Methods of preventing the development of mucositis and related disorders
Inventors
Gutkind, J. Silvio • Iglesias-Bartolome, Ramiro • Patel, Vyomesh • Cotrim, Ana p. • Molinolo, Alfredo • Mitchell, James B.
Assignees
US Department of Health and Human Services
Publication Number
US-9278090-B2
Publication Date
2016-03-08
Expiration Date
2033-03-13
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Abstract
Disclosed is a method of preventing the development of mucositis in a subject undergoing radiation therapy or chemotherapy for a disease in need thereof comprising administering an effective amount of a mammalian target of rapamycin (mTOR) inhibitor, such as rapamycin, to the subject. Further disclosed is a method of increasing the lifespan of a normal oral keratinocyte and/or reducing oxidative stress in a normal epithelial cell, wherein the method comprises administering an effective amount of an mTOR inhibitor to a subject undergoing radiation therapy or chemotherapy for a disease in need thereof.
Core Innovation
The invention provides a method of preventing the development of mucositis in subjects undergoing radiation therapy or chemotherapy for diseases requiring such treatments, by administering an effective amount of an mTOR inhibitor, such as rapamycin. This method surprisingly protects normal epithelial progenitor cells, including hair follicles and oral epithelial cells, from radiation-induced depletion, thereby preventing radiation-induced mucositis and associated tissue damage.
The problem being solved addresses the vulnerability of epithelial tissues, like mucosal epithelia, which rely on self-renewing stem cells that are compromised by radiation or chemotherapy leading to mucositis. Mucositis is a debilitating condition characterized by painful mucosal ulcerations, affecting patient quality of life and increasing healthcare costs. Existing cancer treatments, including radiotherapy, cause indirect damage to normal epithelial tissues, necessitating therapeutic approaches to protect these tissues and improve treatment outcomes.
The invention also discloses that mTOR inhibition increases the lifespan and clonogenic capacity of normal oral keratinocytes by preventing stem cell senescence and reducing oxidative stress specifically in normal epithelial cells compared to cancerous ones. This is achieved through increased expression of mitochondrial superoxide dismutase (MnSOD), resulting in suppression of reactive oxygen species (ROS) accumulation in normal cells. Additionally, the method minimizes hair loss in subjects undergoing radiation or chemotherapy by preserving epithelial progenitor cells.
Claims Coverage
The patent claims four independent methods, each involving administration of an mTOR inhibitor rapamycin under different conditions to achieve protective effects during radiation therapy for cancer.
Method of reducing radiation-induced mucositis by topical mTOR inhibition
Administering rapamycin via application to the oral mucosa during concurrent radiation therapy for oral cancers (including head and neck cancers, HNSCC, and tongue cancer) to reduce development of radiation-induced mucositis.
Method of reducing hair loss by topical mTOR inhibition
Topically administering rapamycin to a subject undergoing radiation therapy for cancer to reduce hair loss.
Method of increasing lifespan of normal oral keratinocytes by topical mTOR inhibition
Administering rapamycin via application to the oral mucosa to a subject undergoing radiation therapy for oral cancers to increase lifespan of normal oral keratinocytes, decrease disappearance of epithelial progenitor marker p63, and increase MnSOD levels.
Method of reducing oxidative stress in normal epithelial cells by topical mTOR inhibition
Administering rapamycin via application to the oral mucosa during radiation therapy for oral cancers to reduce oxidative stress in normal epithelial cells compared to cancerous epithelial cells from the oral mucosa, including reducing reactive oxygen species levels.
The inventive features encompass methods of locally administering rapamycin to subjects undergoing radiation therapy for oral cancers to prevent mucositis, reduce hair loss, preserve epithelial progenitor cells, extend oral keratinocyte lifespan, and reduce oxidative stress in normal epithelial cells relative to cancer cells.
Stated Advantages
mTOR inhibition protects normal epithelial progenitor cells from radiation-induced depletion, preventing mucositis.
The method increases lifespan and clonogenic capacity of normal oral keratinocytes by preventing stem cell senescence.
mTOR inhibition reduces oxidative stress in normal epithelial cells by increasing MnSOD expression and suppressing ROS accumulation.
Prevention or reduction of hair loss in subjects undergoing radiation or chemotherapy.
Preserving proliferative capacity and tissue repopulating function of basal epithelial progenitor cells after radiation therapy.
Documented Applications
Prevention of mucositis and oral ulcers resulting from radiation or chemotherapy in cancer patients, particularly in oral mucosa and head and neck tissues.
Reducing radiation- or chemotherapy-induced hair loss by protecting hair follicle epithelial progenitor cells.
Increasing lifespan and proliferative capacity of normal oral keratinocytes during cancer therapies involving radiation or chemotherapy.
Reducing oxidative stress and DNA damage in normal epithelial cells during radiation or chemotherapy in patients with various cancers, especially oral cancers including HNSCC and tongue cancer.
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