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Medical Advances in Hepatitis D Therapy: Molecular Targets.

An approximate number of 250 million people worldwide are chronically infected with hepatitis B virus, making them susceptible to a coinfection with hepatitis D virus. The superinfection causes the most severe form of a viral hepatitis and thus drastically worsens the course of the disease. Until recently, the only available therapy consisted of interferon-α, only eligible for a minority of patients. In July 2020, the EMA granted Hepcludex conditional marketing authorization throughout the European Union. This first-in-class entry inhibitor offers the promise to prevent the spread in order to

Human RecQL4 as a Novel Molecular Target for Cancer Therapy.

Human RecQ helicases play diverse roles in the maintenance of genomic stability. Inactivating mutations in 3 of the 5 human RecQ helicases are responsible for the pathogenesis of Werner syndrome (WS), Bloom syndrome (BS), Rothmund-Thomson syndrome (RTS), RAPADILINO, and Baller-Gerold syndrome (BGS). WS, BS, and RTS patients are at increased risk for developing many age-associated diseases including cancer. Mutations in RecQL1 and RecQL5 have not yet been associated with any human diseases so far. In terms of disease outcome, RecQL4 deserves special attention because mutations in RecQL4 result

Targeting MDM2 for novel molecular therapy: Beyond oncology.

The murine double minute 2 (MDM2) oncogene exerts major oncogenic activities in human cancers; it is not only the best-documented negative regulator of the p53 tumor suppressor, but also exerts p53-independent activities. There is an increasing interest in developing MDM2-based targeted therapies. Several classes of MDM2 inhibitors have been evaluated in preclinical models, with a few entering clinical trials, mainly for cancer therapy. However, noncarcinogenic roles for MDM2 have also been identified, demonstrating that MDM2 is involved in many chronic diseases and conditions such as inflamma

Molecular targeted therapies for microscopic polyangiitis and granulomatosis with polyangiitis.

Clinical trials and observational studies have established cyclophosphamide (CY) or rituximab plus glucocorticoid (GC) as standard remission … cal trial comparing tocilizumab and intravenous CY in combination with GC is currently in progress. Molecular targeted therapy is expected to transform the treatment strategy for MPA and GPA to allow GC-free or at least less GC-dependent forms of therapy.

[Molecular-targeted therapies for spinal and bulbar muscular atrophy].

Spinal and bulbar muscular atrophy (SBMA) is a polyglutamine-mediated lower motor neuron disease characterized by slowly progressive muscle weakness and atrophy. The cause of this disease is the expansion of a trinucleotide CAG repeat, which encodes the polyglutamine tract, within the first exon of the androgen receptor (AR) gene. SBMA exclusively occurs in adult males, whereas both heterozygous and homozygous females are usually asymptomatic. Testosterone-dependent nuclear accumulation of the pathogenic AR protein has been considered to be a fundamental step of neurodegenerative process, whic

[The plasma cell myeloma--molecular pathogenesis and target therapies].

The cells of the malignant clone of plasmacell myeloma have cytogenetic aberrations in a substantial number of cases. Many of these abnormal karyotypes are predictive for an unfavorable outcome. Gene mutations and abnormal gene expression, particularly of oncogenes and tumor suppressor genes, are often observed in myeloma cells. The cross talk between the myeloma cells and the bone marrow microenvironment plays an important role for growth and survival of the tumor cells. As a consequence of this cell-to-cell-interaction, several cytokines are secreted. The intracellular signaling, evoked by t

Management of chronic myeloid leukemia: targets for molecular therapy.

Chronic myeloid leukemia (CML) is a hematopoietic disorder characterized by malignant expansion of bone marrow stem cells. Currently, the only unequivocally curative treatment for CML is allogeneic stem cell transplant. Unfortunately, a large proportion of CML patients are ineligible for such treatment and alternative forms of therapy must be employed. Conventional chemotherapy makes use of compounds, such as hydroxyurea, that are cytotoxic for actively dividing cells. Although effective, these agents are not selective for the leukemic clone and this is the cause of undesirable side effects. M

HER2 targeted therapy resistance in breast cancer: from molecular landscape to clinical aspects.

HER2-positive breast cancer accounts for approximately 15% of all breast cancer cases and represents an aggressive histological subtype, often associated with poorer prognosis. The advent of HER2-targeted therapies has significantly improved outcomes for patients with HER2-positive breast cancer. However, both primary and acquired resistance remain substantial challenges in clinical practice. Over the past decades, numerous underlying mechanisms of HER2-targeted therapy resistance have been uncovered, and various strategies to overcome them have been proposed. The advancement of novel technolo

Targeted Therapy, Immunotherapy, and Molecular Testing in Advanced Solid Tumors: A Medicare Analysis.

BACKGROUND AND PURPOSE: Biomarker testing and matched therapies are central to precision oncology, but their real-world uptake and clinical impact among older adults with advanced solid tumors remain poorly characterized. This retrospective observational cohort study assessed biomarker testing and guideline-concordant matched first-line therapy use and evaluated their associations with overall survival, diagnosis-to-treatment intervals, and 6-month physical functioning in these patients. MATERIAL AND METHODS: This study used linked US Medicare claims, electronic medical records, and patient-r

Recent advances in molecular targeted therapy for unresectable and metastatic BRAF-mutated melanoma.

The clinical outcome of BRAF-mutated advanced melanoma has been improved by both molecular targeted therapies and immune checkpoint inhibito … herapies for acral and mucosal melanoma, a retrospective analysis may be useful. The combination of molecular targeted therapy plus immune checkpoint inhibitors is expected to elicit further improvement. The results of several trials using combination or sequential therapies will be available in the next few years.

Molecular mechanisms of targeted therapy in breast cancer: An integrated signaling network perspective.

Breast cancer encompasses molecularly distinct subtypes with divergent oncogenic dependencies, each amenable to precision therapeutic intervention. Over the past decade, clinically meaningful advances have reshaped breast cancer management: antibody-drug conjugates (ADCs) have expanded actionable HER2 expression thresholds to include HER2-low and HER2-ultralow populations; cyclin-dependent kinase (CDK) 4/6 inhibitors have become standard-of-care in hormone receptor-positive disease; and immune checkpoint blockade has established durable responses in a defined subset of triple-negative breast c

Molecular targeted therapy for thyroid cancer in Japan: Current status and future perspectives.

Since the introduction of sorafenib in 2014 and lenvatinib in 2015, multikinase inhibitors (MKIs) have substantially advanced systemic therapy for patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-R DTC) in Japan. More recently, the clinical introduction of molecularly targeted agents, including BRAF/MEK inhibitors, selective RET inhibitors, and TRK inhibitors, has shifted therapeutic strategies from predominantly histology-based treatment toward molecularly guided precision medicine. However, because most driver alterations in thyroid cancer are mutually exclusive

Current status and prospects of targeted therapy for cholangiocarcinoma based on molecular characteristics.

Cholangiocarcinoma (CCA) is a serious public health issue due to its insidious onset and dismal prognosis. The past few years have witnessed and highlighted the development of understanding and management of CCA. The combination of gemcitabine and cisplatin (GP) chemotherapy regimen with immunotherapy using immune checkpoint inhibitors has been considered the new standard first-line treatment alternative for advanced CCA. Notably, the proportion of patients with advanced CCA with targetable genetic mutations is approximately 40 %, and these patients may be considered for molecularly targeted t

Molecular biology of cholangiocarcinoma and its implications for targeted therapy in patient management.

Cholangiocarcinoma (CCA) remains a devastating malignancy and a significant challenge to treat. The majority of CCA patients are diagnosed at an advanced stage, making the disease incurable in most cases. The advent of high-throughput genetic sequencing has significantly improved our understanding of the molecular biology underpinning cancer. The identification of 'druggable' genetic aberrations and the development of novel targeted therapies against them is opening up new treatment strategies. Currently, 3 targeted therapies are approved for use in CCA; Ivosidenib in patients with IDH1 mutati

Adrenocortical Carcinomas: Molecular Pathogenesis, Treatment Options, and Emerging Immunotherapy and Targeted Therapy Approaches.

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy in the advanced setting with poor prognosis. This narrative review provides an overview of the epidemiology of ACC and its molecular pathogenesis with a summary of the main involved signaling pathways. We then provide an update on the clinical presentation, diagnosis, and current management strategies of both localized and metastatic disease from a multidisciplinary perspective. We highlight the debate around the use of mitotane in the adjuvant setting and review the use of combination chemotherapy with etoposide, doxorubicin,

Liquid biopsy guides successful molecular targeted therapy of an inoperable pediatric brainstem neoplasm.

Midline CNS tumors are occasionally inaccessible for surgical biopsies. In these instances, cell-free DNA (cfDNA) may serve as a viable alternative for molecular analysis and identification of targetable mutations. Here, we report a young child with an inoperable brainstem tumor in whom a stereotactic biopsy was deemed unsafe. The tumor progressed on steroids and after radiotherapy the patient developed hydrocephalus and received a ventriculoperitoneal shunt. Droplet digital PCR analysis of cfDNA from an intraoperative cerebrospinal fluid liquid biopsy revealed a BRAF V600 mutation enabling ta

Insights into molecular aspects and targeted therapy of thymic carcinoma: a narrative review.

BACKGROUND AND OBJECTIVE: Thymic carcinomas are rare tumors derived from thymic epithelial cells. Owing to their rarity, the search for molecular biology has been conducted in combination with thymoma as one histological subtype, and only a few studies have exclusively focused on thymic carcinoma. Currently, no therapy is more effective than complete surgical resection, and the development of novel therapies, including targeted therapies, is hampered. In this review, we summarize the knowledge regarding altered genes and pathways in thymic carcinoma with recent preclinical and clinical targete

Molecular dynamics simulations of cRGD-conjugated PEGylated TiO2 nanoparticles for targeted photodynamic therapy.

The conjugation of high-affinity cRGD-containing peptides is a promising approach in nanomedicine to efficiently reduce off-targeting effects and enhance the cellular uptake by integrin-overexpressing tumor cells. Herein we utilize atomistic molecular dynamics simulations to evaluate key structural-functional parameters of these targeting ligands for an effective binding activity towards αVβ3 integrins. An increasing number of cRGD ligands is conjugated to PEG chains grafted to highly curved TiO2 nanoparticles to unveil the impact of cRGD density on the ligand's presentation, stability, and co

Molecular-targeted therapy toward precision medicine for gastrointestinal caner: Current progress and challenges.

Gastrointestinal (GI) cancer remains the deadliest cancer in the world. The current standard treatment for GI cancer focuses on 5-fluorouracil-based chemotherapeutic regimens and surgery, and molecular-targeted therapy is expected to be a more effective and less toxic therapeutic strategy for GI cancer. There is well-established evidence for the use of epidermal growth factor receptor-targeted and vascular endothelial growth factor-targeted antibodies, which should routinely be incorporated into treatment strategies for GI cancer. Other potential therapeutic targets involve the PI3K/AKT pathwa

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… LITERATURE SEARCH We first conducted a search of the PubMed database for English articles using the medical subject heading terms in combination with "gastrointestinal cancer," "esophageal cancer," "gastric cancer," "colorectal cancer," "molecular targeted therapy," and "precision medicine." …

Multifunctional Molecular Therapeutic Agent for Targeted and Controlled Dual Chemo- and Photodynamic Therapy.

A novel molecular therapeutic agent was designed and synthesized, which contains three functional components, namely, a zinc(II) phthalocyanine substituted with a 2,4-dinitrobenzenesulfonate (DNBS) group as a glutathione (GSH)-activated photosensitizer, a chemo-prodrug based on combretastatin A-4 (CA4) with a singlet oxygen-cleavable aminoacrylate linker, and a biotin moiety as a tumor-targeting ligand. The conjugate showed preferential uptake toward the biotin-receptor-positive HepG2 cells compared with the low biotin-receptor-expressed HCT-116 cells used as the negative control, resulting in