Use of fenoterol and fenoterol analogues in the treatment of glioblastomas and astrocytomas
Inventors
Wainer, Irving W. • Bernier, Michel • Toll, Lawrence Robert • Jimenez, Lucita Arenas
Assignees
SRI International Inc • US Department of Health and Human Services
Publication Number
US-9492405-B2
Publication Date
2016-11-15
Expiration Date
2031-03-10
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Abstract
This disclosure concerns the discovery of the use of fenoterol and (R,R)- and (R,S)-fenoterol analogs for the treatment of a tumor expressing a β2-adrenergic receptor, such as a primary brain tumor, including a glioblastoma or astrocytoma expressing a β2-adrenergic receptor. In one example, the method includes administering to a subject a therapeutically effective amount of fenoterol, a specific fenoterol analog or a combination thereof to reduce one or more symptoms associated with the tumor, thereby treating the tumor in the subject.
Core Innovation
This disclosure concerns the discovery of the use of fenoterol and (R,R)- and (R,S)-fenoterol analogs for the treatment of tumors expressing a β2-adrenergic receptor, such as primary brain tumors including glioblastomas and astrocytomas. The method includes administering to a subject a therapeutically effective amount of fenoterol, a specific fenoterol analog, or a combination thereof to reduce symptoms associated with such tumors, thereby treating the tumor in the subject.
Cancer, particularly brain cancer, is difficult to treat due to the inability of many therapeutic agents to pass through the blood-brain barrier and late detection of tumors. Gliomas and astrocytomas are highly lethal with median survival of 12-15 months, and current treatments combining surgery, radiation, and chemotherapy have not significantly improved survival. Therefore, new therapies for treating such tumors associated with β2-adrenergic receptor expression are needed.
The inventors have discovered that administration of fenoterol, fenoterol analogues, or combinations thereof inhibits symptoms such as tumor growth associated with tumors expressing β2-adrenergic receptors. The disclosure includes methods of treating primary brain tumors including glioblastoma or astrocytoma that express the β2-adrenergic receptor by administering therapeutically effective amounts of fenoterol compounds to reduce or inhibit tumor signs or symptoms, including tumor growth or volume. These compounds include specific stereoisomers and analogues that have demonstrated binding and activity at β2-adrenergic receptors.
Claims Coverage
The patent includes one independent claim covering a method of treating glioblastoma by administering (R,R) stereoisomer fenoterol compounds.
Use of (R,R)-fenoterol stereoisomer compounds to treat glioblastoma
A method comprising administering to a subject a therapeutically effective amount of a compound of specified (R,R) stereoisomer fenoterol structure to reduce one or more symptoms associated with glioblastoma.
Subject selection excluding those with bleeding disorders
The method includes selecting subjects that do not have a bleeding disorder prior to administration of the fenoterol compound.
Treatment includes inhibition of glioblastoma growth
The treatment method effects reduction or inhibition of glioblastoma growth by administering the therapeutically effective amount of the compound.
Combination therapy with chemotherapeutic agents
The method further comprises administering an additional therapeutic agent such as carmustine, lomustine, procarbazine, streptozocin, or combinations thereof either prior to, concurrently, or subsequent to the fenoterol compound administration.
Administration with pharmaceutically acceptable carriers
The compound is administered in a therapeutically effective amount with a pharmaceutically acceptable carrier.
Applicability to human subjects
The subject receiving the treatment is a human.
The claims define a method of treating glioblastoma using (R,R)-stereoisomer fenoterol compounds, highlighting key aspects including subject selection, treatment effects, possible combination therapies, pharmaceutical formulation, and applicability to humans.
Stated Advantages
Fenoterol analogues have higher binding affinity and selectivity for β2-adrenergic receptors than fenoterol itself.
Certain fenoterol analogues demonstrate improved systemic exposure and longer clearance times, potentially leading to longer acting drugs.
Fenoterol and specific fenoterol analogues effectively inhibit growth and proliferation of glioma and astrocytoma cells by increasing intracellular cAMP, inducing cell cycle arrest, and modulating relevant cell cycle proteins.
Certain disclosed fenoterol analogues can pass through the blood-brain barrier and reach effective concentrations in brain tissue.
Administration of fenoterol analogues such as (R,R)-methoxyfenoterol inhibits astrocytoma growth in vivo in mouse xenograft models.
Documented Applications
Treating tumors expressing β2-adrenergic receptors, specifically primary brain tumors such as glioblastomas and astrocytomas.
Use of fenoterol and its analogues as compounds to inhibit growth and proliferation of glioma and astrocytoma cells.
Intravenous administration of fenoterol analogues for delivery to brain tissue to treat brain tumors.
Pharmaceutical compositions for treatment of primary brain tumors and related therapy modalities.
Combination therapy including fenoterol compounds with chemotherapeutic agents such as carmustine, lomustine, procarbazine, and streptozocin.
Adjuvant therapy to prevent or retard tumor growth and recurrence in malignant astrocytoma patients post-initial treatments including surgery, radiation, or chemotherapy.
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