Recent Advances in Oligonucleotide Therapeutics in Oncology

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(7), P. 3295 - 3295

Published: March 24, 2021

Cancer is one of the leading causes death worldwide. Conventional therapies, including surgery, radiation, and chemotherapy have achieved increased survival rates for many types cancer over past decades. However, recurrence and/or metastasis to distant organs remain major challenges, resulting in a large, unmet clinical need. Oligonucleotide therapeutics, which include antisense oligonucleotides, small interfering RNAs, aptamers, show promising outcomes disease indications such as Duchenne muscular dystrophy, familial amyloid neuropathies, macular degeneration. While no approved oligonucleotide drug currently exists any type cancer, results obtained preclinical studies trials are encouraging. Here, we provide an overview recent developments field therapeutics oncology, review current trials, discuss associated challenges.

Language: Английский

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Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study

The Lancet, Journal Year: 2023, Volume and Issue: 402(10395), P. 41 - 53

Published: June 16, 2023

Language: Английский

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N6-Methyladenosine Reader YTHDF1 Promotes ARHGEF2 Translation and RhoA Signaling in Colorectal Cancer

Gastroenterology, Journal Year: 2021, Volume and Issue: 162(4), P. 1183 - 1196

Published: Dec. 28, 2021

N6-methyladenosine (m6A) governs the fate of RNAs through m6A readers. Colorectal cancer (CRC) exhibits aberrant modifications and expression regulators. However, how readers interpret oncogenic methylome to promote malignant transformation remains be illustrated.YTH RNA binding protein 1 (Ythdf1) knockout mouse was generated determine effect Ythdf1 in CRC tumorigenesis vivo. Multiomic analysis RNA-sequencing, methylated immunoprecipitation sequencing, YTHDF1 proteomics were performed unravel targets CRC. The therapeutic potential targeting YTHDF1-m6A-Rho/Rac guanine nucleotide exchange factor 2 (ARHGEF2) evaluated using small interfering (siRNA) encapsulated by lipid nanoparticles (LNP).DNA copy number gain is a frequent event contributes its overexpression. High significantly associated with metastatic gene signature patient tumors. mice dampened tumor growth an inflammatory model. promotes cell lines primary organoids lung liver metastasis Integrative multiomics identified RhoA activator ARHGEF2 as key downstream target YTHDF1. binds sites messenger RNA, resulting enhanced translation ARHGEF2. Ectopic restored impaired signaling, growth, ability both vitro vivo caused loss, verifying that Finally, siRNA delivered LNP suppressed vivo.We identify novel epitranscriptome axis YTHDF1-m6A-ARHGEF2, which regulates metastasis. siRNA-delivering drug validated this

Language: Английский

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The Role of EREG/EGFR Pathway in Tumor Progression

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(23), P. 12828 - 12828

Published: Nov. 27, 2021

Aberrant activation of the epidermal growth factor receptor (EGFR/ERBB1) by erythroblastic leukemia viral oncogene homolog (ERBB) ligands contributes to various tumor malignancies, including lung cancer and colorectal (CRC). Epiregulin (EREG) is one EGFR low expressed in most normal tissues. Elevated EREG cancers mainly activates signaling pathways promotes progression. Notably, a higher expression level CRC with wild-type Kirsten rat sarcoma (KRAS) related better efficacy therapeutic treatment. By contrast, resistance anti-EGFR therapy was driven expression, aberrant genetic mutation signal pathway alterations. Additionally, overexpression non-small cell (NSCLC) anticipated be target for EGFR-tyrosine kinase inhibitor (EGFR-TKI). However, recent findings indicate that derived from macrophages NSCLC EGFR-TKI The emerging events EREG-mediated promotion signals are generated autocrine paracrine loops arise epithelial cells, fibroblasts, microenvironment (TME). TME crucial element development types drug resistance. regulation EREG/EGFR depends on distinct oncogenic driver mutations contexts allows specific pharmacological targeting alone or combinational treatment tailored therapy. Novel strategies EREG/EGFR, tumor-associated macrophages, alternative oncoproteins under undergoing clinical trials. In this review, we summarize outcomes interaction ligand TME. may potential combined other targets combat cancers.

Language: Английский

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Blockade of GCH1/BH4 Axis Activates Ferritinophagy to Mitigate the Resistance of Colorectal Cancer to Erastin-Induced Ferroptosis

Frontiers in Cell and Developmental Biology, Journal Year: 2022, Volume and Issue: 10

Published: Feb. 10, 2022

Ferroptosis, a type of cell death triggered by excessive accumulation iron-dependent lipid peroxidation, possesses an excellent potential in cancer treatment. However, many colorectal (CRC) lines are resistant to ferroptosis induced erastin and RSL3, the classical ferroptotic inducers. Moreover, underlying mechanism resistance remains poorly elucidated. This study sought discover major factor contributing CRC. The findings will help design strategies for triggering application individualized tumor therapy. Here, we show that tetrahydrobiopterin (BH4) determines sensitivity CRC cells erastin. GTP cyclohydrolase-1 (GCH1) is first rate-limiting enzyme BH4. Genetic or pharmacological inhibition GCH1 decreased BH4 assisted induction, peroxidation enhancement, ferrous iron accumulation. supplementation completely inhibited features resulting from knockdown. Unexpectedly, knockdown failed enhance RSL3-induced Mechanistically, drastically activated ferritinophagy during treatment rather than RSL3 Administration autophagy inhibitor reversed GCH1-knockdown cells. co-treatment vivo synergistically growth Overall, our results identified GCH1/BH4 metabolism as burgeoning defense Inhibiting promoted erastin-induced activating ferritinophagy, suggesting combining inhibitors with novel therapeutic strategy.

Language: Английский

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Application of Green Gold Nanoparticles in Cancer Therapy and Diagnosis

Nanomaterials, Journal Year: 2022, Volume and Issue: 12(7), P. 1102 - 1102

Published: March 27, 2022

Nanoparticles are currently used for cancer theranostics in the clinical field. Among nanoparticles, gold nanoparticles (AuNPs) attract much attention due to their usability and high performance imaging techniques. The wide availability of biological precursors plant-based synthesized AuNPs allows development large-scale production a greener manner. Conventional therapies, such as surgery chemotherapy, have significant limitations frequently fail produce satisfying results. prolonged circulation time, allow easy modification with ligands detected via cell surface receptors, increase uptake through receptor-mediated endocytosis. To exploit these unique features, studies been carried out on use contrast agents X-ray-based techniques (i.e., computed tomography). As nanocarriers, by nontoxic biocompatible plants deliver therapeutic biomolecules could be stride forward effective treatment various cancers. Fluorescent-plant-based markers, including AuNPs, fabricated using Medicago sativa, Olax Scandens, H. ambavilla, lanceolatum, detecting Moreover, green extracts applied different types solid tumors. However, cytotoxicity primarily depends size, reactivity, area. In this review, benefits materials therapy firstly explained. Then, considering valuable position medicine, application detection is highlighted an emphasis faced NPs drug delivery platforms.

Language: Английский

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Emerging trends in colorectal cancer: Dysregulated signaling pathways (Review)

International Journal of Molecular Medicine, Journal Year: 2021, Volume and Issue: 47(3)

Published: Jan. 7, 2021

Colorectal cancer (CRC) is the third most frequently detected type of cancer, and second common cause cancer‑related mortality globally. The American Cancer Society predicted that approximately 147,950 individuals would be diagnosed with CRC, out which 53,200 succumb to disease in USA alone 2020. CRC‑related ranks among both males females USA. CRC arises from 3 major pathways: i) adenoma‑carcinoma sequence; ii) serrated pathway; iii) inflammatory pathway. majority cases are sporadic result risk factors, such as a sedentary lifestyle, obesity, processed diets, alcohol consumption smoking. also preventable cancer. With widespread screening, incidence have decreased developed countries. However, over past few decades, been on rise young adults (age, <50 years). In addition, increasing developing countries low gross domestic product (GDP) due lifestyle changes. an etiologically heterogeneous classified by tumor location alterations global gene expression. Accumulating genetic epigenetic perturbations aberrations time suppressor genes, oncogenes DNA mismatch repair genes could precursor onset colorectal can divided sporadic, familial, inherited depending origin mutation. Germline mutations APC MLH1 proven play etiological role, resulting predisposition CRC. Genetic dysregulation signaling pathways leading drug resistance, inhibition apoptosis induction proliferation, invasion migration, development metastasis. Timely detection effective precision therapies based present knowledge essential for successful treatment patient survival. review presents incidence, dysregulated targeted therapies.

Language: Английский

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Recent Updates on Mechanisms of Resistance to 5-Fluorouracil and Reversal Strategies in Colon Cancer Treatment

Biology, Journal Year: 2021, Volume and Issue: 10(9), P. 854 - 854

Published: Aug. 31, 2021

5-Fluorouracil (5-FU) plus leucovorin (LV) remain as the mainstay standard adjuvant chemotherapy treatment for early stage colon cancer, and preferred first-line option metastatic cancer patients in combination with oxaliplatin FOLFOX, or irinotecan FOLFIRI regimens. Despite success to a certain extent, incidence of failure attributed resistance is still reported many patients. This resistance, which can be defined by tumor tolerance against chemotherapy, either intrinsic acquired, primarily driven dysregulation various components distinct pathways. In recent years, it has been established that 5-FU akin multidrug alterations drug transport, evasion apoptosis, changes cell cycle DNA-damage repair machinery, regulation autophagy, epithelial-to-mesenchymal transition, stem involvement, microenvironment interactions, miRNA dysregulations, epigenetic alterations, well redox imbalances. Certain mechanisms are 5-FU-specific have also ascertained include upregulation thymidylate synthase, dihydropyrimidine dehydrogenase, methylenetetrahydrofolate reductase, downregulation thymidine phosphorylase. Indeed, successful modulation these game plan numerous studies had employed small molecule inhibitors, plant-based molecules, non-coding RNA regulators effectively reverse cells. It hoped would provide fundamental knowledge further our understanding prior developing novel drugs near future synergistically work potentiate its antitumor effects improve patient’s overall survival.

Language: Английский

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Targeted Delivery of Drugs and Genes Using Polymer Nanocarriers for Cancer Therapy

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(17), P. 9118 - 9118

Published: Aug. 24, 2021

Cancer is one of the primary causes worldwide human deaths. Most cancer patients receive chemotherapy and radiotherapy, but these treatments are usually only partially efficacious lead to a variety serious side effects. Therefore, it necessary develop new therapeutic strategies. The emergence nanotechnology has had profound impact on general clinical treatment. application facilitated development nano-drug delivery systems (NDDSs) that highly tumor selective allow for slow release active anticancer drugs. In recent years, vehicles such as liposomes, dendrimers polymer nanomaterials have been considered promising carriers tumor-specific drug delivery, reducing toxicity improving biocompatibility. Among them, nanoparticles (NPs) most innovative methods non-invasive delivery. Here, we review NPs in gene therapy, early diagnostics therapy.

Language: Английский

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The Colorectal Cancer Tumor Microenvironment and Its Impact on Liver and Lung Metastasis

Cancers, Journal Year: 2021, Volume and Issue: 13(24), P. 6206 - 6206

Published: Dec. 9, 2021

Colorectal cancer (CRC) is the third most common malignancy and second cause of cancer-related mortality worldwide. A total 20% CRC patients present with distant metastases, frequently to liver lung. In primary tumor, as well at each metastatic site, cellular components tumor microenvironment (TME) contribute engraftment metastasis. These include immune cells (macrophages, neutrophils, T lymphocytes, dendritic cells) stromal (cancer-associated fibroblasts endothelial cells). this review, we highlight how TME influences progression invasion site its function in fostering niches lungs. We also discuss emerging clinical strategies target TME.

Language: Английский

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