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-10617654-B2
Publication Date
2020-04-14
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 analogues 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 analogue or a combination thereof to reduce one or more symptoms associated with the tumor, thereby treating the tumor in the subject.
Core Innovation
This invention discloses the use of fenoterol and specific fenoterol analogues, including (R,R)- and (R,S)-fenoterol analogues, for treating tumors that express a β2-adrenergic receptor (β2-AR). Exemplary tumors include primary brain tumors such as glioblastomas or astrocytomas expressing β2-AR. The method involves administering a therapeutically effective amount of fenoterol, a specific fenoterol analogue, or a combination thereof to reduce one or more symptoms associated with the tumor, thereby treating the tumor in the subject.
The inventors discovered that fenoterol and certain analogues inhibit one or more signs or symptoms, such as tumor growth or tumor volume, associated with a tumor expressing β2-AR. They developed methods of treating tumors expressing β2-AR by administering fenoterol, a fenoterol analogue, or combinations thereof, including pharmaceutical compositions containing these compounds and pharmaceutically acceptable carriers.
The problem being solved is the difficulty in treating brain cancers such as gliomas and astrocytomas, which are highly lethal with limited survival improvements from current therapeutic approaches. Brain tumors are particularly challenging due to the blood brain barrier limiting drug passage and their late detection. New therapies are needed to improve treatment outcomes for primary brain tumors expressing β2-AR.
Claims Coverage
The patent contains one independent claim defining inventive features relating to methods of treating pancreatic cancer or primary brain tumors by administering certain fenoterol analogues.
Method of treating pancreatic cancer or primary brain tumors by administration of specific fenoterol analogues
The method involves administering to a subject a therapeutically effective amount of a compound selected from (R,R′)-(−)-4-methoxy-1-naphthylfenoterol, (R,S′)-(−)-4-methoxy-1-naphthylfenoterol, (S,R′)-(−)-4-methoxy-1-naphthylfenoterol, or combinations thereof to reduce one or more symptoms associated with pancreatic cancer or a primary brain tumor.
Inhibition of tumor cell growth and symptom reduction
Administering the fenoterol analogue inhibits growth of pancreatic cancer cells or primary brain tumor cells and reduces tumor growth, tumor volume, or both.
Treatment of tumors expressing β2-adrenergic receptor
The method applies to tumors whose cells express a β2-adrenergic receptor, including glioblastoma or astrocytoma as primary brain tumors.
Combination therapy with additional chemotherapeutic agents
The method optionally includes administering additional chemotherapeutic agents prior to, concurrent with, or subsequent to administering the fenoterol analogue.
Pharmaceutical compositions and routes of administration
The fenoterol analogues are administered in pharmaceutical compositions with pharmaceutically acceptable carriers, including injectable fluids and oral dosage forms such as syrups, suspensions, powders, pills, tablets, or capsules in dosages from about 0.001 mg/kg to about 100 mg/kg body weight, administered orally or parenterally.
The claims cover methods of treating pancreatic cancer and primary brain tumors by administering therapeutically effective amounts of specific fenoterol analogues to reduce tumor symptoms and growth, including optional combination with other chemotherapeutic agents and various pharmaceutical compositions and administration routes.
Stated Advantages
Fenoterol analogues described have increased systemic exposure and longer clearance compared to (R,R)-fenoterol, potentially producing a longer acting drug with improved pharmacokinetics.
Fenoterol and specific analogues effectively inhibit glioma and astrocytoma (such as 1321N1 cells) growth in vitro and in vivo, including reducing tumor volume and arresting cell cycle progression.
These compounds can pass through the blood brain barrier when administered intravenously, enabling effective delivery to brain tumors.
Binding affinities of fenoterol analogues to β2-adrenergic receptors are comparable or superior to fenoterol, with β2-AR selectivity over β1-AR, supporting therapeutic use.
Correlation between agonist-induced cAMP accumulation and inhibition of tumor cell proliferation suggests a pharmacological mechanism of action.
Documented Applications
Treatment of primary brain tumors expressing β2-adrenergic receptors, such as glioblastomas and astrocytomas.
Treatment of pancreatic cancer expressing β2-adrenergic receptors.
Inhibition of tumor growth, reduction of tumor volume, and reduction of symptoms associated with β2-AR expressing tumors.
Administration of fenoterol analogues as an adjuvant therapy to reduce, prevent or retard tumor reoccurrence following initial treatments such as surgery, radiation or chemotherapy.
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