Combination therapy for PI3K-associated disease or disorder
Inventors
Cantley, Lewis C. • Hopkins, Benjamin • Goncalves, Marcus • Mukherjee, Siddhartha
Assignees
Columbia University in the City of New York • Cornell University
Publication Number
US-12324807-B2
Publication Date
2025-06-10
Expiration Date
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Abstract
Described herein are compositions and methods for treating a disease or disorder associated with PI3K signaling. For example, such compositions can include use of modulators of glucose metabolism, use of at least one kinase in the insulin-receptor/PI3K/AKT/mTOR pathway, and/or use of diet that influences the subject's metabolic state.
Core Innovation
The present disclosure relates generally to compositions and methods for treating a disease or disorder associated with PI3K signaling that can include administration of a modulator of glucose metabolism with or without a diet that influences the subject's metabolic state. In some cases, the method can include administering an inhibitor of at least one kinase in the insulin-receptor/PI3K/AKT/mTOR pathway and administering a modulator of glucose metabolism. In some cases, the method includes administering the pathway inhibitor and/or a modulator of glucose metabolism to a subject who consumes a ketogenic diet during treatment.
The background identifies an association between some diseases and disorders and the insulin-receptor/PI3K/AKT/mTOR pathway and states that therapies targeting this pathway have struggled to be effective, creating a long-felt and unmet need for compositions and methods for treating a disease or disorder associated with PI3K signaling. The disclosure provides interventions to reduce serum insulin, including administration of metformin, a Na+/Glucose co-transporter inhibitor, use of a ketogenic diet, or a combination thereof, to increase efficacy of pathway inhibitors.
Claims Coverage
Four inventive features are identified from independent claims that recite: (1) a PI3K inhibitor in combination with a ketogenic diet that reduces serum insulin; (2) administration of a pathway inhibitor while the subject consumes a ketogenic diet; (3) a pharmaceutical composition combining a modulator of glucose metabolism with a pathway inhibitor; and (4) combined use of a glucose-uptake inhibitor and a PI3K inhibitor to inhibit cell proliferation.
PI3K inhibitor combined with ketogenic diet
Administering a PI3K inhibitor selected from copanlisib, buparlisib, alpelisib, taselisib, pictilisib or serabelisib in combination with a ketogenic diet that reduces serum insulin levels thereby improving the efficacy of the PI3K inhibitor, wherein the ketogenic diet comprises at least 80% of fat and protein by weight.
Pathway inhibitor administered with ketogenic diet
Administering at least one pathway inhibitor of at least one kinase in the insulin-receptor/PI3K/AKT/mTOR pathway to a subject who consumes or is administered a ketogenic diet during treatment.
Composition comprising modulator of glucose metabolism and pathway inhibitor
A pharmaceutical composition comprising a modulator of glucose metabolism and a pathway inhibitor that inhibits at least one kinase in the insulin-receptor/PI3K/AKT/mTOR pathway.
Glucose-uptake inhibitor combined with PI3K inhibitor to inhibit proliferation
Administering to a subject an effective amount of a glucose-uptake inhibitor and administering to the subject an effective amount of a PI3K inhibitor to inhibit cell proliferation or a cell-proliferative disease.
The independent claims focus on combination strategies that pair pathway inhibitors of the insulin-receptor/PI3K/AKT/mTOR pathway with interventions that reduce serum insulin (ketogenic diet or modulators of glucose metabolism), and on corresponding pharmaceutical compositions and methods to inhibit cell proliferation.
Stated Advantages
Disruption of systemic glucose homeostasis improves efficacy of pathway-inhibitor treatment compared to pathway inhibitor alone.
Administration of modulators of glucose metabolism and/or a ketogenic diet enhances subject responses to PI3K inhibitors across a wide spectrum of cancers.
Combination therapies can reduce or eliminate side effects and provide reduced toxicity compared to monotherapies.
Methods and compositions may allow use of a lower dosage or less frequent administration of a pathway inhibitor when combined with a modulator of glucose metabolism and/or a ketogenic diet.
The inhibition of cell proliferation or cell-proliferative disease is enhanced compared to administration of the PI3K inhibitor without a glucose-uptake inhibitor.
Documented Applications
Treating a disease or disorder associated with PI3K signaling, including administering a modulator of glucose metabolism and administering a pathway inhibitor of the insulin-receptor/PI3K/AKT/mTOR pathway.
Treating cancers or cell-proliferative disorders, including pancreatic, breast, endometrial, bladder, leukemia, lung, and liver cancer, by administering a PI3K inhibitor in combination with a ketogenic diet that reduces serum insulin levels.
Administering a ketogenic diet to subjects during treatment with a pathway inhibitor to increase effectiveness or efficacy of the pathway inhibitor.
Using a glucose-uptake inhibitor (for example SGLT1/SGLT2 inhibitors) together with a PI3K inhibitor to inhibit cell proliferation or a cell-proliferative disease.
Providing pharmaceutical compositions or kits comprising a modulator of glucose metabolism and a pathway inhibitor, or components/instructions for a ketogenic diet together with pathway inhibitors or modulators.
Measuring serum insulin by ELISA or by a level of c-peptide as part of methods related to improving efficacy of PI3K inhibitor treatment.
Treating metabolic disorders, neurodegenerative diseases, or inflammatory diseases associated with PI3K signaling by administering pathway inhibitors and modulators of glucose metabolism and/or ketogenic diet.
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