Dehydroacetic acid (DHAA) and derivative for uses in treating cancer
Inventors
Chen, Jing • Arbiser, Jack • Pollack, Brian • Xia, Siyuan
Assignees
Emory University • US Department of Veterans Affairs
Publication Number
US-10792274-B2
Publication Date
2020-10-06
Expiration Date
2037-11-06
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Abstract
This disclosure relates to methods of managing or treating cancer with agents that lower circulating acetoacetate levels, such as hypolipidemic agents, or other agents that antagonize acetoacetate-BRAF V600 mutant binding to attenuate BRAF V600 mutant tumor growth. In certain embodiments, this disclosure relates to methods of treating cancer comprising administering an effective amount of an agent to a subject in need thereof, wherein the agent is dehydroacetic acid, derivative, prodrug, or salt thereof.
Core Innovation
This disclosure relates to methods of managing or treating cancer with agents that lower circulating acetoacetate levels, such as hypolipidemic agents, or other agents that antagonize acetoacetate-BRAF V600 mutant binding to attenuate BRAF V600 mutant tumor growth. In certain embodiments, methods of treating cancer involve administering an effective amount of an agent to a subject in need thereof, wherein the agent is dehydroacetic acid, a derivative, prodrug, or salt thereof.
Mutations in Ras GTPases and the B-Raf kinase cause sustained activation of the MAPK pathway, leading to increased cell division and survival, which are linked to various human cancers including melanoma. The BRAF V600E mutant upregulates the ketogenesis enzyme HMGCL, increasing levels of acetoacetate, which enhances BRAF V600E binding to MEK1 and promotes tumor growth. Thus, metabolic rewiring is implicated for tumor growth in BRAF V600E cancers.
The invention addresses the problem that dietary fat and ketogenesis increase circulating acetoacetate, fueling tumor growth in BRAF V600E-positive cancers. High-fat diets elevate serum acetoacetate selectively promoting tumor growth in BRAF V600E melanoma. The disclosure proposes managing cancer by lowering circulating acetoacetate levels using agents like dehydroacetic acid or hypolipidemic drugs, antagonizing acetoacetate binding to mutant BRAF, limiting dietary fat intake, or combination therapies to attenuate tumor growth.
Claims Coverage
The patent contains one independent claim focused on a method of treating cancer using dehydroacetic acid or its derivatives. The main inventive features include the chemical nature of the derivative, cancer specificity, and combination therapies.
Use of dehydroacetic acid derivatives for cancer treatment
Administering an effective amount of dehydroacetic acid or its derivatives or salts thereof for treating cancer or neoplasm, wherein the derivative has a defined chemical formula.
Targeting cancers with B-Raf V600E mutation
Treating neoplasms characterized by a mutation encoding a V600E amino acid substitution in the B-Raf coding sequence.
Treatment of metastatic melanoma
Applying dehydroacetic acid or its derivatives in subjects suffering from metastatic melanoma.
Combination therapy with additional agents
Administering dehydroacetic acid or its derivatives in combination with a second therapeutic agent for improved cancer treatment.
The claims focus on methods of treating cancer, particularly BRAF V600E mutant cancers such as metastatic melanoma, by administering dehydroacetic acid derivatives alone or in combination with other therapeutic agents.
Stated Advantages
Agents lowering circulating acetoacetate levels attenuate tumor growth in BRAF V600E-positive cancers.
Dehydroacetic acid selectively inhibits BRAF V600E binding to MEK1, reducing phosphorylation and tumor cell proliferation.
Treatment with hypolipidemic agents or dehydroacetic acid does not affect normal tissue or cause significant toxicity in vivo.
Dehydroacetic acid reverses tumor-promoting effects of a high-fat diet without altering serum acetoacetate levels.
Documented Applications
Treatment of cancers harboring BRAF V600E, V600D, or V600R mutations.
Use in treating metastatic melanoma and other neoplasms with BRAF mutations.
Combination therapies involving dehydroacetic acid derivatives with chemotherapeutic agents including BRAF or MEK inhibitors.
Use of hypolipidemic agents to reduce circulating acetoacetate levels as cancer management.
Dietary fat limitation and monitoring serum acetoacetate levels in cancer prevention and treatment.
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