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1.
Cell ; 187(10): 2521-2535.e21, 2024 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-38697107

RESUMEN

Cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create "onion-like" multi-lamellar RNA lipid particle aggregates (LPAs) to substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became "hot" within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.


Asunto(s)
Inmunoterapia , Lípidos , ARN , Microambiente Tumoral , Animales , Perros , Femenino , Humanos , Ratones , Antígenos de Neoplasias/inmunología , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/inmunología , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Línea Celular Tumoral , Citocinas/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Glioblastoma/terapia , Glioblastoma/inmunología , Glioma/terapia , Glioma/inmunología , Inmunoterapia/métodos , Ratones Endogámicos C57BL , Neoplasias/terapia , Neoplasias/inmunología , ARN/química , ARN/uso terapéutico , ARN Mensajero/metabolismo , ARN Mensajero/genética , Lípidos/química
2.
Cell ; 184(9): 2278-2281, 2021 04 29.
Artículo en Inglés | MEDLINE | ID: mdl-33930294

RESUMEN

Immune evasion and resistance to immunotherapy mark major roadblocks in treating glioblastoma, the deadliest form of brain cancer. In this issue of Cell, Gangoso et al. demonstrate that the immune microenvironment drives glioblastoma cells to hijack myeloid-characteristic transcriptional and epigenetic circuits as a mode of immune evasion.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Conducta Imitativa , Inmunoterapia , Microambiente Tumoral
3.
Cell ; 181(7): 1454-1457, 2020 06 25.
Artículo en Inglés | MEDLINE | ID: mdl-32589956

RESUMEN

Despite its success in multiple tumor types, immunotherapy remains poorly efficacious in brain malignancies. In this issue of Cell, Friebel et al. and Klemm et al. provide in-depth insights into the versatile nuances of immune cells in primary and metastatic brain tumors, granting the field with a rich framework to explore novel therapeutic avenues.


Asunto(s)
Neoplasias Encefálicas , Neoplasias Encefálicas/terapia , Humanos , Inmunoterapia
4.
Genes Dev ; 38(9-10): 360-379, 2024 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-38811170

RESUMEN

Glioblastoma (GBM) is the most aggressive primary brain cancer. These tumors exhibit high intertumoral and intratumoral heterogeneity in neoplastic and nonneoplastic compartments, low lymphocyte infiltration, and high abundance of myeloid subsets that together create a highly protumorigenic immunosuppressive microenvironment. Moreover, heterogeneous GBM cells infiltrate adjacent brain tissue, remodeling the neural microenvironment to foster tumor electrochemical coupling with neurons and metabolic coupling with nonneoplastic astrocytes, thereby driving growth. Here, we review heterogeneity in the GBM microenvironment and its role in low-to-high-grade glioma transition, concluding with a discussion of the challenges of therapeutically targeting the tumor microenvironment and outlining future research opportunities.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Microambiente Tumoral , Humanos , Glioblastoma/terapia , Glioblastoma/fisiopatología , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/fisiopatología , Neoplasias Encefálicas/patología , Animales
5.
Nat Immunol ; 20(9): 1100-1109, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31358997

RESUMEN

Glioblastoma (GBM) is the deadliest form of brain cancer, with a median survival of less than 2 years despite surgical resection, radiation, and chemotherapy. GBM's rapid progression, resistance to therapy, and inexorable recurrence have been attributed to several factors, including its rapid growth rate, its molecular heterogeneity, its propensity to infiltrate vital brain structures, the regenerative capacity of treatment-resistant cancer stem cells, and challenges in achieving high concentrations of chemotherapeutic agents in the central nervous system. Escape from immunosurveillance is increasingly recognized as a landmark event in cancer biology. Translation of this framework to clinical oncology has positioned immunotherapy as a pillar of cancer treatment. Amid the bourgeoning successes of cancer immunotherapy, GBM has emerged as a model of resistance to immunotherapy. Here we review the mechanisms of immunotherapy resistance in GBM and discuss how insights into GBM-immune system interactions might inform the next generation of immunotherapeutics for GBM and other resistant pathologies.


Asunto(s)
Neoplasias Encefálicas/terapia , Resistencia a Antineoplásicos/genética , Glioblastoma/terapia , Inmunoterapia/métodos , Escape del Tumor/genética , Neoplasias Encefálicas/genética , Sistema Nervioso Central/inmunología , Glioblastoma/genética , Humanos
6.
Annu Rev Neurosci ; 45: 199-221, 2022 07 08.
Artículo en Inglés | MEDLINE | ID: mdl-35259916

RESUMEN

Nervous system activity regulates development, homeostasis, and plasticity of the brain as well as other organs in the body. These mechanisms are subverted in cancer to propel malignant growth. In turn, cancers modulate neural structure and function to augment growth-promoting neural signaling in the tumor microenvironment. Approaching cancer biology from a neuroscience perspective will elucidate new therapeutic strategies for presently lethal forms of cancer. In this review, we highlight the neural signaling mechanisms recapitulated in primary brain tumors, brain metastases, and solid tumors throughout the body that regulate cancer progression.


Asunto(s)
Neoplasias Encefálicas , Encéfalo/patología , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Humanos , Transducción de Señal/fisiología , Microambiente Tumoral
7.
CA Cancer J Clin ; 72(5): 454-489, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35708940

RESUMEN

Brain metastases are a challenging manifestation of renal cell carcinoma. We have a limited understanding of brain metastasis tumor and immune biology, drivers of resistance to systemic treatment, and their overall poor prognosis. Current data support a multimodal treatment strategy with radiation treatment and/or surgery. Nonetheless, the optimal approach for the management of brain metastases from renal cell carcinoma remains unclear. To improve patient care, the authors sought to standardize practical management strategies. They performed an unstructured literature review and elaborated on the current management strategies through an international group of experts from different disciplines assembled via the network of the International Kidney Cancer Coalition. Experts from different disciplines were administered a survey to answer questions related to current challenges and unmet patient needs. On the basis of the integrated approach of literature review and survey study results, the authors built algorithms for the management of single and multiple brain metastases in patients with renal cell carcinoma. The literature review, consensus statements, and algorithms presented in this report can serve as a framework guiding treatment decisions for patients. CA Cancer J Clin. 2022;72:454-489.


Asunto(s)
Neoplasias Encefálicas , Carcinoma de Células Renales , Neoplasias Renales , Neoplasias Encefálicas/terapia , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/terapia , Terapia Combinada , Humanos , Neoplasias Renales/patología , Neoplasias Renales/terapia
8.
PLoS Biol ; 22(5): e3002640, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38814900

RESUMEN

Glioblastoma, the most aggressive and prevalent form of primary brain tumor, is characterized by rapid growth, diffuse infiltration, and resistance to therapies. Intrinsic heterogeneity and cellular plasticity contribute to its rapid progression under therapy; therefore, there is a need to fully understand these tumors at a single-cell level. Over the past decade, single-cell transcriptomics has enabled the molecular characterization of individual cells within glioblastomas, providing previously unattainable insights into the genetic and molecular features that drive tumorigenesis, disease progression, and therapy resistance. However, despite advances in single-cell technologies, challenges such as high costs, complex data analysis and interpretation, and difficulties in translating findings into clinical practice persist. As single-cell technologies are developed further, more insights into the cellular and molecular heterogeneity of glioblastomas are expected, which will help guide the development of personalized and effective therapies, thereby improving prognosis and quality of life for patients.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Análisis de la Célula Individual , Humanos , Glioblastoma/genética , Glioblastoma/patología , Glioblastoma/terapia , Análisis de la Célula Individual/métodos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Transcriptoma , Animales
9.
CA Cancer J Clin ; 70(4): 299-312, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32478924

RESUMEN

Glioblastoma is the most common malignant primary brain tumor. Overall, the prognosis for patients with this disease is poor, with a median survival of <2 years. There is a slight predominance in males, and incidence increases with age. The standard approach to therapy in the newly diagnosed setting includes surgery followed by concurrent radiotherapy with temozolomide and further adjuvant temozolomide. Tumor-treating fields, delivering low-intensity alternating electric fields, can also be given concurrently with adjuvant temozolomide. At recurrence, there is no standard of care; however, surgery, radiotherapy, and systemic therapy with chemotherapy or bevacizumab are all potential options, depending on the patient's circumstances. Supportive and palliative care remain important considerations throughout the disease course in the multimodality approach to management. The recently revised classification of glioblastoma based on molecular profiling, notably isocitrate dehydrogenase (IDH) mutation status, is a result of enhanced understanding of the underlying pathogenesis of disease. There is a clear need for better therapeutic options, and there have been substantial efforts exploring immunotherapy and precision oncology approaches. In contrast to other solid tumors, however, biological factors, such as the blood-brain barrier and the unique tumor and immune microenvironment, represent significant challenges in the development of novel therapies. Innovative clinical trial designs with biomarker-enrichment strategies are needed to ultimately improve the outcome of patients with glioblastoma.


Asunto(s)
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Recurrencia Local de Neoplasia/epidemiología , Antineoplásicos/uso terapéutico , Bevacizumab/uso terapéutico , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Encéfalo/cirugía , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Quimioradioterapia Adyuvante/métodos , Glioblastoma/genética , Glioblastoma/mortalidad , Glioblastoma/patología , Humanos , Inmunoterapia/métodos , Incidencia , Isocitrato Deshidrogenasa/genética , Magnetoterapia/métodos , Imagen por Resonancia Magnética , Mutación , Recurrencia Local de Neoplasia/prevención & control , Medicina de Precisión/métodos , Pronóstico , Literatura de Revisión como Asunto , Tasa de Supervivencia , Temozolomida/uso terapéutico , Resultado del Tratamiento , Microambiente Tumoral , Estados Unidos/epidemiología
10.
Genes Dev ; 33(11-12): 591-609, 2019 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-31160393

RESUMEN

Glioblastoma ranks among the most lethal of all human cancers. Glioblastomas display striking cellular heterogeneity, with stem-like glioblastoma stem cells (GSCs) at the apex. Although the original identification of GSCs dates back more than a decade, the purification and characterization of GSCs remains challenging. Despite these challenges, the evidence that GSCs play important roles in tumor growth and response to therapy has grown. Like normal stem cells, GSCs are functionally defined and distinguished from their differentiated tumor progeny at core transcriptional, epigenetic, and metabolic regulatory levels, suggesting that no single therapeutic modality will be universally effective against a heterogenous GSC population. Glioblastomas induce a systemic immunosuppression with mixed responses to oncoimmunologic modalities, suggesting the potential for augmentation of response with a deeper consideration of GSCs. Unfortunately, the GSC literature has been complicated by frequent use of inferior cell lines and a lack of proper functional analyses. Collectively, glioblastoma offers a reliable cancer to study cancer stem cells to better model the human disease and inform improved biologic understanding and design of novel therapeutics.


Asunto(s)
Neoplasias Encefálicas/patología , Neoplasias Encefálicas/fisiopatología , Glioblastoma/patología , Glioblastoma/fisiopatología , Células Madre Neoplásicas/fisiología , Animales , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Diferenciación Celular , Epigénesis Genética , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Microambiente Tumoral
11.
Nature ; 580(7804): 517-523, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32322066

RESUMEN

A high tumour mutational burden (hypermutation) is observed in some gliomas1-5; however, the mechanisms by which hypermutation develops and whether it predicts the response to immunotherapy are poorly understood. Here we comprehensively analyse the molecular determinants of mutational burden and signatures in 10,294 gliomas. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after treatment with the chemotherapy drug temozolomide. Experimentally, the mutational signature of post-treatment hypermutated gliomas was recapitulated by temozolomide-induced damage in cells with MMR deficiency. MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. Moreover, although bulk analyses did not detect microsatellite instability in MMR-deficient gliomas, single-cell whole-genome sequencing analysis of post-treatment hypermutated glioma cells identified microsatellite mutations. These results show that chemotherapy can drive the acquisition of hypermutated populations without promoting a response to PD-1 blockade and supports the diagnostic use of mutational burden and signatures in cancer.


Asunto(s)
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Glioma/genética , Glioma/terapia , Mutación , Animales , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/inmunología , Reparación de la Incompatibilidad de ADN/genética , Frecuencia de los Genes , Genoma Humano/efectos de los fármacos , Genoma Humano/genética , Glioma/inmunología , Humanos , Masculino , Ratones , Repeticiones de Microsatélite/efectos de los fármacos , Repeticiones de Microsatélite/genética , Mutagénesis/efectos de los fármacos , Mutación/efectos de los fármacos , Fenotipo , Pronóstico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Análisis de Secuencia de ADN , Temozolomida/farmacología , Temozolomida/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto
12.
Semin Cancer Biol ; 101: 25-43, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38754752

RESUMEN

Glioblastoma (GBM) is the most aggressive tumor among the gliomas and intracranial tumors and to date prognosis for GBM patients remains poor, with a median survival typically measured in months to a few years depending on various factors. Although standardized therapies are routinely employed, it is clear that these strategies are unable to cope with heterogeneity and invasiveness of GBM. Furthermore, diagnosis and monitoring of responses to therapies are directly dependent on tissue biopsies or magnetic resonance imaging (MRI) techniques. From this point of view, liquid biopsies are arising as key sources of a variety of biomarkers with the advantage of being easily accessible and monitorable. In this context, extracellular vesicles (EVs), physiologically shed into body fluids by virtually all cells, are gaining increasing interest both as natural carriers of biomarkers and as specific signatures even for GBM. What makes these vesicles particularly attractive is they are also emerging as therapeutical vehicles to treat GBM given their native ability to cross the blood-brain barrier (BBB). Here, we reviewed recent advances on the use of EVs as biomarker for liquid biopsy and nanocarriers for targeted delivery of anticancer drugs in glioblastoma.


Asunto(s)
Biomarcadores de Tumor , Neoplasias Encefálicas , Vesículas Extracelulares , Glioblastoma , Humanos , Glioblastoma/metabolismo , Glioblastoma/terapia , Glioblastoma/patología , Glioblastoma/diagnóstico por imagen , Glioblastoma/diagnóstico , Glioblastoma/tratamiento farmacológico , Vesículas Extracelulares/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/diagnóstico por imagen , Animales , Biopsia Líquida/métodos , Barrera Hematoencefálica/metabolismo , Antineoplásicos/uso terapéutico
13.
Cancer Metastasis Rev ; 43(3): 1015-1035, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38530545

RESUMEN

Despite enormous efforts being invested in the development of novel therapies for brain malignancies, there remains a dire need for effective treatments, particularly for pediatric glioblastomas. Their poor prognosis has been attributed to the fact that conventional therapies target tumoral cells, but not glioblastoma stem cells (GSCs). GSCs are characterized by self-renewal, tumorigenicity, poor differentiation, and resistance to therapy. These characteristics represent the fundamental tools needed to recapitulate the tumor and result in a relapse. The mechanisms by which GSCs alter metabolic cues and escape elimination by immune cells are discussed in this article, along with potential strategies to harness effector immune cells against GSCs. As cellular immunotherapy is making significant advances in a variety of cancers, leveraging this underexplored reservoir may result in significant improvements in the treatment options for brain malignancies.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Células Madre Neoplásicas , Humanos , Glioblastoma/inmunología , Glioblastoma/patología , Glioblastoma/metabolismo , Glioblastoma/terapia , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/inmunología , Células Madre Neoplásicas/patología , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Animales , Inmunoterapia/métodos
14.
Eur J Immunol ; 54(2): e2250257, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37940552

RESUMEN

Malignant brain tumors lack effective treatment, that can improve their poor overall survival achieved with standard of care. Advancement in different cancer treatments has shifted the focus in brain tumor research and clinical trials toward immunotherapy-based approaches. The investigation of the immune cell landscape revealed a dominance of myeloid cells in the tumor microenvironment. Their exact roles and functions are the subject of ongoing research. Current evidence suggests a complex interplay of tumor cells and myeloid cells with competing functions toward support vs. control of tumor growth. Here, we provide a brief overview of the three most abundant brain tumor entities: meningioma, glioma, and brain metastases. We also describe the field of ongoing immunotherapy trials and their results, including immune checkpoint inhibitors, vaccination studies, oncolytic viral therapy, and CAR-T cells. Finally, we summarize the phenotypes of microglia, monocyte-derived macrophages, border-associated macrophages, neutrophils, and potential novel therapy targets.


Asunto(s)
Neoplasias Encefálicas , Microambiente Tumoral , Humanos , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patología , Encéfalo/patología , Células Mieloides , Inmunoterapia
15.
Rev Med Virol ; 34(5): e2584, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39304923

RESUMEN

Neurotropic viruses have been implicated in altering the central nervous system microenvironment and promoting brain metastasis of breast cancer through complex interactions involving viral entry mechanisms, modulation of the blood-brain barrier, immune evasion, and alteration of the tumour microenvironment. This narrative review explores the molecular mechanisms by which neurotropic viruses such as Herpes Simplex Virus, Human Immunodeficiency Virus, Japanese Encephalitis Virus, and Rabies Virus facilitate brain metastasis, focusing on their ability to disrupt blood-brain barrier integrity, modulate immune responses, and create a permissive environment for metastatic cell survival and growth within the central nervous system. Current therapeutic implications and challenges in targeting neurotropic viruses to prevent or treat brain metastasis are discussed, highlighting the need for innovative strategies and multidisciplinary approaches in virology, oncology, and immunology.


Asunto(s)
Neoplasias Encefálicas , Neoplasias de la Mama , Humanos , Neoplasias de la Mama/patología , Neoplasias de la Mama/virología , Neoplasias de la Mama/terapia , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/virología , Neoplasias Encefálicas/terapia , Femenino , Barrera Hematoencefálica/virología , Animales , Microambiente Tumoral , Virus de la Rabia/fisiología , Virus de la Rabia/patogenicidad , Virus de la Rabia/inmunología , Simplexvirus/fisiología
17.
Cell Mol Life Sci ; 81(1): 275, 2024 Jun 22.
Artículo en Inglés | MEDLINE | ID: mdl-38907858

RESUMEN

While conventional cancer modalities, such as chemotherapy and radiotherapy, act through direct killing of tumor cells, cancer immunotherapy elicits potent anti-tumor immune responses thereby eliminating tumors. Nevertheless, promising outcomes have not been reported in patients with glioblastoma (GBM) likely due to the immune privileged status of the central nervous system and immunosuppressive micro-environment within GBM. In the past years, several exciting findings, such as the re-discovery of meningeal lymphatic vessels (MLVs), three-dimensional anatomical reconstruction of MLV networks, and the demonstration of the promotion of GBM immunosurveillance by lymphatic drainage enhancement, have revealed an intricate communication between the nervous and immune systems, and brought hope for the development of new GBM treatment. Based on conceptual framework of the updated cancer-immunity (CI) cycle, here we focus on GBM antigen drainage and immune activation, the early events in driving the CI cycle. We also discuss the implications of these findings for developing new therapeutic approaches in tackling fatal GBM in the future.


Asunto(s)
Antígenos de Neoplasias , Neoplasias Encefálicas , Glioblastoma , Inmunoterapia , Humanos , Glioblastoma/inmunología , Glioblastoma/terapia , Glioblastoma/patología , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patología , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/metabolismo , Animales , Microambiente Tumoral/inmunología , Vasos Linfáticos/inmunología , Vasos Linfáticos/patología
18.
Drug Resist Updat ; 76: 101113, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39053384

RESUMEN

Gliomas, the most common CNS (central nerve system) tumors, face poor survival due to severe chemoresistance exacerbated by hypoxia. However, studies on whether altered hypoxic conditions benefit for chemo-sensitivity and how gliomas react to increased oxygen stimulation are limited. In this study, we demonstrated that increased oxygen stimulation promotes glioma growth and chemoresistance. Mechanically, increased oxygen stimulation upregulates miR-1290 levels. miR-1290, in turn, downregulates PLCB1, while PLCB1 facilitates the proteasomal degradation of ß-catenin and active-ß-catenin by increasing the proportion of ubiquitinated ß-catenin in a destruction complex-independent mechanism. This process inhibits PLCB1 expression, leads to the accumulation of active-ß-catenin, boosting Wnt signaling through an independent mechanism and ultimately promoting chemoresistance in glioma cells. Pharmacological inhibition of Wnt by WNT974 could partially inhibit glioma volume growth and prolong the shortened survival caused by increased oxygen stimulation in a glioma-bearing mouse model. Moreover, PLCB1, a key molecule regulated by increased oxygen stimulation, shows promising predictive power in survival analysis and has great potential to be a biomarker for grading and prognosis in glioma patients. These results provide preliminary insights into clinical scenarios associated with altered hypoxic conditions in gliomas, and introduce a novel perspective on the role of the hypoxic microenvironment in glioma progression. Furthermore, the outcomes reveal the potential risks of utilizing hyperbaric oxygen treatment (HBOT) in glioma patients, particularly when considering HBOT as a standalone option to ameliorate neuro-dysfunctions or when combining HBOT with a single chemotherapy agent without radiotherapy.


Asunto(s)
Neoplasias Encefálicas , Resistencia a Antineoplásicos , Glioma , MicroARNs , Oxígeno , Fosfolipasa C beta , Vía de Señalización Wnt , beta Catenina , Glioma/tratamiento farmacológico , Glioma/patología , Glioma/genética , Glioma/terapia , Glioma/metabolismo , Animales , Humanos , Resistencia a Antineoplásicos/efectos de los fármacos , Ratones , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Vía de Señalización Wnt/efectos de los fármacos , Oxígeno/metabolismo , Fosfolipasa C beta/metabolismo , Fosfolipasa C beta/genética , beta Catenina/metabolismo , beta Catenina/genética , Línea Celular Tumoral , MicroARNs/genética , MicroARNs/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Fenotipo , Ratones Desnudos
19.
Proc Natl Acad Sci U S A ; 119(28): e2111003119, 2022 07 12.
Artículo en Inglés | MEDLINE | ID: mdl-35787058

RESUMEN

Immunotherapy has had a tremendous impact on cancer treatment in the past decade, with hitherto unseen responses at advanced and metastatic stages of the disease. However, the aggressive brain tumor glioblastoma (GBM) is highly immunosuppressive and remains largely refractory to current immunotherapeutic approaches. The stimulator of interferon genes (STING) DNA sensing pathway has emerged as a next-generation immunotherapy target with potent local immune stimulatory properties. Here, we investigated the status of the STING pathway in GBM and the modulation of the brain tumor microenvironment (TME) with the STING agonist ADU-S100. Our data reveal the presence of STING in human GBM specimens, where it stains strongly in the tumor vasculature. We show that human GBM explants can respond to STING agonist treatment by secretion of inflammatory cytokines. In murine GBM models, we show a profound shift in the tumor immune landscape after STING agonist treatment, with massive infiltration of the tumor-bearing hemisphere with innate immune cells including inflammatory macrophages, neutrophils, and natural killer (NK) populations. Treatment of established murine intracranial GL261 and CT-2A tumors by biodegradable ADU-S100-loaded intracranial implants demonstrated a significant increase in survival in both models and long-term survival with immune memory in GL261. Responses to treatment were abolished by NK cell depletion. This study reveals therapeutic potential and deep remodeling of the TME by STING activation in GBM and warrants further examination of STING agonists alone or in combination with other immunotherapies such as cancer vaccines, chimeric antigen receptor T cells, NK therapies, and immune checkpoint blockade.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Células Asesinas Naturales , Animales , Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Humanos , Inmunidad , Inmunoterapia , Proteínas de la Membrana/antagonistas & inhibidores , Ratones , Microambiente Tumoral
20.
Proc Natl Acad Sci U S A ; 119(1)2022 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-34969858

RESUMEN

Brain metastases are a leading cause of death in patients with breast cancer. The lack of clinical trials and the presence of the blood-brain barrier limit therapeutic options. Furthermore, overexpression of the human epidermal growth factor receptor 2 (HER2) increases the incidence of breast cancer brain metastases (BCBM). HER2-targeting agents, such as the monoclonal antibodies trastuzumab and pertuzumab, improved outcomes in patients with breast cancer and extracranial metastases. However, continued BCBM progression in breast cancer patients highlighted the need for novel and effective targeted therapies against intracranial metastases. In this study, we engineered the highly migratory and brain tumor tropic human neural stem cells (NSCs) LM008 to continuously secrete high amounts of functional, stable, full-length antibodies against HER2 (anti-HER2Ab) without compromising the stemness of LM008 cells. The secreted anti-HER2Ab impaired tumor cell proliferation in vitro in HER2+ BCBM cells by inhibiting the PI3K-Akt signaling pathway and resulted in a significant benefit when injected in intracranial xenograft models. In addition, dual HER2 blockade using anti-HER2Ab LM008 NSCs and the tyrosine kinase inhibitor tucatinib significantly improved the survival of mice in a clinically relevant model of multiple HER2+ BCBM. These findings provide compelling evidence for the use of HER2Ab-secreting LM008 NSCs in combination with tucatinib as a promising therapeutic regimen for patients with HER2+ BCBM.


Asunto(s)
Antineoplásicos Inmunológicos/metabolismo , Neoplasias Encefálicas , Neoplasias Experimentales , Células-Madre Neurales , Oxazoles/farmacología , Piridinas/farmacología , Quinazolinas/farmacología , Receptor ErbB-2 , Animales , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Línea Celular Tumoral , Humanos , Ratones , Ratones Desnudos , Metástasis de la Neoplasia , Neoplasias Experimentales/genética , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Neoplasias Experimentales/terapia , Células-Madre Neurales/metabolismo , Células-Madre Neurales/patología , Células-Madre Neurales/trasplante , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
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