KRAS G12C and PI3K Combination Therapy Without PIK3CA Pretesting
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Solution Overview
Problem
There is a need for effective therapies, including combination therapies, to treat cancers such as lung cancer, colorectal cancer, and pancreatic cancer harboring KRas G12C mutations, as current treatments provide limited benefit, and PI3K inhibitors like inavolisib require pretesting for PIK3CA mutations.
Innovation Solution
A combination therapy comprising GDC-6036, a KRas G12C inhibitor, and inavolisib, a PI3K inhibitor, is administered in specific dosing regimens to treat cancers with KRas G12C mutations, without the need for pretesting for PIK3CA mutations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PI3K inhibitors like inavolisib are used to treat cancers, then cell proliferation and survival are regulated, but pretesting for PIK3CA mutations is required which complicates treatment accessibility
Solution Approach 1:
The patent applies universality by developing a combination therapy that is effective across multiple cancer types (lung, colorectal, pancreatic) and multiple mutation statuses (PIK3CA mutant and wild-type). The combination of GDC-6036 and inavolisib creates a multi-functional treatment approach that addresses both KRAS G12C-driven and PI3K pathway-driven tumor growth, making the therapy universally applicable without requiring pretesting for PIK3CA mutation status.
2Reliability
If combination therapy with GDC-6036 and inavolisib is administered, then synergistic anti-tumor effects are achieved, but treatment complexity and dosing regimen management increase
Solution Approach 1:
The patent applies parameter changes by optimizing the dosing parameters of both GDC-6036 and inavolisib when administered in combination. The study determines specific dose ranges and administration schedules that achieve synergistic anti-tumor effects while managing toxicity. By adjusting these parameters (dose, frequency, timing), the patent resolves the contradiction between achieving high efficacy through combination therapy and maintaining ease of operation in terms of dosing regimen management.
3Reliability
If KRAS G12C inhibitors are used alone, then tumor growth is inhibited, but resistance develops and efficacy is limited in advanced stage tumors
Solution Approach 1:
The patent applies preliminary anti-action by pre-emptively blocking the PI3K pathway alongside KRAS G12C inhibition. Since PI3K pathway activation is a known mechanism of resistance to KRAS G12C inhibitors, the combination therapy proactively prevents resistance development by simultaneously targeting this escape route. This preliminary blocking action maintains treatment durability and extends the duration of effective tumor growth inhibition.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The combination therapy effectively inhibits tumor growth and proliferation in KRas G12C-positive cancers, including lung, colorectal, and pancreatic cancers, demonstrating synergistic effects and tolerability, as shown in clinical studies.
Implementation Method 1
The Kirsten rat sarcoma viral oncogene homolog (KRAS) is a central component of the RAS/MAPK signal transduction pathway, an intracellular network of proteins that transmit extracellular growth factor signals to regulate cell proliferation, differentiation, and survival.
Implementation Method 2
Pl3K catalyzes the phosphorylation of phosphatidylinositol-4,5-bisphosphate (PIP 2 ) to generate phosphatidylinositol-3,4,5-triphosphate (PIPs), a second messenger involved in the phosphorylation of AKT and other components in the AKT/mTOR pathway.
Data Source
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AI summary
Provided herein are combination therapies comprising a KRasG12C inhibitor (e.g. GDC-6036) and an PI3K-inhibitor (e.g. inavolisib) and methods of using such combination therapies.