adjuvant; Cholangiocarcinoma; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Incidence; Molecular Targeted Therapy; Treatment Outcome; Tumor Microenvironment
PubMed: 31954497
DOI: 10.1016/j.jhep.2019.10.009 -
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 -
Expert Opinion on Therapeutic Targets Aug 2004The continued evolution of targeted liposomal therapeutics has resulted in new agents with remarkable antitumour efficacy and relatively mild toxicity profiles. A... (Review)
Review
The continued evolution of targeted liposomal therapeutics has resulted in new agents with remarkable antitumour efficacy and relatively mild toxicity profiles. A careful selection of the ligand is necessary to reduce immunogenicity, retain extended circulation lifetimes, target tumour-specific cell surface epitopes, and induce internalisation and subsequent release of the therapeutic substance from the liposome. Methods for assembling targeted liposomes, including a novel micellar insertion technology, for incorporation of targeting molecules that efficiently transforms a non-targeted liposomal therapeutic to a targeted one, greatly assist the translation of targeted liposome technology into the clinic. Targeting strategies with liposomes directed at solid tumours and vascular targets are discussed. The authors believe the development of ligand-targeted liposomes is now in the advanced stage and offers unique and important advantages among other targeted therapies. Anti-HER2 immunoliposomal doxorubicin is awaiting Phase I clinical trials, the results of which should provide new insights into the promise of ligand-targeted liposomal therapies.
Topics: Animals; Antineoplastic Agents; Drug Delivery Systems; Humans; Ligands; Liposomes; Neoplasms
PubMed: 15268628
DOI: 10.1517/14728222.8.4.335 -
Journal of Clinical Oncology : Official... Aug 2022Precision medicine has become a dominant theme in the treatment of biliary tract cancers (BTCs). Although prognosis remains poor, technologies for improved molecular... (Review)
Review
Precision medicine has become a dominant theme in the treatment of biliary tract cancers (BTCs). Although prognosis remains poor, technologies for improved molecular characterization along with the US Food and Drug Administration approval of several targeted therapies have changed the therapeutic landscape of advanced BTC. The hallmark of BTC oncogenesis is chronic inflammation of the liver and biliary tract regardless of the anatomical subtype. Subtypes of BTC correspond to distinct molecular characteristics, making BTC a molecularly heterogenous collection of tumors. Collectively, up to 40% of BTCs harbor a potentially targetable molecular abnormality, and the National Comprehensive Cancer Network guidelines recommend molecular profiling for all patients with advanced BTC. Use of circulating tumor DNA, immunohistochemistry, and next-generation sequencing continues to expand the utility for biomarker-driven management and molecular monitoring of BTC. Improving outcomes using biomarker-agnostic treatment for nontargetable tumors also remains a priority, and combinational treatment strategies such as immune checkpoint inhibition plus chemotherapy hold promise for this subgroup of patients.
Topics: Biliary Tract Neoplasms; High-Throughput Nucleotide Sequencing; Humans; Molecular Targeted Therapy; Precision Medicine; Prognosis
PubMed: 35839428
DOI: 10.1200/JCO.21.02576 -
Bioorganic Chemistry May 2022Near-IR fluorescent sensitizers based on heptamethine cyanine (Cy820 and Cy820-IMC) were synthesized and their abilities to target and abolish tumor cells via...
Near-IR fluorescent sensitizers based on heptamethine cyanine (Cy820 and Cy820-IMC) were synthesized and their abilities to target and abolish tumor cells via photodynamic therapy (PDT) were explored. Some hepthamethine cyanine dyes can be transported into cancer cells via the organic anion transporting polypeptides (OATPs). In this study, we aimed to enhance the target ability of the sensitizer by conjugation Cy820 with indomethacin, a non-steroidal anti-inflammatory drug (NSAID), to obtain Cy820-IMC that aimed to target cyclooxygenase-2 (COX-2) which overexpresses in cancer cells. The results showed that Cy820-IMC internalized the cancer cells faster than Cy820 which was verified to be related to COX-2 level and OATPs. Based on PDT experiments, Cy820-IMC has higher photocytotoxicity index than Cy820, >7.13 and 4.90, respectively, implying that Cy820-IMC showed better PDT property than Cy820. However, Cy820 exhibits slightly higher normal-to-cancer cell toxicity ratio than Cy820-IMC, 6.58 and 3.63, respectively. Overall, Cy820-IMC has superior cancer targetability and enhanced photocytoxicity. These characteristics can be further improved towards clinically approved sensitizers for PDT.
Topics: Humans; Indomethacin; Neoplasms; Photochemotherapy; Photosensitizing Agents
PubMed: 35344895
DOI: 10.1016/j.bioorg.2022.105758 -
Molecular Cancer Therapeutics Dec 2017Precision medicine trials and targeted therapies have shifted to the forefront of oncology. Although targeted therapies have shown initial promise, implementation across... (Review)
Review
Precision medicine trials and targeted therapies have shifted to the forefront of oncology. Although targeted therapies have shown initial promise, implementation across the broad landscape of oncology has many challenges. These limitations include an incomplete understanding of the functional significance of variant alleles as well as the need for clinical research and practice models that are more patient-centered and account for the complexity of individual patient tumors. Furthermore, successful implementation of targeted therapies will also be predicated on efforts to standardize the framework for patient management support. Here, we review current implementations of targeted therapies in precision oncology and discuss how "actionability" is defined for molecular targets in cancer therapeutics. We also comment on the growing need for bioinformatics tools and data platforms to complement advances in precision oncology. Finally, we discuss current frameworks for integrating precision oncology into patient management and propose an integrated model that combines features of molecular tumor boards and decision support systems. .
Topics: Humans; Medical Oncology; Molecular Targeted Therapy; Precision Medicine; Psychosocial Support Systems
PubMed: 29203694
DOI: 10.1158/1535-7163.MCT-17-0597 -
Current Opinion in Nephrology and... Mar 2022The aim of this study was to summarize recent findings in kidney gene therapy while proposing cystinuria as a model kidney disease target for genome engineering... (Review)
Review
PURPOSE OF REVIEW
The aim of this study was to summarize recent findings in kidney gene therapy while proposing cystinuria as a model kidney disease target for genome engineering therapeutics.
RECENT FINDINGS
Despite the advances of gene therapy for treating diseases of other organs, the kidney lags behind. Kidney-targeted gene delivery remains an obstacle to gene therapy of kidney disease. Nanoparticle and adeno-associated viral vector technologies offer emerging hope for kidney gene therapy. Cystinuria represents a model potential target for kidney gene therapy due to its known genetic and molecular basis, targetability, and capacity for phenotypic rescue.
SUMMARY
Although gene therapy for kidney disease remains a major challenge, new and evolving technologies may actualize treatment for cystinuria and other kidney diseases.
Topics: Cystinuria; Female; Genetic Therapy; Humans; Kidney; Kidney Calculi; Male
PubMed: 34982522
DOI: 10.1097/MNH.0000000000000768