Scaffold-kinase interaction blockades and uses thereof in treating cancer
Inventors
Jameson, Katherine LaRoque • Khavari, Paul A.
Assignees
US Department of Veterans Affairs
Publication Number
US-9155774-B2
Publication Date
2015-10-13
Expiration Date
2032-04-05
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Abstract
Aspects of the invention include compositions and methods for inhibiting the interaction between scaffold proteins and kinases. These compositions and methods find a number of uses including, for example, suppressing tumor growth and metastasis and reducing tumor size and number in a mammal with cancer.
Core Innovation
Aspects of the invention include compositions and methods for inhibiting the interaction between scaffold proteins and kinases. These compositions and methods find uses including suppressing tumor growth and metastasis and reducing tumor size and number in a mammal with cancer.
The problem being solved is the challenge of targeting dysregulated signaling in cancer, particularly the extracellular signal-regulated kinase (ERK) MAP kinase pathway, which is often pathologically activated in over one-third of all human cancers. Direct inhibition of kinases like ERK affects normal tissue viability and leads to resistance, highlighting the need for alternative approaches.
The invention addresses this problem by providing agents, termed scaffold-kinase interaction blockades (SKIBs), that inhibit interactions between scaffold proteins such as IQGAP1 and their cognate kinases (e.g., ERK and AKT). The methods include using IQGAP1 WW domain peptides or nucleic acids encoding them to inhibit hyperactive RAS pathway signaling, thereby suppressing cancer cell proliferation, metastasis, and tumor growth without harming normal tissue.
Claims Coverage
The patent includes one independent claim focused on methods of inhibiting RAS pathway activity using an IQGAP1 SKIB agent.
Method of inhibiting RAS pathway activity using IQGAP1 WW peptide
A method involving adding to a cell in vitro an effective amount of an IQGAP1 scaffold-kinase interaction blockade agent to block interaction between scaffold protein and kinase, thereby inhibiting RAS pathway activity, wherein the SKIB agent is an isolated IQGAP1 WW peptide or a nucleic acid encoding it, consisting essentially of the WW domain of IQGAP1.
The claims cover the use of isolated IQGAP1 WW peptides or nucleic acids encoding them as SKIB agents to inhibit RAS pathway activity by blocking scaffold-kinase interactions, specifically targeting the RAS pathway-driven cancer cells in vitro.
Stated Advantages
The compositions and methods can suppress tumor growth and metastasis and reduce tumor size and number in mammals with cancer.
Targeting scaffold-kinase interactions, such as IQGAP1-ERK, provides a therapeutic approach that inhibits cancer cell proliferation and metastasis without affecting normal tissue homeostasis.
The WW domain peptide can inhibit established tumor growth and overcome resistance to direct kinase inhibitors like B-Raf inhibitors.
Systemic delivery of WW peptide in vivo diminishes tumorigenesis without adverse toxic effects, suggesting potential for therapeutic use.
Documented Applications
Suppressing tumor growth and metastasis and reducing tumor size and tumor number in mammals with cancer, particularly RAS-driven cancers.
Inhibiting intracellular hyperactive or constitutively active signaling resulting in cancerous phenotypes such as proliferation or metastasis, including in cancer cells such as skin, breast, colorectal, prostate, and lung cancers.
Treatment of cancer in mammalian subjects by administering SKIB agents systemically or intratumorally, alone or in combination with other cancer therapies.
Use as research tools to inhibit scaffold-kinase interactions in vitro and in vivo for understanding signaling and developing therapeutics.
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