US-12622884-B2 - Treatment and prevention of glioblastoma

Abstract

The invention relates to the use of a selective β 2 adrenergic receptor antagonist for treating glioma. In particular, the invention relates to the use of an alkanolamine derivative or a pharmaceutically acceptable acid-addition salt thereof for treating a glioblastoma in a patient.

Inventors

• José María SÁNCHEZ-PUELLES GONZÁLEZ-CARVAJAL
• Luisa María BOTELLA CUBELLS
• Tania AGUADO SANCHEZ
• Ángel CUESTA MARTÍNEZ
• Virginia ALBIÑANA DÍAZ
• Karina VILLAR GOMEZ-DE LAS HERAS

Assignees

• CONSEJO SUPERIOR DE INVESTIGACIONES CIENTÍFICAS
• ALIANZA ESPAÑOLA DE FAMILIAS DE VON HIPPEL-LINDAU-VHL
• Consorcio Centro de Investigación Biomédica en Red, M.P.

Dates

Publication Date

20260512

Application Date

20191212

Priority Date

20181212

Claims (15)

1. 1 . A method of treatment of glioma in a patient comprising administering to said patient a therapeutically effective amount of a selective antagonist of the β 2 -adrenergic receptor, wherein the selective antagonist of the β 2 -adrenergic receptor is the compound of formula or a pharmaceutically acceptable acid addition salt thereof; and wherein the patient is a human patient.
2. 2 . The method according to claim 1 , wherein the glioma is characterized by having increased expression of the β 2 -adrenergic receptor compared to a reference value.
3. 3 . The method according to claim 1 , wherein the antagonist is administered together with an antitumor compound selected from propanonol, temozolomide, leptomycin B and capecitabine.
4. 4 . The method according to claim 3 , wherein the antitumor compound is propranolol.
5. 5 . The method according to claim 1 , wherein the glioma comprises a subpopulation of cancer stem cells.
6. 6 . The method according to claim 1 , wherein the glioma is a high-grade glioma.
7. 7 . The method according to claim 1 , wherein the glioma is a non-recurrent glioma.
8. 8 . The method according to claim 1 , wherein the glioma is astrocytoma.
9. 9 . The method according to claim 8 , wherein the astrocytoma is glioblastoma.
10. 10 . The method according to claim 1 , wherein the pharmaceutically acceptable acid-addition salt is hydrochloride.
11. 11 . The method according to claim 1 , wherein the compound or pharmaceutically acceptable acid-addition salt thereof is administered at a dose between 1 mg/Kg body/day and 4.5 mg/kg body/day.
12. 12 . The method according to claim 11 , wherein the alkanolamine derivative or pharmaceutically acceptable acid-addition salt thereof is administered at a dose between 2 mg/Kg body/day and 3 mg/kg body/day.
13. 13 . The method according to claim 12 , wherein the alkanolamine derivative or pharmaceutically acceptable acid-addition salt thereof is administered at a dose of 2.4 mg/kg body/day.
14. 14 . The method according to claim 1 , wherein the antagonist is administered to a patient as a first line of therapy or after a first line of therapy.
15. 15 . The method according to claim 1 , wherein the selective antagonist of the beta-2 adrenergic receptor is therapeutically effective against glioma.

Description

TECHNICAL FIELD OF THE INVENTION The invention relates to the field of therapeutics and prevention of glioma, more specifically to the treatment and prevention of glioblastoma. BACKGROUND OF THE INVENTION A glioma is a type of cancer that starts in the brain or spine. It is called a glioma because it arises from glial cells and/or its precursors. The most common site of gliomas is the brain. Gliomas are classified by cell type, grade, and location. Gliomas are named according to the specific type of cell they most closely resemble. The main types of gliomas are: Ependymomas, gliomas derived from ependymal cells.Astrocytomas, gliomas derived from astrocytes; the glioblastoma multiforme (GBM) is the most common astrocytoma.Oligodendrogliomas, gliomas derived from oligodendrocytes.Mixed gliomas, such as oligoastrocytomas, that contain cells from different types of glia. Gliomas are further categorized according to their grade, which is determined by pathologic evaluation of the tumor. Thus, it can be distinguished between low-grade gliomas that are well-differentiated (not anaplastic), benign and portend a better prognosis for the patient; and high-grade gliomas, that are undifferentiated or anaplastic, malignant and carry a worse prognosis. Of numerous grading systems in use, the most common is the World Health Organization (WHO) grading system for astrocytoma. The treatment for brain gliomas depends on the location, the cell type and the grade of malignancy. Often, treatment is a combined approach, using surgery, radiation therapy, and chemotherapy. The radiation therapy is in the form of external beam radiation or the stereotactic approach using radiosurgery. Spinal cord tumors can be treated by surgery and radiation. Temozolomide is a chemotherapeutic drug that is able to cross the blood-brain barrier effectively and is being used in therapy. Despite these approaches most high-grade glioma patients succumb to their disease. New therapeutic interventions to critical targets are needed to improve outcome in this patient population. The glioblastoma multiforme (GBM, WHO grade IV) is a highly aggressive brain tumor presenting as one of two subtypes with distinct clinical histories and molecular profiles. The primary GBM presents acutely as a high-grade disease and the secondary GBM subtype evolves from the slow progression of a low-grade disease (Dolecek T A et al. 2012. Neuro Oncol 14 (Suppl 5):v1-v49. Malignant gliomas, such as GBM, are by far the most common brain cancer found in adults and one of the most difficult to treat. Even with aggressive single and multimodal treatment options such as surgery, chemotherapy, radiation and small molecule inhibitors, the survival has remained unchanged over the past three decades with a median survival of less than one year after diagnosis. Reasons for the failure of conventional treatments is multifactorial including the highly infiltrative/invasive nature of GBM, limitation of drug delivery through the blood brain barrier and neural parenchyma, and genetic heterogeneity resulting in intrinsic resistance to available treatments and the rise of aggressive resistant clones. Therefore, there is a requirement for new treatment options. BRIEF DESCRIPTION OF THE INVENTION The inventors of the present invention have found that ICI 118,551 decreases viability of the glioblastoma cell line U-87 (FIG. 1) and inhibits formation and expansion of gliospheres, under the accepted culturing procedures for the subpopulation of cancer stem cells, from human glioblastoma (FIG. 2). Additionally, the inventors have shown that ICI 118,551 decreases stemness biomarker expression in glioblastoma, and increases neural differentiation markers (FIG. 3) and delays tumor progression in a mice xenograft model (FIG. 4). Thus, the invention relates to a selective antagonist of the β2-adrenergic receptor for use in the treatment and/or prevention of glioma. DETAILED DESCRIPTION OF THE FIGURES FIG. 1.—ICI 118,551 is active as an antitumoral agent decreasing cell viability in the glioblastoma cell line and including the stem cell subpopulation. A: U-87 cell line expresses beta-adrenergic receptors type 2, as shown by confocal microscopy using a monoclonal antibody against human β2 adrenergic receptors (Abcam). B: ICI-118551 decreases viability of the human glioblastoma cell line U-87 either when grown in liquid suspension as oncospheres (gliospheres, stem cells) or in adhesion. Viability was quantified by luminescence using the ATP-Glo kit from Promega. C. β2-adrenergic receptor expression in the human glioblastoma cell line U87 was confirmed by mRNA expression by quantitative PCR in 3D cultures as gliospheres (HUVEC as positive control for β2-adrenergic receptor expression). FIG. 2.—ICI 118,551 inhibits the formation and expansion of gliospheres from the human glioblastoma cell line U-87. A: photographs of gliospheres formation after 72 hours of drug treatment. U-87 cells were cultured in medium for