Individualized cancer therapy
Inventors
Shanahan, David M. • Nemunaitis, John J. • Senzer, Neil • Maples, Phillip B. • Rao, Donald
Assignees
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Publication Number
US-9914977-B2
Publication Date
2018-03-13
Expiration Date
Abstract
In certain preferred embodiments, the invention provides methods for treating cancer, which comprise (a) obtaining a specimen of cancer tissue from a patient; (b) obtaining a specimen of normal tissue in the proximity of the cancer tissue from such patient; (c) extracting total protein and RNA from the cancer tissue and normal tissue; (d) obtaining a protein expression profile of the cancer tissue and normal tissue using 2D DIGE and mass spectrometry; (e) identifying proteins that are expressed in such cancer tissue at significantly different levels than in the normal tissue; (f) obtaining a gene expression profile of the cancer tissue and normal tissue using microarray technology and comparing the results thereof to the protein expression profile; (g) prioritizing over-expressed proteins by assessing the connectivity thereof to other cancer-related or stimulatory proteins; (h) designing an appropriate RNA interference expression cassette to, directly or indirectly, modulate the expression of genes encoding such prioritized proteins; (i) incorporating said cassette into an appropriate delivery vehicle; and (j) providing the patient with an effective amount of the delivery vehicle to, directly or indirectly, modify the expression (i.e., production) of such proteins.
Core Innovation
The invention describes a method for treating cancer in an individual in need thereof by administering an RNA interference expression vector. The vector comprises a nucleic acid insert encoding first and second RNA stem loop structures, each with guide sequences and passenger sequences configured for targeting a Target Gene. The guide sequences hybridize with an mRNA transcript of the Target Gene, while the passenger sequences are fully complementary or partially complementary, respectively.
The Target Gene is identified using patient-specific tissue comparison. Total protein and RNA are extracted from a cancer tissue and a normal tissue obtained from a patient, and a protein expression profile and a gene expression profile are obtained for both tissues. Over-expressed proteins and over-expressed genes are identified in the cancer tissue as compared to the normal tissue by comparing the respective profiles.
Biological network pathways are then analyzed to identify one or more prioritized proteins, followed by selecting a Target Gene from the prioritized proteins. The disclosed framework integrates expression profiling from patient tissues with pathway-based prioritization to drive selection of the Target Gene that the RNA interference expression vector targets.
Claims Coverage
The independent claim covers a treating-cancer method combining patient-specific selection of a Target Gene from cancer vs normal tissue protein and gene expression profiles and administration of an RNA interference expression vector encoding two RNA stem loop structures. Dependent refinements specify example Target Genes, quantitative over-expression thresholds, pathway analysis using probabilistic causal modeling, narrower protein-profiling methods, and an assessment step for suppressive capability in transfected cells.
RNA interference expression vector with two RNA stem loop structures targeting a Target Gene
Administering to the individual an RNA interference expression vector comprising a nucleic acid insert encoding a first RNA stem loop structure with a first guide sequence and a first passenger sequence fully complementary to the first guide sequence, and a second RNA stem loop structure with a second guide sequence and a second passenger sequence partially complementary to the second guide sequence, where the guide sequences are capable of hybridizing with an mRNA transcript of a Target Gene.
Patient-specific identification of a Target Gene using cancer-versus-normal protein and gene expression profiles
Identifying the Target Gene by extracting total protein and RNA from a cancer tissue and a normal tissue obtained from a patient; obtaining a protein expression profile and a gene expression profile of the cancer tissue and the normal tissue; comparing the protein expression profile to identify one or more over-expressed proteins in the cancer tissue as compared to the normal tissue; and comparing the gene expression profile to identify one or more over-expressed genes in the cancer tissue as compared to the normal tissue.
Pathway-based prioritization of proteins from over-expressed proteins and over-expressed genes
Analyzing biological network pathways of the over-expressed proteins and the over-expressed genes to identify one or more prioritized proteins, and selecting a Target Gene from the prioritized proteins.
Probabilistic causal network inference for pathway analysis
Analyzing biological network pathway(s) using a network inference software platform that builds a probabilistic causal model from over-expressed proteins, over-expressed genes, or both to identify one or more prioritized proteins.
Protein expression profiling using 2D DIGE and mass spectrometry
Obtaining a protein expression profile using 2D DIGE and mass spectrometry.
Selection of a Target Gene from prioritized proteins exemplified by RACK1, Syntenin, or Stathmin 1
Selecting the Target Gene from the prioritized proteins, where the Target Gene is one of RACK1, Syntenin, or Stathmin 1.
The claim coverage centers on administering an RNA interference expression vector with two RNA stem loop structures targeting a Target Gene selected through patient-specific extraction and comparative profiling of cancer versus normal tissue, followed by biological network pathway analysis to prioritize proteins and select the Target Gene.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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