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-10130594-B2
Publication Date
2018-11-20
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 involves administering a therapeutically effective amount of fenoterol, specific fenoterol analogs, or combinations thereof to reduce one or more symptoms related to the tumor, thereby treating the tumor in the subject.
The problem being solved addresses the significant difficulty in treating brain cancers due to the inability of many therapeutic agents to cross the blood brain barrier and the late detection of such tumors, which are usually highly advanced upon diagnosis. Malignant brain tumors such as gliomas and astrocytomas have a poor prognosis, with median survival of 12-15 months. Currently available treatments like surgery, radiation, and chemotherapy have limited success in improving survival, urging the need for new therapeutic approaches.
The innovation lies in the recognition that fenoterol and its specific analogues can act upon tumors expressing β2-adrenergic receptors to inhibit tumor growth and other associated signs or symptoms. The inventors identified that administration of fenoterol or its analogues specifically targeting β2-AR expressing tumors, especially primary brain tumors such as glioblastomas and astrocytomas, can effectively reduce tumor burden. The described fenoterol analogues possess chemical modifications that enhance or maintain their binding and agonist activity at β2-AR and formulations can be administered via various routes including intravenous and oral, with dosages tailored to therapeutic effect while minimizing cytotoxicity.
Claims Coverage
The claims include one independent claim focused on methods to reduce growth of cancer cells expressing β2-adrenergic receptors, employing specific fenoterol analogues.
Methods to reduce tumor growth using fenoterol analogues
A method of reducing growth of primary brain tumor cells, pancreatic cancer cells, breast cancer cells, or lung cancer cells that express a β2-adrenergic receptor by exposing said cells to an effective amount of a compound.
Use of specific fenoterol analogues
The compounds used include (R,R′)-(−)-4-methoxy-1-naphthylfenoterol, (R,S′)-(−)-4-methoxy-1-naphthylfenoterol, (S,R′)-(−)-4-methoxy-1-naphthylfenoterol, or combinations thereof.
Administration to subjects with tumors expressing β2-AR
The method encompasses administering a therapeutically effective amount of the compound to a subject having a tumor expressing a β2-AR to reduce symptoms such as tumor growth and volume.
Treatment of multiple cancer types
Applicable tumors include primary brain tumors (e.g., astrocytoma or glioblastoma), pancreatic, breast, and lung cancers expressing β2-AR.
Patient selection and concurrent therapies
The method includes selecting subjects without bleeding disorders and optionally administering additional chemotherapeutic agents such as carmustine, lomustine, procarbazine, streptozocin, 5-fluorouracil, or paclitaxel.
Use with pharmaceutically acceptable carriers
The compounds are administered with pharmaceutically acceptable carriers suitable for the intended therapeutic use.
The claims collectively cover methods of treating β2-AR expressing tumors using specified fenoterol analogues administered alone or with additional chemotherapeutics, encompassing cancer types including brain, pancreatic, breast, and lung cancers, and emphasizing selection of appropriate subjects and carriers for administration.
Stated Advantages
Fenoterol analogues inhibit tumor growth associated with β2-adrenergic receptor expression, including primary brain tumors such as glioblastomas and astrocytomas.
Certain fenoterol analogues can pass the blood brain barrier, enabling effective delivery to brain tumors.
Fenoterol analogues show high binding affinity and selectivity for β2-adrenergic receptors, potentially improving therapeutic efficacy.
The compounds can be administered via multiple routes and formulated with pharmaceutically acceptable carriers, allowing versatile therapeutic approaches.
Fenoterol compounds can be used alone or in combination with other therapeutic agents including chemotherapeutics to enhance treatment outcomes.
Documented Applications
Treatment of tumors expressing β2-adrenergic receptors, including primary brain tumors such as glioblastomas and astrocytomas.
Potential treatment of pancreatic cancer, breast cancer, and lung cancer that express β2-adrenergic receptors.
Use as an adjuvant therapy to reduce, prevent, or retard tumor growth following initial treatment such as surgery, chemotherapy, or radiation.
In vitro inhibition of 1321N1 astrocytoma cell growth and in vivo inhibition of tumor growth in xenograft models.
Pharmaceutical formulations for administration to humans or veterinary subjects to treat tumors expressing β2-AR.
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