Individualized cancer therapy

Inventors

Shanahan, David • Nemunaitis, John • Senzer, Neil • Maples, Phillip • Rao, Donald

Assignees

Gradalis Inc

Abstract

In certain embodiments, the invention provides methods for treating cancer, comprising: (a) obtaining a specimen of cancer tissue and normal tissue from a patient; (b) extracting total protein and RNA from the cancer tissue and normal tissue; (c) obtaining a protein expression profile of the cancer tissue and normal tissue; (d) identifying over-expressed proteins in the cancer tissue; (e) comparing the protein expression profile to a gene expression profile; (f) identifying at least one prioritized protein target by assessing connectivity of each said over-expressed protein to other cancer-related or stimulatory proteins; (g) designing a first RNA interference expression cassette to modulate the expression of at least one gene encoding the prioritized target protein; (h): designing a first RNA interference expression cassette to modulate the expression of at least one gene encoding a protein of higher priority in the signaling pathway in which the first protein is a component; (i) incorporating the first cassette into a first delivery vehicle; (j) providing a patient with an effective amount of the first delivery vehicle; (k) extracting total protein and RNA from the treated cancer tissue; (l) identifying over-expressed proteins in the treated cancer tissue; (m) designing a second RNA interference expression cassette to modulate the expression of a second prioritized protein in the treated tissue; (n) incorporating the second cassette into a second delivery vehicle; (o) providing the previously treated patient with an effective amount of the second delivery vehicle; (p) identifying a novel protein signal following prior treatment with protein specific knockdown; (q) identifying a gene mutation provided by gene sequencing/microarray on assessment of other protein signals; and (r) identifying of a novel protein signal as a result of determination of the gene mutation and assessment of other protein signals to, directly or indirectly, modify the expression (i.e., production) of such proteins.

Core Innovation

The patent describes an individualized cancer therapy method for a patient having at least one cancer recurrence. The method obtains a specimen of cancer tissue and normal tissue from the patient, extracts total protein and total RNA from both cancer and normal tissue, and obtains a protein expression profile of the cancer tissue and normal tissue. Over-expressed proteins in the cancer tissue are identified.

The method compares the protein expression profile to a gene expression profile and identifies at least one prioritized protein target from the gene expression profile. An RNA interference expression cassette is designed to modulate the expression of at least one gene encoding the prioritized protein target. The RNA interference expression cassette is a single contiguous bifunctional RNA molecule that comprises a first double stranded sequence and a second double stranded sequence with defined complementary relationships to target mRNA transcripts and a mismatched passenger strand.

The bifunctional RNA molecule activates cleavage-dependent and cleavage-independent RNA-induced silencing complex to reduce the expression level of the target gene. The RNA interference expression cassette is incorporated into a delivery vehicle, and the patient is provided with an effective amount of the delivery vehicle to treat the cancer.

Claims Coverage

The independent claim is directed to an individualized cancer therapy method. The main inventive features include paired cancer/normal tissue profiling, target prioritization based on comparing protein and gene expression profiles, and a bifunctional contiguous RNA interference expression cassette designed to activate both cleavage-dependent and cleavage-independent RNA-induced silencing complex, followed by delivery via a delivery vehicle in an effective amount.

Across the independent claim, the core coverage centers on individualized therapy using paired cancer and normal tissue protein and gene expression profiling to identify over-expressed proteins and prioritized protein targets, and on delivering a single contiguous bifunctional RNA interference expression cassette that activates cleavage-dependent and cleavage-independent RNA-induced silencing complex to reduce target gene expression.

Stated Advantages

Documented Applications