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1.
BMC Med Genomics ; 15(1): 191, 2022 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-36076209

RESUMO

PURPOSE: Patient-derived xenograft (PDX) models were established to reproduce the clinical situation of original cancers and have increasingly been applied to preclinical cancer research. Our study was designed to establish and genetically characterize cervical cancer PDX models. METHODS: A total of 91 fresh fragments obtained from 22 surgically resected cervical cancer tissues were subcutaneously engrafted into female NOD-SCID mice. Hematoxylin and eosin (H&E) staining was performed to assess whether the established PDX models conserved the histological features of original patient cervical cancer tissues. Moreover, a Venn diagram was applied to display the overlap of all mutations detected in whole-genome sequencing (WGS) data from patient original cervical cancer (F0) and F2-, F3-PDX models. The whole exome sequencing (WES) and the "maftools" package were applied to determine the somatic mutations among primary cervical cancers and the established PDX models. RESULTS: Our study successfully developed a panel of cervical cancer PDX models and the latency time of cervical cancer PDX model establishment was variable with a progressive decrease as the passage number increased, with a mean time to initial growth of 94.71 days in F1 engraftment to 40.65 days in F3 engraftment. Moreover, the cervical cancer PDX models preserved the histological features of their original cervical cancer. WGS revealed that the genome of original cervical cancer was preserved with high fidelity in cervical cancer PDX models throughout the xenografting and passaging process. Furthermore, WES demonstrated that the cervical cancer PDX models maintained the majority somatic mutations of original cervical cancer, of which the KMT2D, LRP1B, NAV3, TP53, FAT1, MKI67 and PKHD1L1 genes were identified as the most frequently mutated genes. CONCLUSIONS: The cervical cancer PDX models preserved the histologic and genetic characteristics of their original cervical cancer, which helped to gain a deeper insight into the genetic alterations and lay a foundation for further investigation of the molecular targeted therapy of cervical cancer.


Assuntos
Neoplasias do Colo do Útero , Animais , Modelos Animais de Doenças , Feminino , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Front Immunol ; 13: 963031, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36059488

RESUMO

The clinical efficacy of current therapies for Hepatocellular carcinoma (HCC) are unsatisfactory. In recent years, chimeric antigen receptor (CAR) T-cell therapies have been developed for solid tumors including advanced HCC (aHCC), but limited progress has been made. Glypican-3 is a promising immunotherapeutic target for HCC since it is specifically highly expressed in HCC. A previous study indicated that GPC3-targeted CAR T-(CAR-GPC3) cells were well-tolerated and had prolonged survival for HCC patients and that Sorafenib could increase the antitumor activities of CAR-GPC3 T-cells against HCC in mouse models. Here, we report a patient with aHCC who achieved a complete response (CR) and a long survival period after the combination therapy of CAR-GPC3 T-cell plus sorafenib. A 60-year-old Asian male diagnosed with hepatitis B virus (HBV) related HCC developed liver recurrence and lung metastasis after liver tumor resection and trans-arterial chemoembolization therapy. The patient also previously received microwave ablation therapy for lung metastasis. After the enrollment, the patient underwent leukapheresis for CAR-GPC3 T-cells manufacturing. Seven days after leukapheresis, the patient started to receive 400 mg of Sorafenib twice daily. The patient received 4 cycles of CAR-GPC3 T cells (CT011) treatment and each cycle was divided into two infusions. Prior to each cycle of CT011 treatment, lymphodepletion was performed. The lymphodepletion regimen was cyclophosphamide 500 mg/m2/day for 2 to 3 days, and fludarabine 20-25 mg/m2/day for 3 to 4 days. A total of 4×109 CAR-GPC3 T cells were infused. The CT011 plus Sorafenib combination therapy was well tolerated. All the ≥ grade 3 AEs were hematological toxicities which were deemed an expected event caused by the preconditioning regimen. This patient obtained partial responses from the 3rd month and achieved CR in the 12th month after the first cycle of CT011 infusion according to the RECIST1.1 assessment. The tumor had no progression for more than 36 months and maintained the CR status for more than 24 months after the first infusion.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Neoplasias Pulmonares , Receptores de Antígenos Quiméricos , Animais , Glipicanas , Masculino , Camundongos , Sorafenibe/uso terapêutico , Linfócitos T , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Int J Mol Sci ; 23(17)2022 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-36077182

RESUMO

Paraprobiotics, inactivated microbial cells, regulate immune system and exhibit antioxidant and anti-inflammatory activities in patients with weakened immunity or the elderly. This study evaluated the anti-tumor effects of heat-killed Bifidobacterium and Lactobacillus on human gastric cancer MKN1 cells in vitro and in vivo in xenograft animal models. First, cytotoxicity and apoptosis in MKN1 cells of 11 different heat-killed Bifidobacterium or Lactobacillus strains were examined using the MTT assay or flow cytometry, respectively. Then, BALB/c nude mice xenograft animal models were implanted with human gastric cancer MKN1 cells and orally administered a selected single or a mixture of heat-killed bacterial strains to investigate their inhibitory effect on tumor growth. In addition, the expression of p-Akt, p53, Bax, Bak, cleaved caspase-9, -3, and PARP in the tumor tissues was analyzed using Western blotting assay or immunohistochemistry staining. The results show that heat-killed B. bifidum MG731 (MG731), L. reuteri MG5346 (MG5346), and L. rhamnosus MG5200 (MG5200) induced relatively greater apoptosis than other strains in MKN1 cells. Oral administration of a single dose or a mixture of MG731, MG5346, or MG5200 significantly delayed tumor growth, and MG731 had the most effective anti-tumor effect in the xenograft model. Protein expression of p-Akt, p53, Bax, cleaved caspase-3 and -9, and PARP in tumors derived from the xenograft model correlated with the results of the immunohistochemistry staining.


Assuntos
Bifidobacterium bifidum , Neoplasias Gástricas , Idoso , Animais , Apoptose , Bifidobacterium bifidum/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Xenoenxertos , Temperatura Alta , Humanos , Camundongos , Camundongos Nus , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína X Associada a bcl-2/metabolismo
4.
Molecules ; 27(17)2022 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-36080307

RESUMO

Tyrosine kinase inhibitors are validated therapeutic agents against EGFR-mutated non-small cell lung cancer (NSCLC). However, the associated critical side effects of these agents are inevitable, demanding more specific and efficient targeting agents. Recently, we have developed and reported a non-covalent imidazo[1,2-a]quinoxaline-based EGFR inhibitor (6b), which showed promising inhibitory activity against the gefitinib-resistant H1975(L858R/T790M) lung cancer cell line. In the present study, we further explored the 6b compound in vivo by employing the A549-induced xenograft model in nude mice. The results indicate that the administration of the 6b compound significantly abolished the growth of the tumor in the A549 xenograft nude mice. Whereas the control mice bearing tumors displayed a declining trend in the survival curve, treatment with the 6b compound improved the survival profile of mice. Moreover, the histological examination showed the cancer cell cytotoxicity of the 6b compound was characterized by cytoplasmic destruction observed in the stained section of the tumor tissues of treated mice. The immunoblotting and qPCR results further signified that 6b inhibited EGFR in tissue samples and consequently altered the downstream pathways mediated by EGFR, leading to a reduction in cancer growth. Therefore, the in vivo findings were in corroboration with the in vitro results, suggesting that 6b possessed potential anticancer activity against EGFR-dependent lung cancer. 6b also exhibited good stability in human and mouse liver microsomes.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/metabolismo , Xenoenxertos , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Nus , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/farmacologia , Quinoxalinas/farmacologia , Quinoxalinas/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Cell Rep Med ; 3(9): 100659, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36130479

RESUMO

Local or metastatic relapse following surgery, radiotherapy, and cisplatin is the leading cause of death in patients with head and neck squamous cell carcinoma (HNSCC). Our study shows overexpression of c-MET and AXL in HNSCC cells and patients resistant to radiotherapy and cisplatin. We demonstrate that cabozantinib, an inhibitor of vascular endothelial growth factor receptor (VEGFR), c-MET, and AXL, decreases migration, invasion, and proliferation and induces mitotic catastrophe and apoptotic cell death of naive and radiotherapy- and cisplatin-resistant HNSCC cells. Cabozantinib inhibits the growth and metastatic spread of experimental HNSCC in zebrafish and the growth of experimental HNSCC in mice by blocking tumor cell proliferation and angiogenesis. The efficacy of cabozantinib is also confirmed on viable sections of surgically removed specimens of human HNSCC and on a patient who relapses after five lines of treatment. These results suggest that cabozantinib is relevant for the treatment of patients with HNSCC after relapse under radiotherapy and cisplatin.


Assuntos
Carcinoma , Neoplasias de Cabeça e Pescoço , Anilidas , Animais , Linhagem Celular Tumoral , Cisplatino/farmacologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Camundongos , Recidiva Local de Neoplasia , Piridinas , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
6.
Dis Markers ; 2022: 1479246, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36072895

RESUMO

Commensal microbiome is a key factor of lung cancer immunotherapy efficacy. Elucidating the role of specific strains as bacterial markers in immunotherapy has drawn great attention from the academia. At present, most preclinical studies about the relationship between bacterial markers and immunotherapy rely on the syngeneic mouse models. However, mice differ greatly from humans in immune system and tumor characteristics. In this study, humanized mouse models based on peripheral blood mononuclear cells (PBMCs) immune reconstitution and lung cancer cell line-derived xenograft (CDX) or patient-derived xenograft (PDX) were constructed. The PBMC-PDX model was shown to be superior to the PBMC-CDX model in preserving tumor heterogeneity and construction time-saving. Through optimizing the experimental process, the time it took for humanized models to evaluate the effect of cancer treatment was reduced to 42 days. Next, by utilizing PBMC-PDX mice treated with antibiotics (ATB), the role of Bifidobacterium longum in lung cancer immunotherapy was studied. It was found that although both Bifidobacterium longum and immunotherapy drug pembrolizumab alone showed suppressing tumor growth, the efficacy of pembrolizumab was attenuated when administrated to mice colonized with Bifidobacterium longum. Further exploration revealed that Bifidobacterium longum caused significant changes in the proportion of human CD45+ cells in the PBMC-PDX model. The PBMC-PDX model has the potential to be applied as an efficient platform to support evaluation of bacterial markers in immunotherapy research and facilitate development of precision medicine targeting human commensal bacteria.


Assuntos
Leucócitos Mononucleares , Neoplasias Pulmonares , Animais , Bactérias , Biomarcadores , Modelos Animais de Doenças , Humanos , Fatores Imunológicos , Imunoterapia , Neoplasias Pulmonares/terapia , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
7.
J Med Chem ; 65(18): 12346-12366, 2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36053318

RESUMO

The development of triple-negative breast cancer (TNBC) is highly associated with G-quadruplex (G4); thus, targeting G4 is a potential strategy for TNBC therapy. Because concomitant histone deacetylases (HDAC) inhibition could amplify the impact of G4-targeting compounds, we designed and synthesized two novel series of G4/HDAC dual-targeting compounds by connecting the zinc-binding pharmacophore of HDAC inhibitors to the G4-targeting isaindigotone scaffold (1). Among the new compounds, a6 with the potent HDAC inhibitory and G4 stabilizing activity could induce more DNA G4 formation than SAHA and 1 in TNBC cells. Remarkably, a6 caused more G4-related DNA damage and G4-related differentially expressed genes, consistent with its effect on disrupting the cell cycle, invasion, and glycolysis. Furthermore, a6 significantly suppresses the proliferation of various TNBC cells and the MDA-MB-231 xenograft model without evident toxicity. Our study suggests a novel strategy for TNBC therapeutics through dual-targeting HDAC and G4.


Assuntos
Antineoplásicos , Neoplasias de Mama Triplo Negativas , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , DNA/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/metabolismo , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Zinco/farmacologia
8.
Sci Rep ; 12(1): 15058, 2022 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-36075937

RESUMO

Osteosarcoma is still associated with limited response to standard-of-care therapy and alarmingly elevated mortality rates, especially in low- and middle-income countries. Despite multiple efforts to repurpose ß-blocker propranolol in oncology, its potential application in osteosarcoma management remains largely unexplored. Considering the unsatisfied clinical needs of this aggressive disease, we evaluated the antitumoral activity of propranolol using different in vitro and in vivo osteosarcoma preclinical models, alone or in addition to chemotherapy. Propranolol significantly impaired cellular growth in ß2-adrenergic receptor-expressing MG-63 and U-2OS cells, and was capable of blocking growth-stimulating effects triggered by catecholamines. siRNA-mediated ADRB2 knockdown in MG-63 cells was associated with decreased cell survival and a significant attenuation of PPN anti-osteosarcoma activity. Direct cytostatic effects of propranolol were independent of apoptosis induction and were associated with reduced mitosis, G0/G1 cell cycle arrest and a significant down-regulation of cell cycle regulator Cyclin D1. Moreover, colony formation, 3D spheroid growth, cell chemotaxis and capillary-like tube formation were drastically impaired after propranolol treatment. Interestingly, anti-migratory activity of ß-blocker was associated with altered actin cytoskeleton dynamics. In vivo, propranolol treatment (10 mg/kg/day i.p.) reduced the early angiogenic response triggered by MG-63 cells in nude mice. Synergistic effects were observed in vitro after combining propranolol with chemotherapeutic agent cisplatin. Sustained administration of propranolol (10 mg/kg/day i.p., five days a week), alone and especially in addition to low-dose metronomic cisplatin (2 mg/kg/day i.p., three times a week), markedly reduced xenograft progression. After histological analysis, propranolol and cisplatin combination resulted in low tumor mitotic index and increased tumor necrosis. ß-blockade using propranolol seems to be an achievable and cost-effective therapeutic approach to modulate osteosarcoma aggressiveness. Further translational studies of propranolol repurposing in osteosarcoma are warranted.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Animais , Apoptose , Neoplasias Ósseas/tratamento farmacológico , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Xenoenxertos , Humanos , Camundongos , Camundongos Nus , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologia , Propranolol/farmacologia , Propranolol/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Sci Transl Med ; 14(656): eabn1128, 2022 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-35921473

RESUMO

Glioblastoma multiforme (GBM) remains incurable despite aggressive implementation of multimodal treatments after surgical debulking. Almost all patients with GBM relapse within a narrow margin around the initial resected lesion due to postsurgery residual glioma stem cells (GSCs). Tracking and eradicating postsurgery residual GSCs is critical for preventing postoperative relapse of this devastating disease, yet effective strategies remain elusive. Here, we report a cavity-injectable nanoporter-hydrogel superstructure that creates GSC-specific chimeric antigen receptor (CAR) macrophages/microglia (MΦs) surrounding the cavity to prevent GBM relapse. Specifically, we demonstrate that the CAR gene-laden nanoporter in the hydrogel can introduce GSC-targeted CAR genes into MΦ nuclei after intracavity delivery to generate CAR-MΦs in mouse models of GBM. These CAR-MΦs were able to seek and engulf GSCs and clear residual GSCs by stimulating an adaptive antitumor immune response in the tumor microenvironment and prevented postoperative glioma relapse by inducing long-term antitumor immunity in mice. In an orthotopic patient-derived glioblastoma humanized mouse model, the combined treatment with nanoporter-hydrogel superstructure and CD47 antibody increased the frequency of positive immune responding cells and suppressed the negative immune regulating cells, conferring a robust tumoricidal immunity surrounding the postsurgical cavity and inhibiting postoperative glioblastoma relapse. Therefore, our work establishes a locoregional treatment strategy for priming cancer stem cell-specific tumoricidal immunity with broad application in patients suffering from recurrent malignancies.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Receptores de Antígenos Quiméricos , Animais , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Glioblastoma/genética , Glioma/patologia , Glioma/terapia , Hidrogéis , Macrófagos/patologia , Camundongos , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/patologia , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Nature ; 609(7925): 174-182, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36002574

RESUMO

The efficacy of adoptive T cell therapies for cancer treatment can be limited by suppressive signals from both extrinsic factors and intrinsic inhibitory checkpoints1,2. Targeted gene editing has the potential to overcome these limitations and enhance T cell therapeutic function3-10. Here we performed multiple genome-wide CRISPR knock-out screens under different immunosuppressive conditions to identify genes that can be targeted to prevent T cell dysfunction. These screens converged on RASA2, a RAS GTPase-activating protein (RasGAP) that we identify as a signalling checkpoint in human T cells, which is downregulated upon acute T cell receptor stimulation and can increase gradually with chronic antigen exposure. RASA2 ablation enhanced MAPK signalling and chimeric antigen receptor (CAR) T cell cytolytic activity in response to target antigen. Repeated tumour antigen stimulations in vitro revealed that RASA2-deficient T cells show increased activation, cytokine production and metabolic activity compared with control cells, and show a marked advantage in persistent cancer cell killing. RASA2-knockout CAR T cells had a competitive fitness advantage over control cells in the bone marrow in a mouse model of leukaemia. Ablation of RASA2 in multiple preclinical models of T cell receptor and CAR T cell therapies prolonged survival in mice xenografted with either liquid or solid tumours. Together, our findings highlight RASA2 as a promising target to enhance both persistence and effector function in T cell therapies for cancer treatment.


Assuntos
Antígenos de Neoplasias , Neoplasias , Linfócitos T , Proteínas Ativadoras de ras GTPase , Animais , Antígenos de Neoplasias/imunologia , Medula Óssea , Sistemas CRISPR-Cas , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Humanos , Imunoterapia Adotiva , Leucemia/imunologia , Leucemia/patologia , Leucemia/terapia , Camundongos , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fatores de Tempo , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Ativadoras de ras GTPase/deficiência , Proteínas Ativadoras de ras GTPase/genética
11.
Biomed Pharmacother ; 154: 113602, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36029544

RESUMO

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Although sorafenib is a standard first-line molecule-targeted drug against advanced HCC, the drug resistance development and adverse side effects usually limit its efficacy. This study investigated the effect of fucoidan on the sorafenib sensitivity of sorafenib-resistant human HCC cell line HepG2-SR established by long-time exposure of HepG2 to sorafenib. We demonstrated fucoidan combined with sorafenib synergistically promoted apoptosis and cell cycle arrest whereas inhibited cell migration in HepG2-SR cells. This combination treatment effectively suppressed the cellular epithelial growth factor receptor (EGFR) nuclear distribution and downstream gene transcription. Interestingly, fucoidan bound the cell surface EGFR, dampening EGFR translocation to lipid raft and further nuclear distribution, restoring the sorafenib sensitivity in HepG2-SR cells. Blocking fucoidan-EGFR interaction using EGFR antibody restrained the enhanced anti-tumor effects upon the combined administration. Besides, EGFR knockdown abolished the combination treatment-improved anti-tumor efficacy. This combination also suppressed in vivo xenograft tumor growth in nude mice. Our present study uncovered that fucoidan overcame sorafenib resistance in HCC via its interaction with cell membrane EGFR and further suppression of EGFR redistribution and downstream signaling in sorafenib-resistant cells. Overall, current results suggest that simultaneous treatment of fucoidan and sorafenib might serve as a potential therapeutic strategy against sorafenib-resistant HCC.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/metabolismo , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , Compostos de Fenilureia/farmacologia , Polissacarídeos , Receptores de Fatores de Crescimento , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Cancer Res ; 82(18): 3335-3344, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-35913398

RESUMO

KRAS and NRAS mutations occur in 45% of colorectal cancers, with combined MAPK pathway and CDK4/6 inhibition identified as a potential therapeutic strategy. In the current study, this combinatorial treatment approach was evaluated in a co-clinical trial in patient-derived xenografts (PDX), and safety was established in a clinical trial of binimetinib and palbociclib in patients with metastatic colorectal cancer with RAS mutations. Across 18 PDX models undergoing dual inhibition of MEK and CDK4/6, 60% of tumors regressed, meeting the co-clinical trial primary endpoint. Prolonged duration of response occurred predominantly in TP53 wild-type models. Clinical evaluation of binimetinib and palbociclib in a safety lead-in confirmed safety and provided preliminary evidence of activity. Prolonged treatment in PDX models resulted in feedback activation of receptor tyrosine kinases and acquired resistance, which was reversed with a SHP2 inhibitor. These results highlight the clinical potential of this combination in colorectal cancer, along with the utility of PDX-based co-clinical trial platforms for drug development. SIGNIFICANCE: This co-clinical trial of combined MEK-CDK4/6 inhibition in RAS mutant colorectal cancer demonstrates therapeutic efficacy in patient-derived xenografts and safety in patients, identifies biomarkers of response, and uncovers targetable mechanisms of resistance.


Assuntos
Neoplasias Colorretais , Inibidores de Proteínas Quinases , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Quinase 4 Dependente de Ciclina , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Tirosina/genética , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Nanoscale ; 14(35): 12773-12788, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36001382

RESUMO

Spatiotemporal targeting of anti-glioma drugs remains a pressing issue in glioblastoma (GBM) treatment. We challenge this issue by developing a minimally invasive in situ implantable hydrogel implant comprising transferrin-targeted temozolomide-miltefosine nanovesicles in the surgically resected GBM cavity (tumour bed). Injection of the "nanovesicle in hydrogel system" in orthotopic GBM-bearing mice improved drug penetration into the peri-cavitary region (∼4.5 mm in depth) with the potential to act as a bridge therapy in the immediate postoperative period, before the initiation of adjuvant radiotherapy. The controlled and sustained release of temozolomide over a month in the surgical cavity eradicated the microscopic GBM cells present within the tumour bed, thereby augmenting the efficacy of adjuvant therapy. The drug (temozolomide and miltefosine) combination was tolerable and efficiently inhibited tumour growth, causing significant prolongation of the survival of tumour-bearing mice compared to that with the free drug. Direct implantation at the target site in the brain resulted in spatiotemporal anti-glioma activity with minimal extracranial and systemic distribution. Nanovesicle in flexible hydrogel systems can be used as potential platforms for the post-surgical management of GBM before initiating adjuvant radiation therapy.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Nanopartículas , Animais , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Preparações de Ação Retardada/uso terapêutico , Glioblastoma/patologia , Glioma/tratamento farmacológico , Hidrogéis/farmacologia , Hidrogéis/uso terapêutico , Camundongos , Fosforilcolina/análogos & derivados , Polímeros/uso terapêutico , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Transferrina/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Int J Mol Sci ; 23(16)2022 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-36012152

RESUMO

Oncolytic adenoviruses (OAd) can be employed to efficiently eliminate cancer cells through multiple mechanisms of action including cell lysis and immune activation. Our OAds, AdΔΔ and Ad-3∆-A20T, selectively infect, replicate in, and kill adenocarcinoma cells with the added benefit of re-sensitising drug-resistant cells in preclinical models. Further modifications are required to enable systemic delivery in patients due to the rapid hepatic elimination and neutralisation by blood factors and antibodies. Here, we show data that support the use of coating OAds with gold nanoparticles (AuNPs) as a possible new method of virus modification to help augment tumour uptake. The pre-incubation of cationic AuNPs with AdΔΔ, Ad-3∆-A20T and wild type adenovirus (Ad5wt) was performed prior to infection of prostate/pancreatic cancer cell lines (22Rv, PC3, Panc04.03, PT45) and a pancreatic stellate cell line (PS1). Levels of viral infection, replication and cell viability were quantified 24-72 h post-infection in the presence and absence of AuNPs. Viral spread was assessed in organotypic cultures. The presence of AuNPs significantly increased the uptake of Ad∆∆, Ad-3∆-A20T and Ad5wt in all the cell lines tested (ranging from 1.5-fold to 40-fold), compared to virus alone, with the greatest uptake observed in PS1, a usually adenovirus-resistant cell line. Pre-coating the AdΔΔ and Ad-3∆-A20T with AuNPs also increased viral replication, leading to enhanced cell killing, with maximal effect in the most virus-insensitive cells (from 1.4-fold to 5-fold). To conclude, the electrostatic association of virus with cationic agents provides a new avenue to increase the dose in tumour lesions and potentially protect the virus from detrimental blood factor binding. Such an approach warrants further investigation for clinical translation.


Assuntos
Nanopartículas Metálicas , Terapia Viral Oncolítica , Vírus Oncolíticos , Neoplasias Pancreáticas , Viroses , Adenoviridae/fisiologia , Linhagem Celular Tumoral , Ouro/metabolismo , Humanos , Masculino , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/fisiologia , Neoplasias Pancreáticas/patologia , Próstata/patologia , Replicação Viral , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Cancer Chemother Pharmacol ; 90(3): 239-250, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35922568

RESUMO

PURPOSE: Tumor growth inhibition (TGI) models are regularly used to quantify the PK-PD relationship between drug concentration and in vivo efficacy in oncology. These models are typically calibrated with data from xenograft mice and before being used for clinical predictions, translational methods have to be applied. Currently, such methods are commonly based on replacing model components or scaling of model parameters. However, difficulties remain in how to accurately account for inter-species differences. Therefore, more research must be done before xenograft data can fully be utilized to predict clinical response. METHOD: To contribute to this research, we have calibrated TGI models to xenograft data for three drug combinations using the nonlinear mixed effects framework. The models were translated by replacing mice exposure with human exposure and used to make predictions of clinical response. Furthermore, in search of a better way of translating these models, we estimated an optimal way of scaling model parameters given the available clinical data. RESULTS: The predictions were compared with clinical data and we found that clinical efficacy was overestimated. The estimated optimal scaling factors were similar to a standard allometric scaling exponent of - 0.25. CONCLUSIONS: We believe that given more data, our methodology could contribute to increasing the translational capabilities of TGI models. More specifically, an appropriate translational method could be developed for drugs with the same mechanism of action, which would allow for all preclinical data to be leveraged for new drugs of the same class. This would ensure that fewer clinically inefficacious drugs are tested in clinical trials.


Assuntos
Neoplasias , Animais , Xenoenxertos , Humanos , Camundongos , Modelos Biológicos , Neoplasias/tratamento farmacológico , Critérios de Avaliação de Resposta em Tumores Sólidos , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Integr Cancer Ther ; 21: 15347354221114337, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35912937

RESUMO

The edible Rosa hybrida (RH) petal is utilized in functional foods and cosmetics. Although the biological function of RH petal extract is known, mechanism of action studies involving tumor-associated angiogenesis have not yet been reported. Herein, we investigated the regulatory effect of the ethanol extract of RH petal (EERH) on tumor growth and tumor angiogenesis against bladder cancer. EERH treatment inhibited the bladder carcinoma T24 cell and 5637 cell proliferation because of G1-phase cell cycle arrest by inducing p21WAF1 expression and reducing cyclins/CDKs level. EERH regulated signaling pathways differently in both cells. EERH-stimulated suppression of T24 and 5637 cell migration and invasion was associated with the decline in transcription factor-mediated MMP-9 expression. EERH oral administration to xenograft mice reduced tumor growth. Furthermore, no obvious toxicity was observed in acute toxicity test. Decreased CD31 levels in EERH-treated tumor tissues led to examine the angiogenic response. EERH alleviated VEGF-stimulated tube formation and proliferation by downregulating the VEGFR2/eNOS/AKT/ERK1/2 cascade in HUVECs. EERH impeded migration and invasion of VEGF-induced HUVECs, which is attributed to the repressed MMP-2 expression. Suppression of neo-microvessel sprouting, induced by VEGF, was verified by treatment with EERH using the ex vivo aortic ring assay. Finally, kaempferol was identified as the main active compound of EERH. The present study demonstrated that EERH may aid the development of antitumor agents against bladder cancer.


Assuntos
Rosa , Neoplasias da Bexiga Urinária , Inibidores da Angiogênese/farmacologia , Animais , Movimento Celular , Proliferação de Células , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Camundongos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Rosa/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Cell Death Dis ; 13(8): 724, 2022 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-35985991

RESUMO

Nasopharyngeal carcinoma (NPC) clinical trials show that antiangiogenic drugs (AADs) fail to achieve the expected efficacy, and combining AAD with chemoradiotherapy does not show superiority over chemoradiotherapy alone. Accumulating evidence suggests the intrinsic AAD resistance in NPC patients with poorly understood molecular mechanisms. Here, we describe NPC-specific FGF-2 expression-triggered, VEGF-independent angiogenesis as a mechanism of AAD resistance. Angiogenic factors screening between AAD-sensitive cancer type and AAD-resistant NPC showed high FGF-2 expression in NPC in both xenograft models and clinical samples. Mechanistically, the FGF-2-FGFR1-MYC axis drove endothelial cell survival and proliferation as an alternative to VEGF-VEGFR2-MYC signaling. Genetic knockdown of FGF-2 in NPC tumor cells reduced tumor angiogenesis, enhanced AAD sensitivity, and reduced pulmonary metastasis. Moreover, lenvatinib, an FDA recently approved multi-kinase inhibitor targeting both VEGFR2 and FGFR1, effectively inhibits the tumor vasculature, and exhibited robust anti-tumor effects in NPC-bearing nude mice and humanized mice compared with an agent equivalent to bevacizumab. These findings provide mechanistic insights on FGF-2 signaling in the modulation of VEGF pathway activation in the NPC microenvironment and propose an effective NPC-targeted therapy by using a clinically available drug.


Assuntos
Inibidores da Angiogênese , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Compostos de Fenilureia , Quinolinas , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Fator 2 de Crescimento de Fibroblastos/farmacologia , Humanos , Camundongos , Camundongos Nus , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Neovascularização Patológica/metabolismo , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Proteínas Proto-Oncogênicas c-myc/metabolismo , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Transdução de Sinais , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Front Biosci (Landmark Ed) ; 27(8): 238, 2022 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-36042171

RESUMO

BACKGROUND: To investigate the synergic effect and underlying mechanism of Endostar, a recombinant human endostatin used for anti-angiogenesis, in radiotherapy for cervical cancer. METHODS: The Cell Counting Kit-8 (CCK-8) assay and plate cloning experiment were first employed to analyze the proliferation of HeLa and SiHa cervical cancer cells and human umbilical vein vascular endothelial cells (HUVECs). Flow cytometry was used to detect apoptosis and cell cycle progression. A tube formation assay was used to assess angiogenesis in vitro. The expression of gamma H2A histone family member X (γ-H2AX) and activation of the vascular endothelial growth factor receptor (VEGFR) signaling pathway were detected by immunofluorescence and western blotting, respectively. In a HeLa xenograft model, tumor tissue expression of CD31 and alpha smooth muscle actin and serum expression of VEGF-A were detected by immunohistochemistry (IHC) and enzyme-linked immunosorbent assay, respectively. RESULTS: The CCK-8 and plate cloning assays showed that Endostar and radiotherapy synergistically inhibited the growth of HUVECs but not HeLa and SiHa cells. The flow cytometric results showed that Endostar only promoted radiotherapy-induced apoptosis and G2/M phase arrest in HUVECs (p < 0.05). Endostar combined with radiotherapy also significantly inhibited tube formation by HUVECs (p < 0.05). Furthermore, Endostar inhibited the radiotherapy-induced expression of γH2AX (p < 0.05) and phosphorylation of VEGFR2/PI3K/AKT/DNA-PK in HUVECs (p < 0.05). IHC showed that Endostar enhanced the inhibitory effect of radiotherapy on the microvessel density in xenograft tumor tissues (p < 0.05), as well as serum VEGF-A expression (p < 0.05). The tumor volume in the combination therapy groups (1200 mm3) was significantly lower than in the control group (2500 mm3; p < 0.05). CONCLUSIONS: Our findings provide experimental evidence and a theoretical basis for the application of Endostar in combination with irradiation for anti-cervical cancer treatment.


Assuntos
Endostatinas , Neoplasias do Colo do Útero , Inibidores da Angiogênese/farmacologia , Animais , Proliferação de Células , Modelos Animais de Doenças , Endostatinas/farmacologia , Feminino , Xenoenxertos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Camundongos , Neovascularização Patológica/radioterapia , Fosfatidilinositol 3-Quinases , Proteínas Recombinantes , Sincalida/farmacologia , Neoplasias do Colo do Útero/radioterapia , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Front Biosci (Landmark Ed) ; 27(8): 250, 2022 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-36042181

RESUMO

BACKGROUND: Gui Shao Tea (GST), a long-aged tea with a Chinese herbal aroma, can treat many stubborn and malignant diseases, according to traditional Chinese medicine. This research aimed to discover and define GST, study the anti-gastric cancer effects of GST extracts and preliminarily elucidate the mechanism of action in the PI3K/Akt signaling pathway and the gut microbiota. METHODS: GST was analyzed by GC/MS and HPLC. Cell proliferation, the cell cycle and apoptosis were evaluated by a CCK8 assay and flow cytometry. The effects of GST extracts on tumor inhibition and survival time were explored by a gastric cancer xenograft model in nude mice. The PI3K/Akt signaling pathway was assessed by western blotting and immunohistochemistry. Gut microbiota detection and fecal microbiota transplantation were performed to examine whether the tumor inhibition observed in mice was related to gut microbiota changes. RESULTS: The ingredients in GST, mostly terpenes and their derivatives, were novel and more concentrated than those in tea made from the branches and leaves of the same plant species, Camellia sinensis, picked and produced the same year, while the levels of polyphenols and alkaloids were significantly reduced. In BGC-823, MGC-803, and SGC-7901 gastric cancer cells, GST extracts significantly inhibited proliferation (p = 0.037), induced G0/G1 arrest (p < 0.001) and promoted early apoptosis (p = 0.041). In mice, gastric tumor growth was significantly inhibited in both the high-dose (HTF) and middle-dose (MTF) GST-fed groups. The inhibition rate in the HTF group was 33.77% on Day 14 (p = 0.042), and that in the MTF group was 55.21% on Day 14 (p = 0.002) and 61.6% on Day 28 (p = 0.008). The survival time of MTF group mice was significantly prolonged by 22.2% (p = 0.013). GST extracts inhibited the PI3K/AKT signaling pathway in gastric cancer cells (p = 0.016) and tissues (p = 0.029), downregulated the protein p-Rb and further downregulated E2F1, thereby affecting the cell cycle and proliferation. GST extracts altered the gut microbiota in mice, but these alterations alone were insufficient to inhibit gastric cancer growth. CONCLUSIONS: We confirmed the anti-gastric cancer effects of GST extracts, which might provide new approaches and methods for research and development of gastric cancer drugs.


Assuntos
Neoplasias Gástricas , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Camundongos , Camundongos Nus , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/patologia , Chá , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Eur J Med Chem ; 241: 114617, 2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-35932567

RESUMO

Gastric cancer is a worldwide health problem. Chemotherapy and radiotherapy are of great importance in the management of advanced gastric cancer. However, their therapeutic efficacy is limited by off-target side effects. Peptide-drug conjugates (PDCs) are a novel strategy for tumor-targeted drug delivery to overcome the existing drug resistance mechanisms and improve antitumor effects. Kita-Kyushu lung cancer antigen 1 (KK-LC-1) is exclusively expressed in several types of cancer including gastric cancer, representing a promising target for drug delivery. Here, we suggested KK-LC-1 as a potential target for PDC design for the first time and reported the first KK-LC-1-targeting PDC product 1131-MMAE, which is composed of a KK-LC-1-targeting peptide and an antimitotic drug conjugated by an enzymatically cleavable linker. We observed that 1131-MMAE could be efficiently endocytosed by KK-LC-1 positive gastric cancer cells for subsequent drug release and arrest the cell cycle at the most radiosensitive G2/M phase. We demonstrated that 1131-MMAE could significantly delay tumor growth with reduced toxicity than free drugs as a monotherapy. We further confirmed that 1131-MMAE was also a potent radiosensitizer. 1131-MMAE could selectively enhance the radiation response of KK-LC-1 positive tumor cells and achieve improved tumor control when combined with low-dose radiation. Overall, our study proposed an optimized therapeutic regimen for precision chemoradiotherapy, which has translational potential in multiple types of cancer.


Assuntos
Imunoconjugados , Neoplasias Pulmonares , Neoplasias Gástricas , Aminobenzoatos , Antígenos de Neoplasias , Linhagem Celular Tumoral , Quimiorradioterapia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Oligopeptídeos/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto
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