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Lung cancer, the leading cause of cancer mortality, exhibits diverse histological subtypes and genetic complexities. Numerous preclinical mouse models have been developed to study lung cancer, but data from these models are disparate, siloed, and difficult to compare in a centralized fashion. Here we established the Lung Cancer Mouse Model Database (LCMMDB), an extensive repository of 1,354 samples from 77 transcriptomic datasets covering 974 samples from genetically engineered mouse models (GEMMs), 368 samples from carcinogen-induced models, and 12 samples from a spontaneous model. Meticulous curation and collaboration with data depositors have produced a robust and comprehensive database, enhancing the fidelity of the genetic landscape it depicts. The LCMMDB aligns 859 tumors from GEMMs with human lung cancer mutations, enabling comparative analysis and revealing a pressing need to broaden the diversity of genetic aberrations modeled in GEMMs. Accompanying this resource, we developed a web application that offers researchers intuitive tools for in-depth gene expression analysis. With standardized reprocessing of gene expression data, the LCMMDB serves as a powerful platform for cross-study comparison and lays the groundwork for future research, aiming to bridge the gap between mouse models and human lung cancer for improved translational relevance.
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Acute myeloid leukemia (AML) remains a most lethal hematological malignancy, partly because of its slow development of targeted therapies compared with other cancers. PLK1 inhibitor, volasertib (Vol), is among the few molecular targeted drugs granted breakthrough therapy status for AML; however, its fast clearance and dose-limiting toxicity greatly restrain its clinical benefits. Here, we report that transferrin-guided polymersomes (TPs) markedly augment the targetability, potency and safety of Vol to AML. Vol-loaded TPs (TPVol) with 4% transferrin exhibited best cellular uptake, effective down-regulation of p-PLK1, p-PTEN and p-AKT and superior apoptotic activity to free Vol in MV-4-11 leukemic cells. Intravenous injection of TPVol gave 6-fold higher AUC than free Vol and notable accumulation in AML-residing bone marrow. The efficacy studies in orthotopic MV-4-11 leukemic model demonstrated that TPVol significantly reduced leukemic cell proportions in periphery blood, bone marrow, liver and spleen, effectively enhanced mouse survival rate, and impeded bone loss. This transferrin-guided nano-delivery of molecular targeted drugs appears to be an interesting strategy towards the development of novel treatments for AML.
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Cyclic dinucleotides (CDNs) as stimulator of interferon genes (STING) agonists capable of inducing strong antitumor innate immune response are highly promising for tumor immunotherapy. The efficacy of these CDNs is, however, reduced greatly by their fast clearance, poor cell uptake and inefficient cytosolic transportation. Here, we report that reduction-responsive biodegradable chimaeric polymersomes (CPs) markedly enhance tumor retention and cytosolic delivery of a synthetic CDN, ADU-S100, and bolster STING pathway activation in the tumor microenvironment and tumor draining lymph nodes, giving significantly better tumor repression and survival of B16F10 melanoma-bearing mice compared with free CDN control. The superiority of CPs-mediated CDN delivery is further verified in combination therapy with low-dose fractionated radiation, which brings about clearly stronger and longer-term immunotherapeutic effects and protection against tumor re-challenge. The development of nano-STING agonists that are able to overcome the delivery barriers of CDNs represents an effective strategy to potentiate cancer immunotherapy.
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Immunotherapy with toll like receptor 9 (TLR9) agonist CpG ODN offers an emergent strategy to treat life-threatening malignant glioma. CpG is typically applied invasively by intracranial and intrathecal administration which induces not only poor compliance and lessened potency but also possibly strong adverse effects and immunotoxicity. Here, it is reported that immunotherapy of murine LCPN glioma is greatly boosted by polymersome-steered intravenous and intranasal brain delivery of CpG. CpG is efficiently loaded in apolipoprotein E peptide-directed polymersomes to give blood-brain barrier permeable and glioma and cervical lymph node-homing CpG nano-immunoadjuvant (t-NanoCpG) which strongly stimulates the maturation of dendritic cells, antigen cross-presentation, and production of proinflammatory cytokines in vivo. Intriguingly, both intravenous and intranasal administration of t-NanoCpG brings about significant survival benefits in murine LCPN glioma-bearing mice while free CpG and nontargeted CpG nano-immunoadjuvant (NanoCpG) afford modest therapeutic effects. Moreover, combination of t-NanoCpG with radiotherapy further boosts the immunotherapeutic effects leading to more improved survival rate of mice. This intelligent brain-permeable nano-immunoadjuvant provides a new, minimally invasive and highly potent strategy for immunotherapy of glioma.
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Glioma , Receptor Toll-Like 9 , Adyuvantes Inmunológicos/uso terapéutico , Animales , Glioma/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Inmunoterapia , Ratones , Receptor Toll-Like 9/agonistasRESUMEN
Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Although intensive chemotherapy greatly improved the survival rate, it is often accompanied by severe and lifelong side effects as a result of weak ALL selectivity. The intensive and poorly selective chemotherapy is also detrimental to patients' immune system. There is an urgent need to develop more selective and less toxic chemotherapy for ALL. Here, we report daratumumab-polymersome-vincristine (DP-VCR) as a CD38-directed nanotherapy for ALL. DP-VCR showed selective uptake in CD38-positive 697 and Nalm-6-Luc ALL cells and potent anti-ALL activity with an IC50 as low as 0.06 nM VCR, which was 13.7-fold more potent than free VCR. In contrast, no toxicity to human peripheral blood mononuclear cells was detected for DP-VCR even at 108.3 nM VCR. The apoptotic assays confirmed a high selectivity of DP-VCR to CD38-positive ALL cells. DP-VCR exhibited superior treatment of both 697 and Nalm-6-Luc orthotopic ALL models to all controls, as revealed by significant survival benefit and marked reduction of leukemia burden in bone marrow, blood, spleen, and liver. Importantly, DP-VCR induced few side effects. DP-VCR emerges as a safe and potent nanotherapy for CD38-positive ALL.
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Leucocitos Mononucleares , Leucemia-Linfoma Linfoblástico de Células Precursoras , Recuento de Células , Niño , Humanos , Leucocitos Mononucleares/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Vincristina/farmacología , Vincristina/uso terapéuticoRESUMEN
Targeted molecular therapy, for example, with sorafenib (SF) is considered as a new and potent strategy for glioblastoma (GBM) that remains hard to treat today. Several clinical trials with SF, as monotherapy or combination therapy with current treatments, have not met the clinical endpoints, likely as a result of the blood-brain barrier (BBB) and inferior GBM delivery. Here, we designed and explored small, smart, and LDLR-specific micelles to load SF (LDLR-mSF) and to improve SF therapy of GBM by enhancing BBB penetration, GBM accumulation, and cell uptake. LDLR-mSF with 2.5% ApoE peptide functionality based on poly(ethylene glycol)-poly(ε-caprolactone-co-dithiolane trimethylene carbonate)-mefenamate exhibited nearly quantitative SF loading, small size (24 nm), high colloidal stability, and glutathione-activated SF release. The in vitro and in vivo studies certified that LDLR-mSF greatly enhanced BBB permeability and U-87 MG cell uptake and caused 10.6- and 12.9-fold stronger anti-GBM activity and 6.0- and 2.5-fold higher GBM accumulation compared with free SF and non-LDLR mSF controls, respectively. The treatment of an orthotopic human GBM tumor model revealed that LDLR-mSF at a safe dosage of 15 mg of SF/kg significantly retarded tumor progression and improved the survival rate by inducing tumor cell apoptosis and inhibiting tumor angiogenesis. These small, smart, and LDLR-specific micelles provide a potential solution to enhance targeted molecular therapy of GBM.
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Neoplasias Encefálicas , Glioblastoma , Barrera Hematoencefálica , Neoplasias Encefálicas/tratamiento farmacológico , Línea Celular Tumoral , Glioblastoma/tratamiento farmacológico , Humanos , Micelas , Sorafenib/farmacologíaRESUMEN
The multiplexed cancer cell line screening platform PRISM demonstrated its utility in testing hundreds of cell lines in a single run, possessing the potential to speed up anti-cancer drug discovery, validation and optimization. Here we described the development and implementation of a next-generation PRISM platform combining Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9-mediated gene editing, cell line DNA barcoding and next-generation sequencing to enable genetic and/or pharmacological assessment of target addiction in hundreds of cell lines simultaneously. Both compound and CRISPR-knockout PRISM screens well recapitulated the results from individual assays and showed high consistency with a public database.
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Antineoplásicos/farmacología , Sistemas CRISPR-Cas , Detección Precoz del Cáncer/métodos , Edición Génica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Neoplasias/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Ensayos de Selección de Medicamentos Antitumorales/métodos , Células HEK293 , Humanos , Neoplasias/diagnósticoRESUMEN
Oncolytic peptide LTX-315 while showing clinical promise in treating solid tumors is limited to intratumoral administration, which is not applicable for inaccessible or metastatic tumors. The cationic and amphipathic nature of oncolytic peptides engenders formidable challenges to developing systems for their systemic delivery. Here, we describe cRGD-functionalized chimaeric polymersomes (cRGD-CPs) as a robust systemic delivery vehicle for LTX-315, which in combination with CpG adjuvant and anti-PD-1 boost immunotherapy of malignant B16F10 melanoma in mice. cRGD-CPs containing 14.9 wt% LTX-315 (cRGD-CPs-L) exhibited a size of 53 nm, excellent serum stability, and strong and selective killing of B16F10 cells (versus L929 fibroblasts) in vitro, which provoked similar immunogenic effects to free LTX-315 as revealed by release of danger-associated molecular pattern molecules. The systemic administration of cRGD-CPs-L gave a notable tumor accumulation of 4.8% ID/g and significant retardation of tumor growth. More interestingly, the treatment of B16F10 tumor-bearing mice was further boosted by co-administration of polymersomal CpG and anti-PD-1 antibody, in which two out of seven mice were cured as a result of strong immune response and long-term immune memory protection. The immunotherapeutic effect was evidenced by secretion of IL-6, IFN-γ and TNF-α, tumor infiltration of CD8+ CTLs and Th, and induction of TEM and TCM in spleen. This study opens a new avenue to oncolytic peptides, which enables durable immunotherapy of tumors via systemic administration.
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Melanoma , Neoplasias Cutáneas , Animales , Línea Celular Tumoral , Inmunoterapia , Melanoma/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BL , OligopéptidosRESUMEN
Biodegradable nanostructures displaying aggregation-induced emission (AIE) are desirable from a biomedical point of view, due to the advantageous features of loading capacity, emission brightness, and fluorescence stability. Herein, biodegradable polymers comprising poly (ethylene glycol)-block-poly(caprolactone-gradient-trimethylene carbonate) (PEG-P(CLgTMC)), with tetraphenylethylene pyridinium-TMC (PAIE) side chains have been developed, which self-assembled into well-defined polymersomes. The resultant AIEgenic polymersomes are intrinsically fluorescent delivery vehicles. The presence of the pyridinium moiety endows the polymersomes with mitochondrial targeting ability, which improves the efficiency of co-encapsulated photosensitizers and improves therapeutic index against cancer cells both in vitro and in vivo. This contribution showcases the ability to engineer AIEgenic polymersomes with structure inherent fluorescence and targeting capacity for enhanced photodynamic therapy.
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Antineoplásicos/farmacología , Plásticos Biodegradables/farmacología , Colorantes Fluorescentes/farmacología , Fármacos Fotosensibilizantes/farmacología , Poliésteres/farmacología , Polietilenglicoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/efectos de la radiación , Compuestos de Bencilideno/síntesis química , Compuestos de Bencilideno/farmacología , Compuestos de Bencilideno/efectos de la radiación , Plásticos Biodegradables/síntesis química , Plásticos Biodegradables/efectos de la radiación , Compuestos de Boro/síntesis química , Compuestos de Boro/farmacología , Compuestos de Boro/efectos de la radiación , Línea Celular Tumoral , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/efectos de la radiación , Humanos , Luz , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/efectos de la radiación , Poliésteres/síntesis química , Poliésteres/efectos de la radiación , Polietilenglicoles/síntesis química , Polietilenglicoles/efectos de la radiación , Compuestos de Piridinio/síntesis química , Compuestos de Piridinio/farmacología , Compuestos de Piridinio/efectos de la radiaciónRESUMEN
Acute myeloid leukemia (AML) is a severe blood malignancy associated with a high relapse rate. The current clinical chemotherapy is typically perplexed with serious side effects. Here, A6 peptide-tagged, small and reduction-sensitive polymersomal vincristine sulfate (A6-cPS-VCR) is reported as a novel, smart and specific treatment for CD44 positive AML. A6-cPS-VCR stably loaded with 3.3 wt% VCR displays a size of ≈ 31 nm and pronounced selectivity toward CD44-overexpressed MV4-11 leukemia cells. Intriguingly, A6-cPS-VCR effectively represses the outgrowth of orthotopic MV4-11 AML in vivo, as revealed by significant reduction of leukemia burdens in the circulation, bone marrow, liver and spleen, and significantly extends the median survival time of MV4-11 AML-bearing mice. In addition to active targetability and therapeutic benefits, A6-cPS-VCR has the advantage of easy fabrication, rendering it potentially interesting for clinical translation.
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Leucemia Mieloide Aguda , Animales , Leucemia Mieloide Aguda/tratamiento farmacológico , Ratones , Fragmentos de Péptidos , Activador de Plasminógeno de Tipo Uroquinasa , VincristinaRESUMEN
Hepatocellular carcinoma (HCC) remains a leading malignancy with a high mortality and little improvement in treatments. Protein drugs though known for their extraordinary potency and specificity have rarely been investigated for HCC therapy owing to lack of appropriate delivery systems. Here, we designed GE11 peptide-installed chimaeric polymersomes (GE11-CPs) for high-efficiency EGFR-targeted protein therapy of orthotopic SMMC-7721 HCC-bearing nude mice. GE11-CPs were assembled from poly(ethylene glycol)-b-poly(trimethylene carbonate-co-dithiolane trimethylene carbonate)-b-poly(aspartic acid) (PEG-P(TMC-DTC)-PAsp) and GE11-functionalized PEG-P(TMC-DTC), which allowed efficient loading and protection of proteins in the watery interior and fine-tuning of GE11 densities at the surface. CPs with short PAsp segments (degree of polymerization (DP) = 5, 10 and 15) exhibited a protein loading efficiency of 60%-72% and glutathione-responsive protein release. Saporin-loaded GE11-CPs had a size of 36 - 62 nm depending on GE11 densities and DP of PAsp. Notably, GE11-CPs with 10% GE11 revealed greatly enhanced uptake in SMMC-7721 cells, boosting the anticancer potency of saporin for over 3-folds compared with non-targeted control (half-maximal inhibitory concentration (IC50) = 11.0 versus 36.3 nM). The biodistribution studies using Cy5-labeled cytochrome C as a model protein demonstrated about 3-fold higher accumulation of GE11-CPs formulation than CPs counterpart in both subcutaneous and orthotopic SMMC-7721 tumor models. Notably, saporin-loaded GE11-CPs revealed low toxicity, effective tumor inhibition and significant improvement of survival rate compared with PBS and non-targeted groups (median survival time: 99 versus 37 and 42 days). EGFR-targeted chimaeric polymersomes carrying proteins appear an interesting HCC treatment modality.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Carcinoma Hepatocelular/tratamiento farmacológico , Línea Celular Tumoral , Receptores ErbB , Neoplasias Hepáticas/tratamiento farmacológico , Ratones , Ratones Desnudos , Péptidos , Distribución TisularRESUMEN
Docetaxel (DTX) widely used for treating nonsmall cell lung cancer (NSCLC) patients is associated with dose-limiting side effects, especially neurotoxicity and myelosuppression. Here, we have developed cyclic cNGQGEQc peptide-directed polymersomal docetaxel (cNGQ-PS-DTX) as a targeted and multifunctional formulation for NSCLC. cNGQ-PS-DTX carrying 8.1 wt % DTX had a size of 93 nm, neutral surface charge, high stability, and glutathione-triggered DTX release behavior. Cytotoxicity studies demonstrated a clearly better antitumor activity of cNGQ-PS-DTX in α3ß1 integrin overexpressing A549 human lung cancer cells than free DTX and nontargeted PS-DTX. cNGQ-PS-DTX showed a remarkably high tolerability (over 8 times better than free DTX) and slow elimination in mice. Importantly, cNGQ-PS-DTX exhibited greatly improved tumor accumulation and higher suppression of subcutaneous and orthotopic A549 xenografts as compared to PS-DTX and free DTX controls. α3ß1 integrin-targeting polymersomal docetaxel emerges as an advanced nanotherapeutic for NSCLC treatment.
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Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Docetaxel/química , Integrina alfa3beta1/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Células A549 , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Docetaxel/farmacocinética , Docetaxel/uso terapéutico , Portadores de Fármacos/química , Semivida , Humanos , Integrina alfa3beta1/antagonistas & inhibidores , Integrina alfa3beta1/genética , Ratones , Ratones Desnudos , Nanopartículas/química , Péptidos/química , Péptidos/metabolismo , Distribución Tisular , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Engineering biodegradable nanostructures with precise morphological characteristics is a key objective in nanomedicine. In particular, asymmetric (i.e., nonspherical) nanoparticles are desirable due to the advantageous effects of shape in a biomedical context. Using molecular engineering, it is possible to program unique morphological features into the self-assembly of block copolymers (BCPs). However, the criteria of biocompatibility and scalability limit progress due to the prevalence of nondegradable components and the use of toxic solvents during fabrication. To address this shortfall, a robust strategy for the fabrication of morphologically asymmetric nanoworms, comprising biodegradable BCPs, has been developed. Modular BCPs comprising poly (ethylene glycol)-block-poly(caprolactone-gradient-trimethylene carbonate) (PEG-PCLgTMC), with a terminal chain of quaternary ammonium-TMC (PTMC-Q), undergo self-assembly via direct hydration into well-defined nanostructures. By controlling the solution ionic strength during hydration, particle morphology switches from spherical micelles to nanoworms (of varying aspect ratio). This ionically-induced switch is driven by modulation of chain packing with salts screening interchain repulsions, leading to micelle elongation. Nanoworms can be loaded with cytotoxic cargo (e.g., doxorubicin) at high efficiency, preferentially interact with cancer cells, and increase tumor penetration. This work showcases the ability to program assembly of BCPs and the potential of asymmetric nanosystems in anticancer drug delivery.
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Caproatos/química , Sistemas de Liberación de Medicamentos/métodos , Lactonas/química , Nanomedicina/métodos , Nanoestructuras/química , Micelas , Polímeros/químicaRESUMEN
Lung cancer, with its high mortality and increasing morbidity, has become one of the most lethal malignancies worldwide. Here, we developed cyclic RGD peptide-directed and disulfide-crosslinked polymersomal doxorubicin (cRGD-PS-Dox) as a targeted chemotherapy for human non-small cell lung cancer (NSCLC). Notably, cRGD-PS-Dox exhibited a high Dox loading (15.2 wt.%), small hydrodynamic diameter (96 nm), superb stability, prominent targetability to αvß3 integrin overexpressing A549 human lung cancer cells, and rapid release of the drug into nuclei, leading to a significantly improved antitumor activity compared with the control groups, i.e., PS-Dox and Lipo-Dox (a liposome injection employed in clinical settings). The pharmacokinetic and biodistribution results for cRGD-PS-Dox revealed similar elimination half-lives but two-fold enhanced tumor accumulation compared with PS-Dox and Lipo-Dox. Intriguingly, cRGD-PS-Dox effectively suppressed the growth of A549 lung tumors in both subcutaneous and orthotopic models with minimal adverse effects at a Dox dose of 12 mg/kg, leading to significant survival benefits compared with PS-Dox and Lipo-Dox. This αvß3 integrin-targeting multifunctional polymersomal doxorubicin is highly promising for targeted chemotherapy of human NSCLC.
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BACKGROUND: The aberrant status of target genes and their associations with clinicopathologic characteristics are still unclear in primary lung adenocarcinoma. METHODS: The common mutations and translocations of nine target genes were evaluated in 1,247 specimens of surgically-resected primary lung adenocarcinoma. Immunohistochemistry was used to analyze the expressions of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) in 731 specimens. The frequency of the aberrations and their associations with clinicopathologic characteristics were analyzed. RESULTS: Overall, 952 (76.3%) of 1,247 patients harbored at least one target mutation or translocation: epidermal growth factor receptor (EGFR) (729, 58.5%), v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) (83, 6.7%), human epidermal growth factor receptor 2 (HER2) (82, 6.6%), anaplastic lymphoma kinase (ALK) (23, 1.8%), phosphoinositide-3-kinase catalytic alpha polypeptide (PIK3CA) (20, 1.6%), Ret proto-oncogene RET (15, 1.2%), ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) (12, 1.0%), B-raf proto-oncogene (BRAF) (9, 0.7%), neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) (3, 0.2%). Fourteen (1.9%) of 731 patients were PD-1 positive and 95 (13.0%) were PD-L1 positive in tumor cells. In men and smokers, there were more frequent KRAS mutations (both P<0.001) and PD-L1 positive tumors (P<0.001, P=0.005, respectively), and less frequent EGFR mutations (P=0.049, <0.001, respectively). In ground-glass opacity (GGO) or ground-glass nodules (GGN), there were more HER2 (P=0.033) but less EGFR (P=0.025) and PIK3CA mutations (P=0.012), and ALK translocations (P=0.014). EGFR (P<0.001), KRAS mutations (P=0.004) and PD-L1 positive tumors (P=0.046) were more frequent in older patients, while HER2 (P<0.001), ALK (P=0.005) and ROS1 aberrations (P=0.044) were less frequent. Invasive mucinous adenocarcinoma was significantly associated with KRAS and ALK aberrations (both P<0.001), while solid predominant adenocarcinoma was associated with ROS1 translocations (P=0.036) and PD-L1 expression (P<0.001). KRAS, HER2, and ALK aberrations were scarce in patients with EGFR mutations (all P<0.001), while PD-L1 positive tumors positively correlated with ALK translocations (P=0.031) and negatively correlated with HER2 mutations (P=0.019). CONCLUSIONS: Most patients with primary lung adenocarcinoma harbored target gene aberrations. The frequency of each alteration differed in patients depending on clinicopathologic characteristics.
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Ovarian cancer as a recurrent disease is often refractory to treatment including pegylated liposomal doxorubicin hydrochloride (Lipo-Dox). Here, GE11 peptide-modified reversibly cross-linked polymersomal doxorubicin (GE11-PS-Dox) was investigated as an advanced treatment for SKOV3 human ovarian tumors, which overexpress epidermal growth factor receptor (EGFR). The in vitro experiments using SKOV3 cancer cells demonstrated that GE11-PS-Dox induced obviously higher cellular uptake, Dox delivery to the nuclei, and antitumor activity than the nontargeted PS-Dox and Lipo-Dox controls. In vivo biodistribution experiments displayed 2.5-fold higher tumor accumulation for GE11-PS-Dox as compared to Lipo-Dox. Notably, GE11-PS-Dox could effectively suppress the progression of SKOV3 tumors and cause little adverse effects at 12 mg of Dox equiv/kg, leading to a remarkably increased survival rate of 100% over 78 days. In contrast, continued tumor growth and body weight loss were discerned for Lipo-Dox treated mice at 6 mg of Dox equiv/kg. Moreover, a single dose of GE11-PS-Dox at 60 mg of Dox equiv/kg showed also effective treatment and low toxicity toward SKOV3-tumor bearing mice. GE11-directed reversibly cross-linked polymersomal doxorubicin has emerged as an advanced alternative to Lipo-Dox for treatment of EGFR-overexpressing ovarian cancers.
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Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/uso terapéutico , Doxorrubicina/análogos & derivados , Sistemas de Liberación de Medicamentos/métodos , Liposomas/química , Péptidos/química , Animales , Línea Celular Tumoral , Doxorrubicina/química , Doxorrubicina/uso terapéutico , Receptores ErbB/metabolismo , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Ováricas/tratamiento farmacológico , Polietilenglicoles/química , Polietilenglicoles/uso terapéutico , Distribución AleatoriaRESUMEN
Small cell lung cancer (SCLC) is the most deadly subtype of lung cancer due to its dismal prognosis. We have developed a lentiviral vector-mediated SCLC mouse model and have explored the role of both the NF-κB and CREB families of transcription factors in this model. Surprisingly, induction of NF-κB activity, which promotes tumor progression in many cancer types including non-small cell lung carcinoma (NSCLC), is dispensable in SCLC. Instead, suppression of NF-κB activity in SCLC tumors moderately accelerated tumor development. Examination of gene expression signatures of both mouse and human SCLC tumors revealed overall low NF-κB but high CREB activity. Blocking CREB activation by a dominant-negative form of PKA (dnPKA) completely abolished the development of SCLC. Similarly, expression of dnPKA or treatment with PKA inhibitor H89 greatly reduced the growth of SCLC tumors in syngeneic transplantation models. Altogether, our results strongly suggest that targeting CREB is a promising therapeutic strategy against SCLC.Implications: Activity of the transcription factor CREB is elevated in SCLC tumors, which helps to maintain its neuroendocrine signature and cell proliferation. Our results highlight the importance of targeting the CREB pathway to develop new therapeutics to combat SCLC. Mol Cancer Res; 16(5); 825-32. ©2018 AACR.
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Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Neoplasias Pulmonares/genética , Carcinoma Pulmonar de Células Pequeñas/genética , Animales , Modelos Animales de Enfermedad , Humanos , Neoplasias Pulmonares/patología , Ratones , Transducción de Señal , Carcinoma Pulmonar de Células Pequeñas/patologíaRESUMEN
Lung cancer is one of the worldwide leading and fast-growing malignancies. Pemetrexed disodium (PEM, Alimta®), a small hydrophilic drug, is currently used for treating lung cancer patients. However, PEM suffers from issues like fast elimination, low bioavailability, poor tumor cell selectivity and penetration. Here, we report on lung cancer specific CSNIDARAC (CC9) peptide-functionalized reduction-responsive chimaeric polymersomes (CC9-RCPs) for efficient encapsulation and targeted delivery of PEM to H460 human lung cancer cells in vitro and in vivo. PEM-loaded CC9-RCPs (PEM-CC9-RCPs) was obtained from co-self-assembly of poly(ethylene glycol)-b-poly(trimethylene carbonate-co-dithiolane trimethylene carbonate)-b-polyethylenimine (PEG-P(TMC-DTC)-PEI) and CC9-functionalized PEG-P(TMC-DTC) in the presence of PEM followed by self-crosslinking. PEM-CC9-RCPs displayed an optimal CC9 density of 9.0% in targeting H460 cells, a high PEM loading content of 14.2â¯wt%, a small hydrodynamic size of ca. 60â¯nm and glutathione-triggered PEM release. MTT assays showed that PEM-CC9-RCPs was 2.6- and 10- fold more potent to H460 cells than the non-targeting PEM-RCPs and free PEM controls, respectively. Interestingly, PEM-CC9-RCPs exhibited 22-fold longer circulation time and 9.1-fold higher accumulation in H460 tumor than clinical formulation Alimta®. Moreover, CC9-RCPs showed obviously better tumor penetration than RCPs. Remarkably, PEM-CC9-RCPs at 12.5â¯mg PEM equiv./kg effectively suppressed growth of H460 xenografts and significantly prolonged mouse survival time as compared to PEM-RCPs and Alimta® controls. These lung cancer specific and reduction-responsive chimaeric polymersomes provide a unique pemetrexed nanoformulation for targeted lung cancer therapy. STATEMENT OF SIGNIFICANCE: Multitargeted antifolate agent pemetrexed (PEM, Alimta®) is currently used for treating lung cancer patients and has low side-effects. However, PEM suffers from issues like fast elimination, low bioavailability, poor tumor cell selectivity and penetration. Scarce work on targeted delivery of PEM has been reported, partly because most conventional nanocarriers show a low and instable loading for hydrophilic, negatively charged drugs like PEM. Herewith, we report on lung cancer specific CSNIDARAC (CC9) peptide-functionalized reduction-responsive chimaeric polymersomes (CC9-RCPs) which showed efficient PEM encapsulation (14.2â¯wt%, 60â¯nm) and targeted delivery of PEM to H460 human lung cancer cells, leading to effective suppression of H460 tumor xenografts and significantly prolonged survival rates of mice than Alimta®. To the best of our knowledge, this represents a first report on targeted nanosystems that are capable of efficient loading and targeted delivery of PEM to lung tumors.