Brain tumor hypoxia: tumorigenesis, angiogenesis, imaging, pseudoprogression, and as a therapeutic target

Abstract Background Hypoxia is a prominent feature of solid tumors and can function as fertile environment for oncolytic anaerobic bacteria such as Clostridium novyi-NT (C. novyi-NT) where it can induce tumor destruction in mice and patients. However, two major obstacles have limited its use, namely the host inflammatory response and the incomplete clearance of normoxic tumor areas. Methods In this study, we first used a subcutaneous tumor model of a glioblastoma (GBM) cell line in immunocompetent mice to investigate the local distribution of tumor hypoxia, kinetics of C.novyi-NT germination and spread, and the local host immune response. We subsequently applied the acquired knowledge to develop a C.novyi-NT therapy in an orthotopic rabbit brain tumor model. Results We found that local accumulation of granular leukocytes, mainly neutrophils, could impede the spread of bacteria through the tumor and prevented complete oncolysis. Depletion of neutrophils via anti-Ly6G antibody or bone marrow suppression using hydroxyurea significantly improved tumor clearance. We then applied this approach to rabbits implanted with an aggressive intracranial brain tumor and achieved long term survival in majority of the animals without apparent toxicity. Conclusion These results indicated that depleting neutrophils can greatly enhance the safety and efficacy of C.novyi-NT cancer therapy for brain tumors.

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Carbonic Anhydrase XII is a Clinically Significant, Molecular Tumor-Subtype Specific Therapeutic Target in Glioma with the Potential to Combat Invasion of Brain Tumor Cells

OncoTargets and Therapy ◽

10.2147/ott.s300623 ◽

2021 ◽

Vol Volume 14 ◽

pp. 1707-1718

Author(s):

Guanzhang Li ◽

Ting-Wei Chen ◽

Ann-Christin Nickel ◽

Sajjad Muhammad ◽

Hans-Jakob Steiger ◽

...

Keyword(s):

Brain Tumor ◽

Carbonic Anhydrase ◽

Tumor Cells ◽

Therapeutic Target ◽

Tumor Subtype ◽

Brain Tumor Cells ◽

Clinically Significant

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Expression of pluripotency-related genes in human glioblastoma

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab163 ◽

2021 ◽

Author(s):

Álvaro Fabrício Lopes Rios ◽

Daniela Pretti da Cunha Tirapelli ◽

Mucio Luiz de Assis Cirino ◽

Andressa Romualdo Rodrigues ◽

Ester S Ramos ◽

...

Keyword(s):

Brain Tumor ◽

Human Brain ◽

Tumor Cells ◽

Therapeutic Target ◽

Cell Biology ◽

Master Regulator ◽

Human Brain Tumor ◽

Poorly Differentiated ◽

Aggressive Tumors ◽

Regulator Genes

Abstract Background Cancer is a group of heterogeneous diseases characterized by several disruptions of the genetic and epigenetic components of cell biology. Some types of cancer have been shown to be constituted by a mosaic of cells with variable differentiation states, with more aggressive tumors being more undifferentiated. In most cases, undifferentiated tumor cells express associated embryonic markers such as the OCT4, NANOG, SOX2 and CARM1 genes. The ectopic or reminiscent expression of some master regulator genes of pluripotency has been indicated as the cause of the poorly differentiated state of tumors, and based on the evidence of some reports, can be used as a possible therapeutic target. Considering this information, a more detailed investigation of the expression of pluripotency-associated genes is necessary to evaluate the roles of these genes in the etiology of some tumors and their use targets of therapy. Methods The expression of four pluripotency-related genes was investigated (OCT4, NANOG, SOX2 and CARM1) in the most malignant primary human brain tumor, glioblastoma (GBM). Results and Conclusion The results demonstrated a signature of OCT4/SOX2/CARM1 genes and a significant increase of CARM1 expression in GBM cases.

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SPINK1 as a plasma marker for tumor hypoxia and a therapeutic target for radiosensitization

JCI Insight ◽

10.1172/jci.insight.148135 ◽

2021 ◽

Vol 6 (21) ◽

Author(s):

Tatsuya Suwa ◽

Minoru Kobayashi ◽

Yukari Shirai ◽

Jin-Min Nam ◽

Yoshiaki Tabuchi ◽

...

Keyword(s):

Therapeutic Target ◽

Tumor Hypoxia ◽

Plasma Marker

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Memapsin 2, a drug target for Alzheimer's disease

Biochemical Society Symposium ◽

10.1042/bss0700213 ◽

2003 ◽

Vol 70 ◽

pp. 213-220 ◽

Cited By ~ 1

Author(s):

Gerald Koelsch ◽

Robert T. Turner ◽

Lin Hong ◽

Arun K. Ghosh ◽

Jordan Tang

Keyword(s):

Crystal Structure ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transition State ◽

Amyloid Precursor Protein ◽

Therapeutic Target ◽

Drug Target ◽

Aspartic Protease ◽

Precursor Protein ◽

Memapsin 2

Mempasin 2, a ϐ-secretase, is the membrane-anchored aspartic protease that initiates the cleavage of amyloid precursor protein leading to the production of ϐ-amyloid and the onset of Alzheimer's disease. Thus memapsin 2 is a major therapeutic target for the development of inhibitor drugs for the disease. Many biochemical tools, such as the specificity and crystal structure, have been established and have led to the design of potent and relatively small transition-state inhibitors. Although developing a clinically viable mempasin 2 inhibitor remains challenging, progress to date renders hope that memapsin 2 inhibitors may ultimately be useful for therapeutic reduction of ϐ-amyloid.

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