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المؤلفون: Vaynrub, Anna, Healey, John H, Tap, William, Vaynrub, Max
المصدر: OncoTargets and therapy
مصطلحات موضوعية: hepatotoxicity, colony-stimulating factor 1, PVNS, Oncology, giant cell tumor of tendon sheath, CSF1, Pharmacology (medical), Review, pigmented villonodular synovitis, GCT-TS, radiotherapy, synovectomy
الوصف: Tenosynovial giant cell tumor (TGCT) is a neoplasm of the joint synovium that can have severe impacts on joint mobility, function, and quality of life. Traditionally, treatment modalities included partial or complete surgical synovectomy, radiotherapy (typically as an adjunct to surgery), and watchful monitoring (no medical or surgical intervention). However, these approaches have been met with varying degrees of success and high recurrence rates, as well as onerous complications and clinical sequelae. Pexidartinib, a colony-stimulating factor 1 receptor (CSF1R) inhibitor, presents a promising molecular approach that targets a neoplastic driver of TGCT. While the introduction of pexidartinib allows clinicians to avoid the significant morbidity associated with traditional treatment options, there are also defined risks associated with pexidartinib treatment. Therefore, patient selection is critical in optimizing treatment modalities in TGCT. The purpose of this literature review is to identify the TGCT patient population that would derive maximal benefit with minimal risk from pexidartinib, and to determine the specific indications and contraindications for selecting pexidartinib over other therapeutic approaches. Specifically, this paper compares the efficacy and safety profile of pexidartinib across clinical and preclinical studies to that of surgery, radiotherapy, and watchful monitoring. Rates of improvement in joint mobility, pain, and recurrence-free survival across studies of pexidartinib have been encouraging. The most common adverse events are mild (hypopigmentation of the hair) or reversible (transient aminotransferase elevation). Severe or permanent adverse events (notably cholestatic hepatotoxicity) are rare. While the optimal treatment strategy remains highly dependent on a patient’s clinical circumstances and treatment goals, pexidartinib has surfaced as a promising therapeutic in cases where the morbidity of surgery or radiotherapy outweighs the benefits.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1d36a9bad4111798c94afe9802664a1aTest
https://doi.org/10.2147/ott.s345878Test -
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المؤلفون: Hong-wu Li, Shi-lei Tang
المصدر: Journal of Cancer
مصطلحات موضوعية: Macrophage colony-stimulating factor, Tumor microenvironment, business.industry, tumor-associated macrophages, medicine.medical_treatment, Cancer, Review, medicine.disease, colony stimulating factor-1, Metastasis, Colony stimulating factor 1 receptor, Cytokine, Oncology, Cancer immunotherapy, colony stimulating factor-1 receptor, Cancer research, Medicine, business, Receptor, gastrointestinal malignant tumors
الوصف: Gastrointestinal malignant tumor is the fourth most common cancer in the world and the second cause of cancer death. Due to the susceptibility to lymphatic metastasis and liver metastasis, the prognosis of advanced tumor patients is still poor till now. With the development of tumor molecular biology, the tumor microenvironment and the cytokines, which are closely related to the proliferation, infiltration and metastasis, have become a research hotspot in life sciences. Colony stimulating factor-1 (CSF-1), a polypeptide chain cytokine, and its receptor CSF-1R are reported to play important roles in regulating tumor-associated macrophages in tumor microenvironment and participating in the occurrence and development in diversities of cancers. Targeted inhibition of the CSF-1/CSF-1R signal axis has broad application prospects in cancer immunotherapy. Here, we reviewed the biological characters of CSF-1/CSF-1R and their relationship with gastrointestinal malignancies.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f31a69d40715bcfb2b579a5ad6a80581Test
http://europepmc.org/articles/PMC8558652Test -
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المؤلفون: Fiona Pakiam, Emily J. Girard, Ken Brasel, Erin E. Crotty, Yamicia D. Connor, Andrew J. Mhyre, Frederique Zindy, Stephanie M.C. Smith, James M. Olson, Martine F. Roussel
المصدر: J Neurooncol
مصطلحات موضوعية: Cancer Research, Proliferation index, Receptor, Macrophage Colony-Stimulating Factor, Article, Metastasis, Colony stimulating factor 1 receptor, 03 medical and health sciences, 0302 clinical medicine, Immunophenotyping, Tumor Microenvironment, Humans, Medicine, Hedgehog Proteins, Cerebellar Neoplasms, Child, Medulloblastoma, Microglia, business.industry, Macrophage Colony-Stimulating Factor, Macrophages, Receptor Protein-Tyrosine Kinases, medicine.disease, medicine.anatomical_structure, Neurology, Oncology, PTCH1, Tumor progression, 030220 oncology & carcinogenesis, Cancer research, Neurology (clinical), business, 030217 neurology & neurosurgery, Signal Transduction
الوصف: PURPOSE: Tumor infiltration by immunosuppressive myeloid cells or tumor-associated macrophages (TAMs) contributes to tumor progression and metastasis. In contrast to their adult counterparts, higher TAM signatures do not correlate with aggressive tumor behavior in pediatric brain tumors. While prominent TAM infiltrates exist before and after radiation, the degree to which irradiated macrophages and microglia support progression or leptomeningeal metastasis remains unclear. Patients with medulloblastoma often present with distant metastases and tumor recurrence is largely incurable, making them prime candidates for the study of novel approaches to prevent neuroaxis dissemination and recurrence. METHODS: Macrophage depletion was achieved using CSF-1 receptor inhibitors (CSF-1Ri), BLZ945 and AFS98, with or without whole brain radiation in a variety of medulloblastoma models, including patient-derived xenografts bearing Group 3 medulloblastoma and a transgenic Sonic Hedgehog (Ptch1(+/−), Trp53(−/−)) medulloblastoma model. RESULTS: Effective reduction of microglia, TAM, and spinal cord macrophage with CSF-1Ri resulted in negligible effects on the rate of local and spinal recurrences or survival following radiation. Results were comparable between medulloblastoma subgroups. While notably few tumor-infiltrating lymphocytes (TILs) were detected, average numbers of CD3+ TILs and FoxP3+ Tregs did not differ between groups following treatment and tumor aggressiveness by Ki67 proliferation index was unaltered. CONCLUSION: In the absence of other microenvironmental influences, medulloblastoma-educated macrophages do not operate as tumor-supportive cells or promote leptomeningeal recurrence in these models. Our data add to a growing body of literature describing a distinct immunophenotype amid the medulloblastoma microenvironment and highlight the importance of appropriate pediatric modeling prior to clinical translation.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c96891dab0182433afe322c08f1c5d92Test
https://doi.org/10.1007/s11060-021-03767-xTest -
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المؤلفون: Yirun Li, Lifeng He, Daizhan Zhou, Hui Lin, Bin Cui, Dandan Li, Xiaoxiao Fan
المصدر: Oncology Letters
مصطلحات موضوعية: 0301 basic medicine, Cancer Research, Biology, Metastasis, Colony stimulating factor 1 receptor, 03 medical and health sciences, 0302 clinical medicine, medicine, Tumor microenvironment, Oncogene, tumor-associated macrophages, Cancer, Articles, hepatocellular carcinoma, Methylation, medicine.disease, microenvironment, digestive system diseases, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, DNA methylation, Cancer research, methylation, colony stimulating factor 1 receptor
الوصف: Tumor-associated macrophages (TAMs) are important in tumor microenvironments and are closely associated with cancer occurrence, metastasis and progression. Colony stimulating factor 1 receptor (CSF1R) serves a crucial role in TAM formation. Whether CSF1R expression is regulated by DNA methylation in hepatocellular carcinoma (HCC) has not been fully elucidated. In the current study, HCC and adjacent non-cancerous tissue (ANT) samples were collected from 160 patients with HCC. CSF1R methylation levels were analyzed using a Mass ARRAY Analyzer to establish the potential impact of CSF1R methylation alternations on HCC clinicopathological characteristics. The mean methylation level of the CSF1R promoter (chr 5:149492491-149492958) was demonstrated to be significantly higher in ANTs compared with HCC tissues (65.3±7.5% vs. 57.3±14.4%, respectively; P0.4; P
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3d432e6a0f905bc7f8f6517473c7264eTest
https://doi.org/10.3892/ol.2020.11726Test -
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المؤلفون: Andrea Wang-Gillam, A. Craig Lockhart, Benjamin R. Tan, Ashley Morton, Chris Liang, Joel Picus, Bruce J. Roth, Katrina S. Pedersen, Emily Chan, Patrick M. Grierson, Jingxia Liu, Jesse Huffman
المصدر: Investigational New Drugs. 39:1298-1305
مصطلحات موضوعية: 0301 basic medicine, Oncology, medicine.medical_specialty, medicine.drug_class, Tyrosine-kinase inhibitor, Colony stimulating factor 1 receptor, 03 medical and health sciences, 0302 clinical medicine, Renal cell carcinoma, Internal medicine, Mucositis, medicine, Pharmacology (medical), Pharmacology, Everolimus, biology, business.industry, medicine.disease, 030104 developmental biology, 030220 oncology & carcinogenesis, biology.protein, business, Tyrosine kinase, Platelet-derived growth factor receptor, Hypophosphatemia, medicine.drug
الوصف: Background Anti-vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI) combined with mTOR inhibitors, like everolimus, result in significant responses and prolonged progression-free survival (PFS) among patients with renal cell carcinoma (RCC) [1]. However, everolimus doses >5 mg are often not tolerated when combined with other TKIs2,3. Vorolanib (X-82), an oral anti-VEGFR/platelet derived growth factor receptor (PDGFR)/colony stimulating factor 1 receptor (CSF1R) multitarget TKI, has a short half-life and limited tissue accumulation. We conducted a Phase 1 study of vorolanib with everolimus (10 mg daily) in patients with solid tumors. Methods A 3 + 3 dose escalation design was utilized to determine dose limiting toxicities (DLT) and recommended Phase 2 dose (RP2D) of vorolanib/everolimus. Oral vorolanib at 100, 150, 200, 300, or 400 mg was combined with 10 mg oral everolimus daily. The phase 2 portion was terminated after enrolling two patients due to funding. Results Eighteen patients were evaluable for DLT among 22 treated subjects. Observed DLTs were grade 3 fatigue, hypophosphatemia, and mucositis. The RP2D is vorolanib 300 mg with everolimus 10 mg daily. In 15 patients evaluable for response, three had partial response (PR; 2 RCC, 1 neuroendocrine tumor [NET]) and eight had stable disease (SD; 2 RCC, 6 NET). Conclusions Vorolanib can safely be combined with everolimus. Encouraging activity is seen in RCC and NET. Further studies are warranted. Trial Registration Number: NCT01784861.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::b5bd6e4cce1893034b2c412489168a2aTest
https://doi.org/10.1007/s10637-021-01093-7Test -
6
المؤلفون: David A. Hume, Michelle Ferrari-Cestari, Andy Wu, Jean-Pierre Levesque, Anuj Sehgal, Liza J. Raggatt, Lena Batoon, Simranpreet Kaur, Allison R. Pettit, Susan M. Millard, Cheyenne J. Sandrock
المصدر: Journal of Hematology & Oncology, Vol 14, Iss 1, Pp 1-19 (2021)
Journal of Hematology & Oncologyمصطلحات موضوعية: Macrophage colony-stimulating factor, Cancer Research, Recombinant Fusion Proteins, lcsh:RC254-282, Mice, Granulocyte Colony-Stimulating Factor, medicine, Animals, Autologous transplantation, Progenitor cell, Molecular Biology, business.industry, Colony-stimulating factor 1, lcsh:RC633-647.5, Macrophage Colony-Stimulating Factor, Research, Macrophages, Hematopoietic Stem Cell Transplantation, Hematopoietic stem cell, Hematology, lcsh:Diseases of the blood and blood-forming organs, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Hematopoietic Stem Cell Mobilization, Hematopoiesis, Mice, Inbred C57BL, Transplantation, Haematopoiesis, medicine.anatomical_structure, Oncology, Cancer research, Female, HSC mobilisation, Bone marrow, Stem cell, business, Hematopoietic stem cells
الوصف: Background Prior chemotherapy and/or underlying morbidity commonly leads to poor mobilisation of hematopoietic stem cells (HSC) for transplantation in cancer patients. Increasing the number of available HSC prior to mobilisation is a potential strategy to overcome this deficiency. Resident bone marrow (BM) macrophages are essential for maintenance of niches that support HSC and enable engraftment in transplant recipients. Here we examined potential of donor treatment with modified recombinant colony-stimulating factor 1 (CSF1) to influence the HSC niche and expand the HSC pool for autologous transplantation. Methods We administered an acute treatment regimen of CSF1 Fc fusion protein (CSF1-Fc, daily injection for 4 consecutive days) to naive C57Bl/6 mice. Treatment impacts on macrophage and HSC number, HSC function and overall hematopoiesis were assessed at both the predicted peak drug action and during post-treatment recovery. A serial treatment strategy using CSF1-Fc followed by granulocyte colony-stimulating factor (G-CSF) was used to interrogate HSC mobilisation impacts. Outcomes were assessed by in situ imaging and ex vivo standard and imaging flow cytometry with functional validation by colony formation and competitive transplantation assay. Results CSF1-Fc treatment caused a transient expansion of monocyte-macrophage cells within BM and spleen at the expense of BM B lymphopoiesis and hematopoietic stem and progenitor cell (HSPC) homeostasis. During the recovery phase after cessation of CSF1-Fc treatment, normalisation of hematopoiesis was accompanied by an increase in the total available HSPC pool. Multiple approaches confirmed that CD48−CD150+ HSC do not express the CSF1 receptor, ruling out direct action of CSF1-Fc on these cells. In the spleen, increased HSC was associated with expression of the BM HSC niche macrophage marker CD169 in red pulp macrophages, suggesting elevated spleen engraftment with CD48−CD150+ HSC was secondary to CSF1-Fc macrophage impacts. Competitive transplant assays demonstrated that pre-treatment of donors with CSF1-Fc increased the number and reconstitution potential of HSPC in blood following a HSC mobilising regimen of G-CSF treatment. Conclusion These results indicate that CSF1-Fc conditioning could represent a therapeutic strategy to overcome poor HSC mobilisation and subsequently improve HSC transplantation outcomes.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8c9673943aa041e04cef531603b15574Test
https://doaj.org/article/a35dbeec550140e9ade7a9eec3072d08Test -
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المؤلفون: Yen-Shen Lu, Liqiong Fan, Sherko Kuemmel, Rafael López, Richard Greil, Esther Zamora Adelantado, Delphine Loirat, Mustafa Ozguroglu, Ava Kwong, Arlene Chan, Nelson Guerreiro, Claudio Zamagni, Ariadna Tibau, Seock-Ah Im, Christian F. Singer, Jennifer Marie Mataraza, Irene Kuter, Janna Sand-Dejmek, Sung Bae Kim, Guenther G. Steger, Pauline Wimberger, J. Thaddeus Beck, Christian W Scholz, Michelino De Laurentiis, Xuan-Mai Couillebault, Estela Vega, François Duhoux, Mario Campone
المساهمون: UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie
المصدر: CLINICAL CANCER RESEARCH
r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname
Clinical cancer research : an official journal of the American Association for Cancer Research, Vol. 28, no.1, p. 106-115 (2022)مصطلحات موضوعية: Cancer Research, medicine.medical_specialty, endocrine system diseases, Phases of clinical research, Triple Negative Breast Neoplasms, Gastroenterology, Deoxycytidine, Carboplatin, chemistry.chemical_compound, Breast cancer, Pharmacokinetics, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, controlled study, human, Triple-negative breast cancer, antineoplastic agent, business.industry, Macrophage Colony-Stimulating Factor, Area under the curve, gemcitabine, Antibodies, Monoclonal, clinical trial, medicine.disease, Gemcitabine, phase 2 clinical trial, female, Treatment Outcome, Oncology, Tolerability, chemistry, monoclonal antibody, triple negative breast cancer, randomized controlled trial, Female, pathology, colony stimulating factor 1, doxecitine, business, medicine.drug
الوصف: Purpose: This phase II study determined the efficacy of lacnotuzumab added to gemcitabine plus carboplatin (gem-carbo) in patients with advanced triple-negative breast cancer (TNBC). Patients and Methods: Female patients with advanced TNBC, with high levels of tumor-associated macrophages not amenable to curative treatment by surgery or radiotherapy were enrolled. Lacnotuzumab was dosed at 10 mg/kg every 3 weeks, ± a dose on cycle 1, day 8. Gemcitabine (1,000 mg/m2) and carboplatin (dose in mg calculated by area under the curve [mg/mL/min] × (glomerular filtration rate [mL/min] + 25 [mL/min]) were dosed every 3 weeks. Treatment continued until unacceptable toxicity, disease progression, or discontinuation by physician/patient. Results: Patients received lacnotuzumab + gem-carbo (n = 34) or gem-carbo (n = 15). Enrollment was halted due to recruitment challenges owing to rapid evolution of the therapeutic landscape; formal hypothesis testing of the primary endpoint was therefore not performed. Median progression-free survival was 5.6 months [90% confidence interval (CI), 4.47–8.64] in the lacnotuzumab + gem-carbo arm and 5.5 months (90% CI, 3.45–7.46) in the gem-carbo arm. Hematologic adverse events were common in both treatment arms; however, patients treated with lacnotuzumab experienced more frequent aspartate aminotransferase, alanine aminotransferase, and creatine kinase elevations. Pharmacokinetic results showed that free lacnotuzumab at 10 mg/kg exhibited a typical IgG pharmacokinetic profile and target engagement of circulating colony-stimulating factor 1 ligand. Conclusions: Despite successful target engagement and anticipated pharmacokinetic profile, lacnotuzumab + gem-carbo showed comparable antitumor activity to gem-carbo alone, with slightly poorer tolerability. However, the data presented in this article would be informative for future studies testing agents targeting the CSF1–CSF1 receptor pathway in TNBC.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3994fb167e6ec33daa1239d15b3e852eTest
https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=7710Test -
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المصدر: Frontiers in Oncology
Frontiers in Oncology, Vol 11 (2021)مصطلحات موضوعية: 0301 basic medicine, Cancer Research, medicine.medical_treatment, tumor-stroma, Review, acute myeloid leukemia, lcsh:RC254-282, Targeted therapy, Colony stimulating factor 1 receptor, 03 medical and health sciences, 0302 clinical medicine, Medicine, Tumor microenvironment, therapy development, business.industry, Myeloid leukemia, biomarkers, targeted therapy, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Clinical trial, Haematopoiesis, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Cancer research, Bone marrow, Stem cell, business, signal transduction, colony stimulating factor 1 receptor
الوصف: Acute myeloid leukemia (AML) is an aggressive heterogeneous blood cancer derived from hematopoietic stem cells. Tumor-stromal interactions in AML are of importance for disease development and therapy resistance, and bone marrow stroma seem like an attractive therapeutic target. Of particular interest is colony stimulating factor 1 receptor (CSF1R, M-CSFR, c-FMS, CD115) and its role in regulating plasticity of tumor-associated macrophages. We discuss first the potential of CSF1R-targeted therapy as an attractive concept with regards to the tumor microenvironment in the bone marrow niche. A second therapy approach, supported by preclinical research, also suggests that CSF1R-targeted therapy may increase the beneficial effect of conventional and novel therapeutics. Experimental evidence positioning inhibitors of CSF1R as treatment should, together with data from preclinical and early phase clinical trials, facilitate translation and clinical development of CSF1R-targeted therapy for AML.
وصف الملف: application/pdf
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::081e017ffdbaa7ac0420fda7f6ab3277Test
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9
المؤلفون: Hung-Kai Chen, Huey-Wen Hsiao, Pandelakis Koni, Chih-Lun Hsiao, Muh Hwa Yang, Yao-Wen Chang, Ju-Pei Chen, Jing-Yi Huang
المصدر: Journal for ImmunoTherapy of Cancer, Vol 9, Iss Suppl 2 (2021)
مصطلحات موضوعية: Pharmacology, Cancer Research, Tumor microenvironment, business.industry, Immunology, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Monocyte proliferation, medicine.disease, Metastasis, Colony stimulating factor 1 receptor, Oncology, Tumor progression, Cancer research, Molecular Medicine, Immunology and Allergy, Medicine, Cytotoxic T cell, business, CD8, Triple-negative breast cancer, RC254-282
الوصف: BackgroundTumor-associated macrophages (TAMs) are a significantly-poor prognostic factor for patients with triple-negative breast cancer (TNBC). The tumor microenvironment of TNBC features highly-infiltrating TAMs that contribute to tumor progression and metastasis. Therefore, TAM-targeted immunotherapies are recognized as a potential approach for treating TNBC. However, depleting TAMs alone by use of monoclonal antibodies against colony-stimulating factor 1 receptor (CSF1R) was insufficient to cause substantial tumor control. Recent studies revealed that interleukin-10 (IL-10) can directly activate terminally-exhausted CD8+ T cells to boost anti-tumor activity. We set forth to investigate whether a combination of anti-CSF1R antibody with a half-life-extended IL-10-Fc fusion protein (IL-10-Fc) may enhance anti-tumor immunity, and whether synergistic effects could be achieved with bifunctional antibody forms.MethodsAntibodies and recombinant proteins were produced in-house. In vitro CSF1R activity was evaluated by Western blot analysis of CSF1-mediated CSF1R phosphorylation and monocyte proliferation assays. In vitro IL10 activity was evaluated by MC/9 cell proliferation and CD8 T cell activation assays. 4T1 mouse breast tumor studies were performed at the National Yang Ming Chiao Tung University (Taiwan). Other tumor model studies employed the services of Crownbio (China). Methods of RNAseq analysis of 4T1 tumor masses included Cibersort, gene set enrichment analysis (GSEA) and immune gene signature score analysis.ResultsCo-treatment with a recombinant human IL-10-Fc protein significantly improved the anti-tumor efficacy of anti-mouse CSF1R antibody in a mouse CT26 colon tumor model. It was then hypothesized that a better synergistic effect could be achieved by a bifunctional anti-mouse CSF1R-IL-10 fusion protein (anti-mCSF1R-IL-10), to allow targeted-delivery of IL-10 to CSF1R-positive-TAM-rich tumor microenvironments. Indeed, anti-mCSF1R-IL-10 showed greatly increased anti-tumor efficacy in both EMT-6 and 4T1 mouse models of breast cancer. Consistent with the in vivo efficacy, gene expression profiling revealed an enhanced intratumoral interferon-gamma signature by treatment with anti-mCSF1R-IL-10 as compared to either anti-mCSF1R or IL-10-Fc alone. An anti-human CSF1R-IL-10 (hCSF1R-IL-10) was also constructed using a newly-produced anti-human CSF1R antibody and tested in cell-based functional assays, demonstrating that anti-hCSF1R-IL-10 could both inhibit CSF1-dependent cell growth and activate tumor-infiltrating T cells isolated from tumor biopsies of triple-negative breast cancer patients. Further validation of this bifunctional form will be presented.ConclusionsOur findings provide a potential strategy for simultaneously targeting TAM and exhausted T cells to potentiate anti-tumor immunity for treatment of triple-negative breast cancer.Ethics ApprovalThe studies were approved by the institutional animal care and use committee of National Yang Ming Chiao Tung University; approval numbers 1081025 and 109060.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fd3f340565ab4d4538fc0f17cfe413f7Test
https://doaj.org/article/02455fd8b7024b5a844d3d2ab290a69fTest -
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المؤلفون: Cody J. Peer, William D. Figg, Priya Shankarappa, Cynthia McCully, Rafael C. Garcia, Arman Odabas, Katherine E. Warren
المصدر: Cancer Chemother Pharmacol
مصطلحات موضوعية: 0301 basic medicine, Cancer Research, Cmax, Aminopyridines, Biological Availability, Antineoplastic Agents, Receptor, Macrophage Colony-Stimulating Factor, Pharmacology, Toxicology, Article, Colony stimulating factor 1 receptor, 03 medical and health sciences, 0302 clinical medicine, Cerebrospinal fluid, Pharmacokinetics, Oral administration, Glioma, medicine, Animals, Pyrroles, Pharmacology (medical), Receptor, Dose-Response Relationship, Drug, Brain Neoplasms, business.industry, Protein-Tyrosine Kinases, medicine.disease, Macaca mulatta, 030104 developmental biology, Oncology, Blood-Brain Barrier, 030220 oncology & carcinogenesis, Cerebrospinal fluid penetration, Drug Monitoring, business
الوصف: PURPOSE: Pexidartinib (PLX3397) is a colony-stimulating factor-1 receptor (CSF-1R) inhibitor under clinical evaluation for potential CNS tumor treatment. This study aims to evaluate plasma pharmacokinetic parameters and estimate CNS penetrance of pexidartinib in a non-human primate (NHP) cerebrospinal fluid (CSF) reservoir model. METHODS: Five male rhesus macaques, each with a previously implanted subcutaneous CSF ventricular reservoir and central venous lines, were used. NHPs received a single dose of 40 mg/kg pexidartinib (human equivalent dose of 800 mg/m(2)), administered orally as 200 mg tablets. Serial paired samples of blood and CSF were collected at 0–8, 24, 48, and 72 h. Pex-idartinib concentrations were assayed by Integrated Analytical Solutions, Inc. (Berkeley, CA, USA) using HPLC/MS/MS. Pharmacokinetic (PK) analysis was performed using noncompartmental methods. RESULTS: Samples from four NHPs were evaluable. Average (± SD) plasma PK parameters were as follows: C(max) = 16.50 (± 6.67) μg/mL; T(max) = 5.00 (± 2.58) h; AUC (last) = 250.25 (± 103.76) h*μg/mL; CL = 0.18 (± 0.10) L/h/kg. In CSF, pexidarti-n ib was either quantifiable (n = 2), with C(max) values of 16.1 and 10.1 ng/mL achieved 2–4 h after plasma T(max), or undetected at all time points (n = 2, LLOQ(CSF) = 5 ng/mL). CONCLUSION: Pexidartinib was well-tolerated in NHPs, with no Grade 3 or Grade 4 toxicities. The CSF penetration of pex-idartinib after single-dose oral administration to NHPs was limited.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7c5710742a7f5b902c1e2b55637e5722Test
https://doi.org/10.1007/s00280-020-04071-7Test