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Frontiers in Endocrinology 2020Thyroid cancer is the most common endocrine cancer. The discovery of new biomarkers for thyroid cancer has significantly improved the understanding of the molecular... (Review)
Review
Thyroid cancer is the most common endocrine cancer. The discovery of new biomarkers for thyroid cancer has significantly improved the understanding of the molecular pathogenesis of thyroid cancer, thus allowing more personalized treatments for patients with thyroid cancer. Most of the recently discovered targeted therapies inhibit the known oncogenic mechanisms in thyroid cancer initiation and progression such as MAPK pathway, PI3K/Akt-mTOR pathways, or VEGF. Despite the significant advances in molecular testing and the discoveries of new and promising therapeutics, effective treatments for advanced and metastatic, iodine-refractory thyroid cancer are still lacking. Here, we aim to summarize the current understanding of the genetic alterations and the dysregulated pathways in thyroid cancer and to discuss the most recent targeted therapies and immunotherapy for advanced thyroid cancer with a promising anti-tumor activity and clinical benefit.
Topics: History, 21st Century; Humans; Immunotherapy; Molecular Targeted Therapy; Mutation; Signal Transduction; Therapies, Investigational; Thyroid Neoplasms
PubMed: 32528402
DOI: 10.3389/fendo.2020.00082 -
Medicinal Research Reviews Mar 2021There is an urgent need to identify novel therapies for childhood cancers. Neuroblastoma is the most common pediatric solid tumor, and accounts for ~15% of childhood... (Review)
Review
There is an urgent need to identify novel therapies for childhood cancers. Neuroblastoma is the most common pediatric solid tumor, and accounts for ~15% of childhood cancer-related mortality. Neuroblastomas exhibit genetic, morphological and clinical heterogeneity, which limits the efficacy of existing treatment modalities. Gaining detailed knowledge of the molecular signatures and genetic variations involved in the pathogenesis of neuroblastoma is necessary to develop safer and more effective treatments for this devastating disease. Recent studies with advanced high-throughput "omics" techniques have revealed numerous genetic/genomic alterations and dysfunctional pathways that drive the onset, growth, progression, and resistance of neuroblastoma to therapy. A variety of molecular signatures are being evaluated to better understand the disease, with many of them being used as targets to develop new treatments for neuroblastoma patients. In this review, we have summarized the contemporary understanding of the molecular pathways and genetic aberrations, such as those in MYCN, BIRC5, PHOX2B, and LIN28B, involved in the pathogenesis of neuroblastoma, and provide a comprehensive overview of the molecular targeted therapies under preclinical and clinical investigations, particularly those targeting ALK signaling, MDM2, PI3K/Akt/mTOR and RAS-MAPK pathways, as well as epigenetic regulators. We also give insights on the use of combination therapies involving novel agents that target various pathways. Further, we discuss the future directions that would help identify novel targets and therapeutics and improve the currently available therapies, enhancing the treatment outcomes and survival of patients with neuroblastoma.
Topics: Child; Humans; Molecular Targeted Therapy; Neuroblastoma; Signal Transduction
PubMed: 33155698
DOI: 10.1002/med.21750 -
Nature Reviews. Nephrology Jul 2023Kidney disease is a leading cause of morbidity and mortality across the globe. Current interventions for kidney disease include dialysis and renal transplantation, which... (Review)
Review
Kidney disease is a leading cause of morbidity and mortality across the globe. Current interventions for kidney disease include dialysis and renal transplantation, which have limited efficacy or availability and are often associated with complications such as cardiovascular disease and immunosuppression. There is therefore a pressing need for novel therapies for kidney disease. Notably, as many as 30% of kidney disease cases are caused by monogenic disease and are thus potentially amenable to genetic medicine, such as cell and gene therapy. Systemic disease that affects the kidney, such as diabetes and hypertension, might also be targetable by cell and gene therapy. However, although there are now several approved gene and cell therapies for inherited diseases that affect other organs, none targets the kidney. Promising recent advances in cell and gene therapy have been made, including in the kidney research field, suggesting that this form of therapy might represent a potential solution for kidney disease in the future. In this Review, we describe the potential for cell and gene therapy in treating kidney disease, focusing on recent genetic studies, key advances and emerging technologies, and we describe several crucial considerations for renal genetic and cell therapies.
Topics: Humans; Renal Dialysis; Kidney Diseases; Kidney; Kidney Transplantation; Genetic Therapy
PubMed: 36973494
DOI: 10.1038/s41581-023-00702-3 -
Nature Reviews. Clinical Oncology Aug 2022Structural imaging remains an essential component of diagnosis, staging and response assessment in patients with cancer; however, as clinicians increasingly seek to... (Review)
Review
Structural imaging remains an essential component of diagnosis, staging and response assessment in patients with cancer; however, as clinicians increasingly seek to noninvasively investigate tumour phenotypes and evaluate functional and molecular responses to therapy, theranostics - the combination of diagnostic imaging with targeted therapy - is becoming more widely implemented. The field of radiotheranostics, which is the focus of this Review, combines molecular imaging (primarily PET and SPECT) with targeted radionuclide therapy, which involves the use of small molecules, peptides and/or antibodies as carriers for therapeutic radionuclides, typically those emitting α-, β- or auger-radiation. The exponential, global expansion of radiotheranostics in oncology stems from its potential to target and eliminate tumour cells with minimal adverse effects, owing to a mechanism of action that differs distinctly from that of most other systemic therapies. Currently, an enormous opportunity exists to expand the number of patients who can benefit from this technology, to address the urgent needs of many thousands of patients across the world. In this Review, we describe the clinical experience with established radiotheranostics as well as novel areas of research and various barriers to progress.
Topics: Humans; Medical Oncology; Neoplasms; Precision Medicine; Radiopharmaceuticals
PubMed: 35725926
DOI: 10.1038/s41571-022-00652-y -
Advanced Drug Delivery Reviews Sep 2018Precision medicine holds great promise to harness genetic and epigenetic cues for targeted treatment of a variety of diseases, ranging from many types of cancers,... (Review)
Review
Precision medicine holds great promise to harness genetic and epigenetic cues for targeted treatment of a variety of diseases, ranging from many types of cancers, neurodegenerative diseases, to cardiovascular diseases. The proteomic profiles resulting from the unique genetic and epigenetic signatures represent a class of relatively well accessible molecular targets for both interrogation (e.g., diagnosis, prognosis) and intervention (e.g., targeted therapy) of these diseases. Aptamers are promising for such applications by specific binding with cognate disease biomarkers. Nucleic acid aptamers are a class of DNA or RNA with unique three-dimensional conformations that allow them to specifically bind with target molecules. Aptamers can be relatively easily screened, reproducibly manufactured, programmably designed, and chemically modified for various biomedical applications, including targeted therapy. Aptamers can be chemically modified to resist enzymatic degradation or optimize their pharmacological behaviors, which ensured their chemical integrity and bioavailability under physiological conditions. In this review, we will focus on recent progress and discuss the challenges and opportunities in the research areas of aptamer-based targeted therapy in the forms of aptamer therapeutics and aptamer-drug conjugates (ApDCs).
Topics: Antineoplastic Agents; Aptamers, Nucleotide; Cardiovascular Diseases; Drug Delivery Systems; Humans; Neoplasms; Neurodegenerative Diseases; Neuroprotective Agents; Precision Medicine
PubMed: 30125604
DOI: 10.1016/j.addr.2018.08.005 -
Frontiers of Medicine Dec 2020The cure rate of childhood acute lymphoblastic leukemia (ALL) has exceeded 90% in some contemporary clinical trials. However, the dose intensity of conventional... (Review)
Review
The cure rate of childhood acute lymphoblastic leukemia (ALL) has exceeded 90% in some contemporary clinical trials. However, the dose intensity of conventional chemotherapy has been pushed to its limit. Further improvement in outcome will need to rely more heavily on molecular therapeutic as well as immuno-and cellular-therapy approaches together with precise risk stratification. Children with ETV6-RUNX1 or hyperdiploid > 50 ALL who achieve negative minimal residual disease during early remission induction are suitable candidates for reduction in treatment. Patients with Philadelphia chromosome (Ph)-positive or Ph-like ALL with ABL-class fusion should be treated with dasatinib. BH3 profiling and other preclinical methods have identified several high-risk subtypes, such as hypodiplod, early T-cell precursor, immature T-cell, KMT2A-rearranged, Ph-positive and TCF-HLF-positive ALL, that may respond to BCL-2 inhibitor venetoclax. There are other fusions or mutations that may serve as putative targets, but effective targeted therapy has yet to be established. For other high-risk patients or poor early treatment responders who do not have targetable genetic lesions, current approaches that offer hope include blinatumomab, inotuzumab and CAR-T cell therapy for B-ALL, and daratumumab and nelarabine for T-ALL. With the expanding therapeutic armamentarium, we should start focus on rational combinations of targeted therapy with non-overlapping toxicities.
Topics: Child; Dasatinib; Humans; Neoplasm, Residual; Philadelphia Chromosome; Precision Medicine; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 33074527
DOI: 10.1007/s11684-020-0759-8 -
European Journal of Pharmaceutics and... Jun 2015Cancer is the second worldwide cause of death, exceeded only by cardiovascular diseases. It is characterized by uncontrolled cell proliferation and an absence of cell... (Review)
Review
Cancer is the second worldwide cause of death, exceeded only by cardiovascular diseases. It is characterized by uncontrolled cell proliferation and an absence of cell death that, except for hematological cancers, generates an abnormal cell mass or tumor. This primary tumor grows thanks to new vascularization and, in time, acquires metastatic potential and spreads to other body sites, which causes metastasis and finally death. Cancer is caused by damage or mutations in the genetic material of the cells due to environmental or inherited factors. While surgery and radiotherapy are the primary treatment used for local and non-metastatic cancers, anti-cancer drugs (chemotherapy, hormone and biological therapies) are the choice currently used in metastatic cancers. Chemotherapy is based on the inhibition of the division of rapidly growing cells, which is a characteristic of the cancerous cells, but unfortunately, it also affects normal cells with fast proliferation rates, such as the hair follicles, bone marrow and gastrointestinal tract cells, generating the characteristic side effects of chemotherapy. The indiscriminate destruction of normal cells, the toxicity of conventional chemotherapeutic drugs, as well as the development of multidrug resistance, support the need to find new effective targeted treatments based on the changes in the molecular biology of the tumor cells. These novel targeted therapies, of increasing interest as evidenced by FDA-approved targeted cancer drugs in recent years, block biologic transduction pathways and/or specific cancer proteins to induce the death of cancer cells by means of apoptosis and stimulation of the immune system, or specifically deliver chemotherapeutic agents to cancer cells, minimizing the undesirable side effects. Although targeted therapies can be achieved directly by altering specific cell signaling by means of monoclonal antibodies or small molecules inhibitors, this review focuses on indirect targeted approaches that mainly deliver chemotherapeutic agents to molecular targets overexpressed on the surface of tumor cells. In particular, we offer a detailed description of different cytotoxic drug carriers, such as liposomes, carbon nanotubes, dendrimers, polymeric micelles, polymeric conjugates and polymeric nanoparticles, in passive and active targeted cancer therapy, by enhancing the permeability and retention or by the functionalization of the surface of the carriers, respectively, emphasizing those that have received FDA approval or are part of the most important clinical studies up to date. These drug carriers not only transport the chemotherapeutic agents to tumors, avoiding normal tissues and reducing toxicity in the rest of the body, but also protect cytotoxic drugs from degradation, increase the half-life, payload and solubility of cytotoxic agents and reduce renal clearance. Despite the many advantages of all the anticancer drug carriers analyzed, only a few of them have reached the FDA approval, in particular, two polymer-protein conjugates, five liposomal formulations and one polymeric nanoparticle are available in the market, in contrast to the sixteen FDA approval of monoclonal antibodies. However, there are numerous clinical trials in progress of polymer-protein and polymer-drug conjugates, liposomal formulations, including immunoliposomes, polymeric micelles and polymeric nanoparticles. Regarding carbon nanotubes or dendrimers, there are no FDA approvals or clinical trials in process up to date due to their unresolved toxicity. Moreover, we analyze in detail the more promising and advanced preclinical studies of the particular case of polymeric nanoparticles as carriers of different cytotoxic agents to active and passive tumor targeting published in the last 5 years, since they have a huge potential in cancer therapy, being one of the most widely studied nano-platforms in this field in the last years. The interest that these formulations have recently achieved is stressed by the fact that 90% of the papers based on cancer therapeutics with polymeric nanoparticles have been published in the last 6 years (PubMed search).
Topics: Animals; Antineoplastic Agents; Chemistry, Pharmaceutical; Diffusion of Innovation; Disease Models, Animal; Drug Carriers; Drug Delivery Systems; Forecasting; Humans; Medical Oncology; Nanomedicine; Nanoparticles; Neoplasms; Technology, Pharmaceutical; Treatment Outcome
PubMed: 25813885
DOI: 10.1016/j.ejpb.2015.03.018 -
Cell Metabolism Apr 2018RNA-targeted therapies represent a platform for drug discovery involving chemically modified oligonucleotides, a wide range of cellular RNAs, and a novel target-binding... (Review)
Review
RNA-targeted therapies represent a platform for drug discovery involving chemically modified oligonucleotides, a wide range of cellular RNAs, and a novel target-binding motif, Watson-Crick base pairing. Numerous hurdles considered by many to be impassable have been overcome. Today, four RNA-targeted therapies are approved for commercial use for indications as diverse as Spinal Muscular Atrophy (SMA) and reduction of low-density lipoprotein cholesterol (LDL-C) and by routes of administration including subcutaneous, intravitreal, and intrathecal delivery. The technology is efficient and supports approaching "undruggable" targets. Three additional agents are progressing through registration, and more are in clinical development, representing several chemical and structural classes. Moreover, progress in understanding the molecular mechanisms by which these drugs work has led to steadily better clinical performance and a wide range of mechanisms that may be exploited for therapeutic purposes. Here we summarize the progress, future challenges, and opportunities for this drug discovery platform.
Topics: Animals; Drug Discovery; Genetic Therapy; Humans; Molecular Targeted Therapy; Muscular Atrophy, Spinal; Oligoribonucleotides, Antisense; RNA, Small Interfering
PubMed: 29617640
DOI: 10.1016/j.cmet.2018.03.004 -
Molecular Cancer Jul 2023Breast cancer is the second leading cause of death for women worldwide. The heterogeneity of this disease presents a big challenge in its therapeutic management.... (Review)
Review
Breast cancer is the second leading cause of death for women worldwide. The heterogeneity of this disease presents a big challenge in its therapeutic management. However, recent advances in molecular biology and immunology enable to develop highly targeted therapies for many forms of breast cancer. The primary objective of targeted therapy is to inhibit a specific target/molecule that supports tumor progression. Ak strain transforming, cyclin-dependent kinases, poly (ADP-ribose) polymerase, and different growth factors have emerged as potential therapeutic targets for specific breast cancer subtypes. Many targeted drugs are currently undergoing clinical trials, and some have already received the FDA approval as monotherapy or in combination with other drugs for the treatment of different forms of breast cancer. However, the targeted drugs have yet to achieve therapeutic promise against triple-negative breast cancer (TNBC). In this aspect, immune therapy has come up as a promising therapeutic approach specifically for TNBC patients. Different immunotherapeutic modalities including immune-checkpoint blockade, vaccination, and adoptive cell transfer have been extensively studied in the clinical setting of breast cancer, especially in TNBC patients. The FDA has already approved some immune-checkpoint blockers in combination with chemotherapeutic drugs to treat TNBC and several trials are ongoing. This review provides an overview of clinical developments and recent advancements in targeted therapies and immunotherapies for breast cancer treatment. The successes, challenges, and prospects were critically discussed to portray their profound prospects.
Topics: Humans; Female; Triple Negative Breast Neoplasms; Immunotherapy; Combined Modality Therapy; Molecular Targeted Therapy
PubMed: 37415164
DOI: 10.1186/s12943-023-01805-y -
Journal of Hematology & Oncology Sep 2021Immunotherapies such as immune checkpoint blockade (ICB) and adoptive cell therapy (ACT) have revolutionized cancer treatment, especially in patients whose disease was... (Review)
Review
Immunotherapies such as immune checkpoint blockade (ICB) and adoptive cell therapy (ACT) have revolutionized cancer treatment, especially in patients whose disease was otherwise considered incurable. However, primary and secondary resistance to single agent immunotherapy often results in treatment failure, and only a minority of patients experience long-term benefits. This review article will discuss the relationship between cancer immune response and mechanisms of resistance to immunotherapy. It will also provide a comprehensive review on the latest clinical status of combination therapies (e.g., immunotherapy with chemotherapy, radiation therapy and targeted therapy), and discuss combination therapies approved by the US Food and Drug Administration. It will provide an overview of therapies targeting cytokines and other soluble immunoregulatory factors, ACT, virotherapy, innate immune modifiers and cancer vaccines, as well as combination therapies that exploit alternative immune targets and other therapeutic modalities. Finally, this review will include the stimulating insights from the 2020 China Immuno-Oncology Workshop co-organized by the Chinese American Hematologist and Oncologist Network (CAHON), the China National Medical Product Administration (NMPA) and Tsinghua University School of Medicine.
Topics: Animals; Cancer Vaccines; Combined Modality Therapy; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Neoplasms; Oncolytic Virotherapy
PubMed: 34579759
DOI: 10.1186/s13045-021-01164-5