scholarly journals Genetic Alterations in Gliomas Remodel the Tumor Immune Microenvironment and Impact Immune-Mediated Therapies

2021 ◽  
Vol 11 ◽  
Author(s):  
Maria B. Garcia-Fabiani ◽  
Santiago Haase ◽  
Andrea Comba ◽  
Stephen Carney ◽  
Brandon McClellan ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Current Knowledge ◽  
Malignant Gliomas ◽  
Standard Of Care ◽  
Genetic Alterations ◽  
Immune Microenvironment ◽  
Malignant Brain Tumors ◽  
Immune Mediated ◽  
Tumor Immune Microenvironment ◽  
The Impact

High grade gliomas are malignant brain tumors that arise in the central nervous system, in patients of all ages. Currently, the standard of care, entailing surgery and chemo radiation, exhibits a survival rate of 14-17 months. Thus, there is an urgent need to develop new therapeutic strategies for these malignant brain tumors. Currently, immunotherapies represent an appealing approach to treat malignant gliomas, as the pre-clinical data has been encouraging. However, the translation of the discoveries from the bench to the bedside has not been as successful as with other types of cancer, and no long-lasting clinical benefits have been observed for glioma patients treated with immune-mediated therapies so far. This review aims to discuss our current knowledge about gliomas, their molecular particularities and the impact on the tumor immune microenvironment. Also, we discuss several murine models used to study these therapies pre-clinically and how the model selection can impact the outcomes of the approaches to be tested. Finally, we present different immunotherapy strategies being employed in clinical trials for glioma and the newest developments intended to harness the immune system against these incurable brain tumors.

scholarly journals SPINT1 regulates the aggressiveness of skin cutaneous melanoma and its crosstalk with tumor immune microenvironment

2019 ◽  
Author(s):  
Elena Gómez-Abenza ◽  
Sofía Ibáñez-Molero ◽  
Diana García Moreno ◽  
Inmaculada Fuentes ◽  
Leonard I. Zon ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Serine Protease ◽  
Cutaneous Melanoma ◽  
Serine Protease Inhibitor ◽  
Genetic Alterations ◽  
Oncogenic Transformation ◽  
Immune Microenvironment ◽  
Zebrafish Model ◽  
Tumor Immune Microenvironment ◽  
The Impact

AbstractSkin cutaneous melanoma (SKCM) is the deadliest form of skin cancer and while incidence rates are declining for most cancers, they have been steadily rising for SKCM worldwide. Serine protease inhibitor, kunitz-type, 1 (SPINT1) is a type II transmembrane serine protease inhibitor that has been shown to be involved in the development of several types of cancer. We report here a high prevalence ofSPINT1genetic alterations in SKCM patients and their association with altered tumor immune microenvironment and poor patient survival. We used the unique advantages of the zebrafish to model the impact of SPINT1 deficiency in early transformation, progression and metastatic invasion of SKCM. Our results reveal that Spint1a deficiency facilitates oncogenic transformation, regulates the tumor/immune microenvironment crosstalk, accelerates the onset of SKCM and promotes metastatic invasion. Notably, Spint1a deficiency is required at both cell autonomous and nonautonomous levels to enhance invasiveness of SKCM. These results suggest the relevance of clinical intervention on this signaling pathway for precision SKCM medicine.Summary statementA zebrafish model shows that Spint1a deficiency facilitates oncogenic transformation, regulates the tumor/immune microenvironment crosstalk, accelerates the onset of SKCM, and promotes metastatic invasion in cell autonomous and non-autonomous manners.

scholarly journals Zebrafish modeling reveals that SPINT1 regulates the aggressiveness of skin cutaneous melanoma and its crosstalk with tumor immune microenvironment

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Elena Gómez-Abenza ◽  
Sofía Ibáñez-Molero ◽  
Diana García-Moreno ◽  
Inmaculada Fuentes ◽  
Leonard I. Zon ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Serine Protease ◽  
Cutaneous Melanoma ◽  
Serine Protease Inhibitor ◽  
Genetic Alterations ◽  
Incidence Rates ◽  
Immune Microenvironment ◽  
Zebrafish Model ◽  
Tumor Immune Microenvironment ◽  
The Impact

Abstract Background Skin cutaneous melanoma (SKCM) is the most lethal form of skin cancer and while incidence rates are declining for most cancers, they have been steadily rising for SKCM. Serine protease inhibitor, kunitz-type, 1 (SPINT1) is a type II transmembrane serine protease inhibitor that has been shown to be involved in the development of several types of cancer, such as squamous cell carcinoma and colorectal cancer. Methods We used the unique advantages of the zebrafish to model the impact of Spint1a deficiency in early transformation, progression and metastatic invasion of SKCM together with in silico analysis of the occurrence and relevance of SPINT1 genetic alterations of the SKCM TCGA cohort. Results We report here a high prevalence of SPINT1 genetic alterations in SKCM patients and their association with altered tumor immune microenvironment and poor patient survival. The zebrafish model reveals that Spint1a deficiency facilitates oncogenic transformation, regulates the tumor immune microenvironment crosstalk, accelerates the onset of SKCM and promotes metastatic invasion. Notably, Spint1a deficiency is required at both cell autonomous and non-autonomous levels to enhance invasiveness of SKCM. Conclusions These results reveal a novel therapeutic target for SKCM.

Cytostatic Agents in the Management of Malignant Gliomas

1998 ◽  
Vol 5 (2) ◽  
pp. 150-162 ◽  
Author(s):  
Tom Mikkelsen
Keyword(s):  
Signal Transduction ◽  
Brain Tumors ◽  
Tumor Invasion ◽  
Proteinase Inhibitors ◽  
Malignant Gliomas ◽  
Cytotoxic Agents ◽  
Management Approach ◽  
Cytostatic Agents ◽  
Management Options ◽  
Malignant Brain Tumors

Background: Cytotoxic therapy for malignant gliomas is limited by poor delivery and drug resistance, and local therapy is ineffective in managing migratory cells. However, recent developments in malignant glioma therapy involve trials of cytostatic rather than conventional cytotoxic agents. Methods: The biology of the brain extracellular matrix, tumor invasion, and angiogenesis are reviewed, and the cytostatic agents that inhibit matrix metalloproteinases, angiogenesis, cell proliferation, and signal transduction are discussed, as well as studies of the angiogenic and migratory capacity of malignant brain tumors. Results: Two specific and interrelated areas, anti-invasion (migration) and anti-angiogenesis, are potential areas to develop new treatment strategies. Tumor invasion and angiogenesis are important components of the spread and biologic effects of malignant gliomas. Several proteinase inhibitors are in clinical trial, as well as anti-angiogenic agents and signal transduction cascade inhibitors. Conclusions: Biologic control of brain tumor cell populations may offer a new management approach to add to currently available management options for malignant brain tumors.

scholarly journals Implantable Slow-Release Chemotherapeutic Polymers for the Treatment of Malignant Brain Tumors

1998 ◽  
Vol 5 (2) ◽  
pp. 130-137 ◽  
Author(s):  
Prakash Sampath ◽  
Henry Brem
Keyword(s):  
Brain Tumors ◽  
Slow Release ◽  
Malignant Gliomas ◽  
Polymer System ◽  
Chemotherapeutic Agents ◽  
Local Concentration ◽  
Malignant Brain Tumors ◽  
Polymeric Delivery ◽  
Double Blinded ◽  
Controlled Release Polymer

Background: Despite significant advances in neurosurgery, radiation therapy, and chemotherapy, the prognosis for patients with malignant brain tumors remains dismal. In an effort to improve control of local disease, we have developed a biodegradable, controlled-release polymer that is implanted directly at the tumor site. Methods: The preclinical and clinical development of the polymeric delivery of chemotherapeutic agents for treatment of patients with malignant gliomas is reviewed. Results: Carmustine (BCNU)-impregnated biodegradable polymer is the first new therapy approved by the FDA for patients with gliomas in 23 years. This delivery system provides high local concentration of drug with minimal systemic toxicity and obviates the need for drug to cross the blood-brain barrier. Randomized, multi-institutional, double-blinded, placebo-controlled studies have shown improved survival in patients treated for gliomas both at initial presentation and at recurrence. Several clinical principles have emerged from the use of this polymer system, and further applications are currently being investigated. Conclusions: Local delivery of therapeutic agents via biodegradable polymers may play an increasing role in patients with brain tumors.

Glioblastoma: Background, Standard Treatment Paradigms, and Supportive Care Considerations

2014 ◽  
Vol 42 (2) ◽  
pp. 171-182 ◽  
Author(s):  
Susan V. Ellor ◽  
Teri Ann Pagano-Young ◽  
Nicholas G. Avgeropoulos
Keyword(s):  
Central Nervous System ◽  
Brain Tumors ◽  
Standard Treatment ◽  
Malignant Gliomas ◽  
Survival Rates ◽  
Terminally Ill ◽  
Ethical Considerations ◽  
The Third ◽  
Malignant Brain Tumors ◽  
Median Survival Rate

While primary malignant brain tumors account for only two percent of all adult cancers, these neoplasms cause a disproportionate amount of cancer-related disabilities and death. The five-year survival rates for brain tumors are the third lowest among all types of cancer. Malignant gliomas (glioblastoma and anaplastic astrocytoma) comprise the most common types of primary central nervous system (CNS) tumors and have a combined incidence of five to eight cases per 100,000 people. The median survival rate of conservatively treated patients with malignant gliomas is 14 weeks; with surgical resection alone, 20 weeks; with surgery and radiation, 36 weeks; and with the addition of newer biochemotherapies such as temozolomide and bevacizumab, upward of 14-18 months.The profound cost of caring for terminally ill patients with primary malignant brain tumors raises ethical considerations for the American public; the stewardship of health care dollars for the population at large maintains a juxtaposed tension against a dynamic, necessary balance of hope, care, rehabilitation and research efforts for affected patients and their advocates.

scholarly journals Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma

2021 ◽  
Vol 11 ◽  
Author(s):  
Stefanie Hiltbrunner ◽  
Laura Mannarino ◽  
Michaela B. Kirschner ◽  
Isabelle Opitz ◽  
Angelica Rigutto ◽  
...  
Keyword(s):  
Asbestos Exposure ◽  
Standard Of Care ◽  
Genetic Alterations ◽  
Transcriptional Analysis ◽  
Small Subset ◽  
Industrialized Countries ◽  
Molecular Events ◽  
Genomic Landscape ◽  
Platinum Based Chemotherapy ◽  
Tumor Immune Microenvironment

Malignant pleural mesothelioma (MPM) is a rare and fatal disease of the pleural lining. Up to 80% of the MPM cases are linked to asbestos exposure. Even though its use has been banned in the industrialized countries, the cases continue to increase. MPM is a lethal cancer, with very little survival improvements in the last years, mirroring very limited therapeutic advances. Platinum-based chemotherapy in combination with pemetrexed and surgery are the standard of care, but prognosis is still unacceptably poor with median overall survival of approximately 12 months. The genomic landscape of MPM has been widely characterized showing a low mutational burden and the impairment of tumor suppressor genes. Among them, BAP1 and BLM are present as a germline inactivation in a small subset of patients and increases predisposition to tumorigenesis. Other studies have demonstrated a high frequency of mutations in DNA repair genes. Many therapy approaches targeting these alterations have emerged and are under evaluation in the clinic. High-throughput technologies have allowed the detection of more complex molecular events, like chromotripsis and revealed different transcriptional programs for each histological subtype. Transcriptional analysis has also paved the way to the study of tumor-infiltrating cells, thus shedding lights on the crosstalk between tumor cells and the microenvironment. The tumor microenvironment of MPM is indeed crucial for the pathogenesis and outcome of this disease; it is characterized by an inflammatory response to asbestos exposure, involving a variety of chemokines and suppressive immune cells such as M2-like macrophages and regulatory T cells. Another important feature of MPM is the dysregulation of microRNA expression, being frequently linked to cancer development and drug resistance. This review will give a detailed overview of all the above mentioned features of MPM in order to improve the understanding of this disease and the development of new therapeutic strategies.

scholarly journals P.038 Investigating the role of long non-coding RNAs in glioblastoma multiforme

2018 ◽  
Vol 45 (s2) ◽  
pp. S26-S26
Author(s):  
A Lebel ◽  
V Charest ◽  
P Whitlock ◽  
D Charest ◽  
P Morin
Keyword(s):  
Survival Rate ◽  
Glioblastoma Multiforme ◽  
Brain Tumors ◽  
Malignant Gliomas ◽  
Standard Of Care ◽  
Qrt Pcr ◽  
Resistance Modulation ◽  
Non Coding Rnas ◽  
One Year

Background: Malignant gliomas are the most common and deadly brain tumors. Mean survival rate for a patient diagnosed with a glioblastoma multiforme (GBM) remains slightly over one year. Standard of care consists of treatment with temozolomide (TMZ) and radiotherapy. Recent work has highlighted functions of long non-coding RNAs (lncRNAs) in GBM progression and TMZ response even though the information regarding these newly discovered molecules is sparse. The overarching objective of this project was thus to assess the expression of select lncRNAs in GBM tumor samples and in models of TMZ resistance. Methods: A qRT-PCR-based approach was undertaken to measure six lncRNAs in 19 primary GBM samples, four GBM cell lines and in-house developed TMZ-resistant GBM cells. Results: Elevated levels of Hotair and H19 were observed in primary GBM tumors while decreased expression of MEG3 was recorded in the same samples. Interestingly, levels of PANDA increased 3.4-fold in GBM cells resistant to TMZ when compared with their sensitive counterparts. Conclusions: Overall, this work provides evidence of lncRNA deregulation in GBM tumors and reveals a previously unexplored lncRNA potentially involved in TMZ resistance. Modulation of lncRNA targets via RNAi-mediated approaches is envisioned to clarify their function and to strengthen their position as therapeutic options in GBMs.

Bevacizumab, a monoclonal antibody to the vascular endothelial growth factor (VEGF), and irinotecan for treatment of recurrent primary malignant brain tumors in adults

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 12503-12503 ◽  
Author(s):  
U. Lassen ◽  
K. Grunnet ◽  
M. Kosteljanetz ◽  
B. Hasselbalch ◽  
H. Laursen ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Tumor Regression ◽  
Malignant Gliomas ◽  
Complete Response ◽  
Consecutive Series ◽  
Topoisomerase 1 ◽  
Malignant Brain Tumors ◽  
Macdonald Criteria ◽  
Number Of Patients ◽  
Tumor Reduction

12503 Background: The prognosis of recurrent malignant brain tumors is poor, and no efficacious therapy exists in patients previously treated with radiotherapy and standard chemotherapy. Bevacizumab (B) binds to VEGF and inhibits tumor angiogenesis, and treatment with this drug might induce tumor regression and prolongation of life. Irinotecan (I) is a topoisomerase 1 inhibitor with modest effect on recurrent primary brain tumors. The combination of B and I in recurrent malignant gliomas was presented at ASCO 2006 and showed very encouraging responses. Methods: We report confirmatory results of the combination of B and I in a consecutive series of patients with primary malignant brain tumors recurring after standard primary and secondary treatment (surgery, radiotherapy and standard or secondline chemotherapy).With standard inclusion criteria, including PS 0–2, patients received B as 10mg/kg, and I 125 mg/m2 in patients not treated with enzyme inducing antiepileptic drugs (EIAED) or 340 mg/m2 in patients treated with EIAED every other week until progression or non-manageable toxicity. Response evaluation was performed by MacDonald criteria and MRI scans. Results: The results of 31 patients is presented, 15 with grade IV tumors (Glioblastoma multiforme), 7 with grade III anaplastic astrocytomas, 5 with anaplastic oligodendrogliomas, 1 with anaplastic ependymoma, 1 with hemangiopericytoma, 1 with prolactinoma, and 1 with medulloblastoma. Four patients had complete response, 3 grade IV tumors and 1 anaplastic oligodendroglioma. One patient had partial response (> 50% tumor reduction), 12 had stable disease (3 had tumor reduction between 31 - 45 %). 14 progressed. No grade 4 toxicity was observed and most patients experienced grade 1–2 toxicity. Two tromboembolic events and 1 intestinal perforation were observed. Conclusion: The combination of B and I is safe, induces tumor regression in a substantial number of patients, and can be used as treatment to patients recurring after standard treatment. No significant financial relationships to disclose.

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