Combination therapy for pi3k-associated disease or disorder

An OSI-906, inhibitor technology, applied in the field of increasing insulin receptor/PI3K/AKT/mTOR pathway inhibitors

Pending Publication Date: 2021-07-30
CORNELL UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Accordingly, there is a long felt and unmet need for compositions and methods of treating diseases or disorders associated with PI3K signaling

Method used

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  • Combination therapy for pi3k-associated disease or disorder
  • Combination therapy for pi3k-associated disease or disorder
  • Combination therapy for pi3k-associated disease or disorder

Examples

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example

[0160] The following examples are given to illustrate various embodiments of the disclosure and are not meant to limit the disclosure in any way. Variations therein and other uses encompassed within the spirit of the disclosure as defined by the scope of the claims will occur to those skilled in the art. Appendix A provides a further description of the experimental work involved in the development of the methods and compositions described herein.

[0161] overview

[0162] Gain-of-function mutations in PIK3CA, which encodes insulin-activated phosphoinositide-3-kinase (PI3K), and loss-of-function mutations in PTEN, the phosphatase that degrades phosphoinositide lipids produced by PI3K, are among the most frequent events in human cancers . However, pharmacological inhibition of PI3K using different classes of inhibitors has resulted in variable clinical responses in humans, raising the possibility that there are intrinsic resistance mechanisms to PI3K inhibition. Here, the in...

example 1

[0165] Example 1: Disruption of systemic glucose homeostasis using therapeutic doses of compounds targeting various kinases in the insulin receptor / PI3K / mTOR pathway

[0166] Hyperglycemia is largely treated as a treatment-related complication and only needs to be managed in the subset of patients in whom hyperglycemia persists. Due to the body's normal blood glucose regulation, patients treated with these agents develop some degree of systemic hyperinsulinemia as the pancreas attempts to normalize serum glucose levels. Since insulin is a potent stimulator of PI3K signaling in tumors and can have profound effects on cancer progression, the inventors hypothesized that treatment-induced hyperinsulinemia limits the therapeutic potential of agents targeting the PI3K pathway.

[0167] Wild-type mice were treated with therapeutic doses of compounds targeting multiple kinases in the insulin receptor / PI3K / mTOR pathway, including inhibitors of INSR / IGFR, PI3K, AKT, and mTOR, after trea...

example 2

[0169] Example 2: Insulin stimulates PI3K signaling in the context of PI3K inhibition

[0170] To test whether these spikes in insulin stimulate PI3K signaling in the presence of PI3K inhibition, KPC cells were treated in vitro with PI3K inhibitors in the presence or absence of 10 ng / ml insulin, which was 15 ng / ml after drug administration. - the level observed in mice within 30 minutes ( Figure 1D). This level of insulin is sufficient to partially rescue PI3K signaling in the presence of PI3K inhibitors, as shown by partial reactivation of phosphorylated AKT (pAKT) and almost complete reactivation of phosphorylated S6 (pS6), a phosphorylated S6 is a reporter molecule for growth signaling through the mTORC1 complex ( Figure 2A ). Furthermore, this enhanced signaling was associated with a partial restoration of cell proliferation ( Figure 2B-2C ).

[0171] Similar effects of insulin-stimulated proliferation were observed in various other tumor cell lines and patient-der...

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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.

Description

[0001] This application claims priority to the filing date of U.S. Provisional Application Serial No. 62 / 679,329, filed June 1, 2018, the contents of which are specifically incorporated herein by reference in their entirety. technical field [0002] The present disclosure generally relates to methods of treating diseases or disorders associated with insulin receptor / PI3K / AKT / mTOR pathway signaling, including hematological malignancies and solid tumors. In particular, the present disclosure relates to increasing the efficacy of insulin receptor / PI3K / AKT / mTOR pathway inhibitors through pharmacological or dietary modulation of glucose metabolism. Background technique [0003] Several diseases and disorders are linked to the insulin receptor phosphatidylinositol kinase (phosphoinositide 3-kinase (PI3K)), protein kinase B (AKT), and mammalian target of rapamycin (mTOR) signaling pathways (known as the insulin receptor / PI3K / AKT / mTOR pathway) is linked. In cancer, mutations in PIK...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A23L33/20A61K31/155A61K38/00A61P3/10A61P35/00C07C279/00
CPCA23L33/20A61K31/155A61P3/10A61P35/00A61K45/06A61K31/70A61K31/7048A61K31/7042A61K31/7056A61K31/34A61K31/5377A61K31/4439A61K31/553A61K31/4985A61K31/4375A61K31/519A61K31/52A23V2002/00A61K2300/00A23V2200/08A61K31/4745
Inventor L·C·坎特利B·霍普金斯S·慕克吉M·冈萨维斯
Owner CORNELL UNIVERSITY
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