PI3Kδ Isoform Therapy Combining Idelalisib and SRPIN340
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Solution Overview
Problem
Existing treatments for endocrine and solid tumors are hindered by the overexpression of PI3Kδ-S, which confers drug resistance and is exempt from PTEN regulation, necessitating a novel therapeutic approach.
Innovation Solution
Combining the PI3Kδ inhibitor Idelalisib with the SRPK1/2 inhibitor SRPIN340 to target and inhibit PI3Kδ-S, reversing aberrant mRNA splicing and synergistically reducing tumor cell viability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PI3Kδ inhibitor Idelalisib is used to treat tumors, then AKT/mTOR signaling is inhibited, but tumor cells with PI3Kδ-S overexpression develop drug resistance
Solution Approach 1:
The patent segments the therapeutic approach into two distinct components: a PI3Kδ inhibitor (idelalisib) and an SRPK1/2 inhibitor (SRPIN340). This segmentation allows each agent to target specific aspects of the PI3Kδ-S mediated resistance mechanism, with idelalisib inhibiting PI3Kδ-L and SRPIN340 reversing the aberrant splicing to convert PI3Kδ-S back to the drug-sensitive PI3Kδ-L form.
Solution Approach 2:
SRPIN340 acts as an intermediary that modifies the splicing machinery (SRPK1/2 kinases) to convert the resistant PI3Kδ-S isoform back into the sensitive PI3Kδ-L isoform. This intermediary action restores the tumor cells' susceptibility to idelalisib, effectively mediating the reversal of drug resistance.
2Adaptability or versatility
If SRPK1/2 inhibitor SRPIN340 is used to reverse aberrant splicing, then PI3Kδ-S is converted to PI3Kδ-L, but single agent therapy is insufficient for complete inhibition
Solution Approach 1:
The patent merges two therapeutic agents with complementary mechanisms of action: SRPIN340 (which reverses splicing to convert PI3Kδ-S to PI3Kδ-L) and idelalisib (which inhibits PI3Kδ-L). This combination ensures both the conversion of resistant isoforms and the inhibition of the resulting sensitive isoforms, achieving complete therapeutic efficacy that neither agent can achieve alone.
Solution Approach 2:
SRPIN340 performs a preliminary action by reversing the aberrant splicing and converting PI3Kδ-S back to PI3Kδ-L before idelalisib can effectively inhibit the pathway. This preliminary splicing reversal creates the necessary condition for idelalisib to exert its full inhibitory effect on AKT/mTOR signaling.
Data Source
AI summary
PI3Kδ implicates hematologic cancers and solid tumors. Alternative splicing is a post-transcriptional process for acquiring proteomic diversity in eukaryotic cells. Emerging evidence highlights the involvement of aberrant mRNA splicing in cancer development/progression. PI3Kδ-L and PI3Kδ-S are overexpressed in advanced solid tumors, such as prostate, breast, colon, lung and pancreatic cancers. Differential PI3Kδ and PI3Kδ-S expression profiles were identified in a panel of solid tumor cells. PI3Kδ inhibitor Idelalisib and SRPK1/2 inhibitor SRPIN340 were employed to assess their efficacies on inhibiting the PI3Kδ-expressing solid tumors. Idelalisib effectively inhibits PI3Kδ-L and its downstream signaling. Idelalisib fails to inhibit PI3Kδ-S activity and its downstream signaling. SRPIN340 reverses the aberrant mRNA splicing, thereby inhibiting the downstream AKT/mTOR signaling. In vitro functional assays further demonstrate that a combination of Idelalisib and SRPIN340 achieve a synergistic drug effect, with drastically reduced cell viabilities/growths of tumor spheroids, in inhibiting the advanced tumor cells.