Aptamer-Antisense Composition for Targeted KRAS Inhibition in PDAC
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Solution Overview
Problem
Pancreatic ductal adenocarcinoma (PDAC) has limited treatment options, with activating KRAS mutations being prevalent in over 90% of cases, necessitating new therapies targeting the RAS genes and proteins that regulate Ras activity.
Innovation Solution
Compositions comprising RNA aptamers and antisense oligonucleotides are developed to target pancreatic cancer cells, inhibiting key signaling pathways like KRAS-RAF-MEK-ERK and RTK-RAS-ERK by delivering antisense oligonucleotides selectively to inhibit KRAS and SOS1 mRNA expression, using chemically modified aptamers and linkers to enhance specificity and reduce off-target effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional chemotherapy is used to treat pancreatic ductal adenocarcinoma, then tumor growth may be inhibited, but toxicity to normal cells and limited treatment options persist
Solution Approach 1:
The treatment approach is segmented into two distinct functional components: an aptamer for selective targeting of pancreatic cancer cells and an antisense oligonucleotide for specific mRNA inhibition. This segmentation allows the therapeutic agent to concentrate its action on cancer cells while sparing normal cells, thereby reducing toxicity while maintaining efficacy.
Solution Approach 2:
The aptamer component provides local quality by conferring cell-type specificity to the treatment. Through aptamer sequences selected for binding to surface markers on pancreatic ductal adenocarcinoma cells, the therapy achieves localized action at the cancer cell surface, enabling selective delivery of the antisense oligonucleotide payload to the intended target while avoiding damage to normal cells.
2Adaptability or versatility
If KRAS mutations are targeted in over 90% of PDAC cases, then a prevalent dependency is addressed, but the need for new therapies targeting RAS genes and regulating proteins arises
Solution Approach 1:
The antisense oligonucleotide mechanism provides universality by targeting the mRNA level rather than requiring mutation-specific binding. The same general mechanism can be adapted to target different KRAS mutations (G12C, G12V, G12D, G12A) and even wild-type KRAS by simply changing the oligonucleotide sequence, making the approach universally applicable to over 90% of PDAC cases without requiring fundamentally different therapeutic strategies.
Solution Approach 2:
The aptamer serves as an intermediary that bridges the gap between systemic administration and cell-specific action. By binding to surface markers on pancreatic cancer cells, the aptamer mediates selective uptake and delivery of the antisense oligonucleotide to the cytoplasm of target cells, simplifying the overall therapeutic mechanism while achieving high specificity.
3Quantity of substance
If antisense oligonucleotides are delivered systemically, then broad coverage is achieved, but off-target effects increase
Solution Approach 1:
The aptamer and antisense oligonucleotide are merged into a single conjugate molecule, combining the targeting function of the aptamer with the therapeutic function of the antisense oligonucleotide. This merging ensures that the antisense oligonucleotide is delivered systemically with broad coverage but is released and activated only at the specific target of pancreatic cancer cells, thereby maintaining both distribution coverage and targeting precision.
Solution Approach 2:
The aptamer performs preliminary action by binding to and accumulating at the surface of pancreatic cancer cells before the antisense oligonucleotide is released and exerts its inhibitory effect on KRAS or SOS1 mRNA. This preliminary targeting step ensures that subsequent antisense oligonucleotide activity is concentrated at the correct location, preventing off-target effects while maintaining broad systemic coverage.
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 compositions effectively inhibit pancreatic cancer cell proliferation by specifically targeting and downregulating KRAS and SOS1, offering a potential therapeutic approach with reduced toxicity to normal cells.
Implementation Method 1
antisense oligonucleotides that inhibit the expression of an mRNA
Data Source
AI summary
In the various aspects and embodiments, the present disclosure provides compositions and methods for treating pancreatic cancer (e.g., pancreatic ductal adenocarcinoma, or PDAC). In accordance with aspects of the disclosure, the composition comprises an aptamer that targets accumulation of the composition to pancreatic cancer cells, and an antisense oligonucleotide that inhibits the expression of an mRNA associated with key signaling pathways that promote proliferation or survival in pancreatic cancer cells, such as the KRAS-RAF-MEK-ERK signaling pathway or RTK-RAS-ERK cascade. Exemplary antisense oligonucleotides described herein target KRAS, including mutant KRAS. Exemplary antisense oligonucleotides described herein target SOS1 and/or SOS2 transcripts.