SAE Inhibitor and Checkpoint Blockade for Resistant Cancers
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Solution Overview
Problem
Current cancer treatments, including immunotherapy and chemotherapy, are ineffective for a significant portion of patients with cancers lacking specific genetic alterations, and there is a need for new combination therapies to improve treatment outcomes and overcome resistance.
Innovation Solution
Administering a small ubiquitin-like modifier (SUMO) activating enzyme (SAE) inhibitor in combination with checkpoint inhibitors, such as anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies, to enhance immune response and target cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If checkpoint inhibitors are used as first line treatment for advanced NSCLC, then overall survival is improved, but the disease is incurable and will eventually progress
Solution Approach 1:
The patent combines checkpoint inhibitors with Type I interferon pathway activators in a single treatment regimen. This combination merges the immune checkpoint blocking mechanism with interferon-mediated immune activation, creating a synergistic effect that both improves overall survival and extends duration of response by reinvigorating pre-existing immune responses and initiating new antitumor immune responses simultaneously
Solution Approach 2:
The treatment approach uses a composite therapeutic strategy combining multiple mechanisms of action: checkpoint inhibition (anti-PD-1, anti-PD-L1, anti-CTLA-4) with Type I interferon pathway activation. This composite approach addresses both the immediate need for survival benefit and the long-term need for durable response by integrating two complementary immunotherapy mechanisms
2Reliability
If targeted therapies are used for molecularly defined NSCLC, then treatment effectiveness is improved, but these therapies are ineffective in patients whose tumors lack specific genetic alterations
Solution Approach 1:
The patent employs checkpoint inhibitors that can be applied universally across different patient subgroups regardless of specific genetic alterations. These inhibitors target conserved immune checkpoint molecules (PD-1, PD-L1, CTLA-4) that are expressed on tumor cells and immune cells across various cancer types, making the therapy effective both in molecularly defined NSCLC and in patients whose tumors lack specific driver mutations
Solution Approach 2:
The treatment strategy changes the therapeutic parameter from targeting specific tumor-derived mutations to targeting conserved immune checkpoint pathways. This parameter change enables the therapy to work across diverse tumor types and patient subgroups by focusing on the immune system's response to cancer rather than specific tumor genetics
3Reliability
If combination therapy with SAE inhibitor and checkpoint inhibitor is administered, then treatment efficacy and patient survival are improved, but treatment complexity increases
Solution Approach 1:
The patent merges the administration of SAE inhibitor and checkpoint inhibitor into a coordinated combination therapy protocol. By combining these two agents with complementary mechanisms of action (SUMOylation inhibition and immune checkpoint blocking), the treatment achieves enhanced efficacy while managing complexity through integrated dosing schedules and monitoring protocols
Data Source
AI summary
The present disclosure provides methods, pharmaceutical compositions, and kits for treating cancer in patients in need thereof. The methods comprise administering to a patient in need a small ubiquitin-like modifier (SUMO) activating enzyme (SAE) inhibitor, such as [(1R,2S,4R)-4-{[5-({4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate or a pharmaceutically acceptable salt, in combination with one or more checkpoint inhibitors. Also provided are medicaments for use in treating cancer.