Nitroxide therapy for the treatment of von Hippel—Lindau disease (VHL) and renal clear cell carcinoma (RCC)
Inventors
Linehan, W. Marston • ROUAULT, TRACEY A. • Mitchell, James • Cherukuri, Murali K.
Assignees
US Department of Health and Human Services
Publication Number
US-8853277-B2
Publication Date
2014-10-07
Expiration Date
2030-11-30
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Abstract
The invention provides therapeutic methods that include administering a stable nitroxide to a subject that has, is suspected to have, or is at risk for having a condition associated with reduced VHL or elevated HIF-2α.
Core Innovation
The invention provides therapeutic methods that involve administering a stable nitroxide composition to subjects who have, are suspected to have, or are at risk for having a condition associated with elevated hypoxia-inducible transcription factor HIF-2α or compromised von Hippel-Lindau (VHL) function. The administration of the stable nitroxide reduces the level of HIF-2α in such subjects and thereby treats conditions including VHL disease and renal clear cell carcinoma (RCC), which are associated with elevated HIF-2α or reduced VHL gene product.
The problem addressed by the invention is the lack of effective molecular therapies for diseases associated with elevated HIF-2α expression, such as inherited VHL disease and sporadic or inherited RCC. VHL disease is characterized by a variety of tumors and cysts across organs including the kidney, brain, and pancreas, with RCC being a major cause of mortality. Existing treatments for RCC are limited, with resistance to chemotherapy and low response rates to immunotherapy and other agents, highlighting the need for new therapeutic options.
The invention is based on the unexpected discovery that stable nitroxides, particularly compounds such as 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol), effectively reduce HIF-2α expression. This enables the use of stable nitroxide compositions for treating subjects with compromised VHL function or elevated HIF-2α levels by lowering the HIF-2α gene product and inhibiting tumor growth or vascular remodeling related to these conditions.
Claims Coverage
The patent includes a primary independent method claim that discloses administering a nitroxide composition for treating subjects with VHL disease or RCC based on genetic and biomarker criteria.
Method of treating subjects with VHL disease or RCC
A method comprising: (a) determining if a subject's sample has a deleterious mutation in at least one allele of the VHL gene, (b) detecting elevated levels of HIF-2α mRNA or protein in the sample, and (c) administering an effective amount of a nitroxide composition to the subject when both conditions are met, thereby treating the subject.
The claims center on a diagnostic-guided method of treating VHL disease or RCC by administering a stable nitroxide composition to subjects identified with deleterious VHL mutations and elevated HIF-2α levels, thereby reducing HIF-2α and providing therapeutic benefit.
Stated Advantages
The stable nitroxide effectively reduces HIF-2α levels in tumor cells lacking functional VHL.
Administration of stable nitroxides inhibits the growth of VHL-compromised tumors in mammals.
Dietary supplementation of stable nitroxide compounds reduces tumor growth in immune-compromised mouse models.
The methods provide a rational medical approach that can diminish the incidence of tumor formation or vascular remodeling and reduce mortality associated with VHL disease or RCC.
Documented Applications
Treatment of subjects with inherited or sporadic von Hippel-Lindau (VHL) disease.
Treatment of subjects with sporadic or inherited renal clear cell carcinoma (RCC).
Reducing growth or persistence of cysts or tumors associated with compromised VHL function.
Reducing vascular remodeling of pulmonary vasculature due to prolonged alveolar hypoxia.
Treating pulmonary arterial hypertension and cor pulmonale associated with elevated HIF-2α.
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