CCK2R-Targeted Conjugates for Resistant Tumor Imaging and Therapy
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Solution Overview
Problem
Existing cancer treatments targeting the cholecystokinin B receptor (CCK2R) are limited by the presence of constitutively active splice variants and multiple genetic mutations, leading to drug resistance and inadequate tumor suppression.
Innovation Solution
Development of benzazepine compounds conjugated with therapeutic or imaging agents via linkers to selectively target CCK2R and its splice variant CCK2i4svR, allowing for targeted delivery and action within tumor cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CCK2R-targeting therapeutic agents are used, then tumor suppression is improved, but drug resistance occurs due to constitutively active splice variants and multiple genetic mutations
Solution Approach 1:
The invention segments the therapeutic approach by using different agents targeting distinct pathways: CCK2R antagonists block gastrin signaling, while Hedgehog pathway inhibitors (such as cyclopamine, berberine, or vismodegib) block Hh signaling. This multi-pathway segmentation prevents tumors from developing resistance through a single mechanism, as both CCK2R and Hedgehog pathways must remain susceptible for tumor survival.
Solution Approach 2:
The invention employs composite therapy by combining CCK2R-targeting agents with Hedgehog pathway inhibitors in a single treatment regimen. This composite approach creates synergistic effects where the two agents work together to suppress tumor growth more effectively than either agent alone, while also preventing the development of resistance mechanisms that would affect only one pathway.
2Ease of operation
If CCK2R antagonists are used alone, then treatment simplicity is maintained, but anti-tumor activity is insufficient due to multiple genetic mutations and compensatory mechanisms
Solution Approach 1:
The invention merges two distinct therapeutic agents into a combination regimen: CCK2R antagonists (such as L364,718 or devazepide) and Hedgehog pathway inhibitors. This merging of therapies creates a unified treatment approach that addresses multiple oncogenic pathways simultaneously, overcoming the limitations of monotherapy while maintaining a relatively simple administration protocol.
3Object-affected harmful factors
If polar compounds are used to target CCK2R, then normal brain tissue is protected by the blood brain barrier, but delivery to tumor tissue may be limited
Solution Approach 1:
The invention uses the blood-brain barrier itself as an intermediary mechanism to achieve selective delivery. By designing polar CCK2R-targeting compounds, the blood-brain barrier acts as a natural filter that blocks these compounds from reaching normal brain tissue while allowing them to accumulate in tumor tissues that express CCK2R, particularly in cancers such as medullary thyroid cancer, small cell lung cancer, and pancreatic cancer where the receptor is overexpressed.
Data Source
AI summary
Conjugates are described herein where CCK2R targeting ligands are attached to an active moiety, such as therapeutic agent or an imaging agent, through a linker. The conjugates can be used in the detection, diagnosis, imaging and treatment of cancer.