Provided herein are Compositions and Methods of Generating Novel amiRNA's. Provided herein are methods for producing or generating one or more amiRNAs; also provided are constructs and compositions useful in the methods. The methods and constructs provided in this disclosure are highly efficient methods for production of a new generation of amiRNAs.

PI3K 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. PI3K-L and PI3K-S are overexpressed in advanced solid tumors, such as prostate, breast, colon, lung and pancreatic cancers. Differential PI3K and PI3K-S expression profiles were identified in a panel of solid tumor cells. PI3K inhibitor Idelalisib and SRPK1/2 inhibitor SRPIN340 were employed to assess their efficacies on inhibiting the PI3K-expressing solid tumors. Idelalisib effectively inhibits PI3K-L and its downstream signaling. Idelalisib fails to inhibit PI3K-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.