Individualized cancer therapy
Inventors
Shanahan, David M. • Nemunaitis, I, John J. • Senzer, Neil • Maples, Phillip B. • Rao, Donald
Assignees
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Publication Number
US-9528991-B2
Publication Date
2016-12-27
Expiration Date
Abstract
In certain embodiments, the invention provides methods for treating cancer, comprising: obtaining a specimen of cancer tissue and normal tissue from a patient; extracting total protein; obtaining a protein expression profile; identifying over-expressed proteins; comparing the protein expression profile to a gene expression profile; identifying at least one prioritized protein target; designing a first RNA interference expression cassette; designing a first RNA interference expression cassette to modulate the expression of at least one gene encoding; incorporating the first cassette into a delivery vehicle; and providing a patient with an effective amount of the first delivery vehicle.
Core Innovation
The invention provides a method for treating cancer by obtaining a specimen of cancer tissue and normal tissue from a patient and extracting total protein and RNA from the cancer tissue and the normal tissue. A protein expression profile of the cancer tissue and the normal tissue is obtained, and over-expressed proteins in the cancer tissue are identified.
The protein expression profile is compared to a gene expression profile, and at least one prioritized protein target is identified. The prioritized protein target is determined by assessing connectivity of each over-expressed protein, using protein connectivity for prioritization.
An RNA interference expression cassette is designed to modulate the expression of at least one gene encoding the prioritized target protein. The RNA interference expression cassette encodes one or more shRNA molecules, siRNA molecules, or shRNA molecules that direct the target RNA into both a cleavage-dependent RISC and a cleavage-independent RISC degradation pathway, and the RNA interference expression cassette is incorporated into a delivery vehicle.
A patient is provided with an effective amount of the delivery vehicle sufficient to treat the cancer. The approach includes individualized selection based on the patient’s cancer tissue and normal tissue specimens, and embodiments include incorporating a first RNA interference expression cassette into a first delivery vehicle and providing the patient with an effective amount to treat the cancer.
Claims Coverage
The document includes two independent claims (clm-00001 and clm-00014), each covering an individualized cancer-treatment workflow comprising paired cancer/normal tissue profiling, prioritization of protein targets via expression and connectivity, and delivery of an RNA interference expression cassette targeting prioritized genes through both cleavage-dependent and cleavage-independent RISC degradation pathways. Across the independent claims, the key inventive features are the paired proteomic/transcriptomic profiling and protein-target prioritization logic, combined with the specific RNA interference cassette design directing RNA into both RISC pathways, followed by incorporation into a delivery vehicle and administration of an effective amount.
Paired cancer/normal tissue proteomic and RNA profiling and over-expressed protein identification
Obtaining a specimen of cancer tissue and normal tissue from a patient; extracting total protein and RNA from the cancer tissue and normal tissue; obtaining a protein expression profile of the cancer tissue and normal tissue; identifying over-expressed proteins in the cancer tissue.
Protein target prioritization using gene expression comparison and connectivity
Comparing the protein expression profile to a gene expression profile; identifying at least one prioritized protein target; identifying at least one prioritized protein target by assessing connectivity of each over-expressed protein.
RNA interference expression cassette directing target RNA into both cleavage-dependent and cleavage-independent RISC pathways
Designing an RNA interference expression cassette to modulate the expression of at least one gene encoding the prioritized target protein, wherein the RNA interference expression cassette encodes one or more shRNA molecules, siRNA molecules, or shRNA molecules that direct the target RNA into both a cleavage-dependent RISC and a cleavage-independent RISC degradation pathway; designing a first RNA interference expression cassette to modulate the expression of at least one gene encoding the prioritized target protein with the same dual-pathway RISC routing.
Delivery vehicle incorporation and providing an effective amount to treat cancer
Incorporating the RNA interference expression cassette into a delivery vehicle; providing a patient with an effective amount of the delivery vehicle sufficient to treat the cancer; incorporating the first cassette into a first delivery vehicle; providing a patient with an effective amount of the first delivery vehicle sufficient to treat the cancer.
Both independent claims converge on the same inventive combination: paired cancer/normal tissue extraction and protein expression profiling to find over-expressed proteins, prioritization of protein targets (including connectivity-based prioritization), design of an RNA interference expression cassette that directs target RNA into both cleavage-dependent and cleavage-independent RISC degradation pathways, and delivery-vehicle-based administration of an effective amount to treat the cancer.
Stated Advantages
Documented Applications
No documented applications found
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