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-10925840-B2
Publication Date
2021-02-23
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 disclosure concerns the discovery of the use of fenoterol and (R,R)- and (R,S)-fenoterol analogues for the treatment of tumors expressing a β2-adrenergic receptor (β2-AR), 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 analogue, or a combination thereof to reduce symptoms associated with the tumor, thereby treating the tumor.
The inventors identified that fenoterol and specific analogues inhibit signs and symptoms such as tumor growth associated with β2-AR expressing tumors. Chemical structures of effective fenoterol analogues that bind β2-ARs are provided, with specific embodiments including (R,R)- and (R,S)-fenoterol analogues capable of crossing the blood brain barrier.
The problem being solved relates to the difficulty in treating brain cancers such as gliomas and astrocytomas due to poor drug penetration through the blood brain barrier and limited effectiveness of current treatments like surgery, radiation, and chemotherapy. There is an unmet need for new therapies that effectively inhibit growth and progression of β2-AR expressing tumors.
Claims Coverage
The claims primarily focus on a method of treating lung cancer using specific fenoterol analogues and related pharmaceutical compositions.
Method of treating lung cancer by administering therapeutically effective compounds
A method of treating lung cancer is provided comprising administering to a subject a therapeutically effective amount of a compound to reduce one or more symptoms associated with lung cancer.
Use of specific fenoterol analogues for treatment
The compounds include (R,R′)-(−)-4-methoxy-1-naphthylfenoterol, (R,S′)-(−)-4-methoxy-1-naphthylfenoterol, (S,R′)-(−)-4-methoxy-1-naphthylfenoterol, or combinations thereof for lung cancer treatment.
Inhibition of lung cancer cell growth
Administering these compounds inhibits growth of lung cancer cells.
Reduction of tumor growth or volume
Treatment results in reducing tumor growth, tumor volume, or both.
Targeting β2-adrenergic receptor expressing cells
The method is effective where lung cancer cells express a β2-adrenergic receptor.
Combination therapy with chemotherapeutic agents
The method optionally includes administration of additional chemotherapeutic agents prior to, concurrent with, or subsequent to compound administration.
Pharmaceutical composition formulations and administration routes
Compounds are administered in pharmaceutical compositions comprising pharmaceutically acceptable carriers in injectable fluids or oral dosage forms including syrups, solutions, suspensions, powders, pills, tablets, or capsules.
Dosage ranges and regimen
Oral dosage forms contain about 1.0 to about 50 mg of the compound, administered two to four times a day; therapeutically effective oral dose range is about 0.001 mg/kg to about 10 mg/kg; parenteral doses range from about 1 mg/kg to about 100 mg/kg body weight.
The claims cover administering specific optically active fenoterol analogues to treat lung cancer by reducing symptoms and inhibiting tumor growth, optionally in combination with other chemotherapeutic agents, using various pharmaceutical formulations and dosing regimens.
Stated Advantages
Fenoterol analogues have higher binding affinity for β2-adrenergic receptors than fenoterol.
Certain fenoterol analogues effectively cross the blood brain barrier allowing brain tumor treatment.
(R,R)-methoxyfenoterol and (R,S)-naphthylfenoterol demonstrate significantly longer systemic exposure and slower clearance compared to (R,R)-fenoterol, potentially enabling longer acting drugs.
β2-AR agonists including fenoterol analogues inhibit growth and proliferation of astrocytoma cells in vitro and in vivo.
The methods allow for selective targeting of tumors expressing β2-adrenergic receptors.
Documented Applications
Treatment of primary brain tumors expressing β2-adrenergic receptors, including glioblastomas and astrocytomas.
Use in inhibiting or reducing tumor growth or volume associated with β2-AR expressing tumors.
Use as an adjuvant therapy to prevent or retard tumor recurrence in subjects treated for malignant astrocytoma.
Pharmacokinetic applications for intravenous administration to deliver fenoterol analogues to the brain for brain tumor treatment.
Use in inhibiting cell proliferation in 1321N1 astrocytoma cells and xenograft models via β2-AR stimulation.
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