Methods and systems for determining oncogenic index of patient specific mutations
Inventors
Tarcic, Gabi • Altschuler, Yoram • VIDNE, Michael
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11015229-B2
Publication Date
2021-05-25
Expiration Date
Abstract
Methods for determining various oncogenic-related indexes of patient specific mutations are provided. The methods provided allow determination and grading of various patient specific mutations and qualitative and quantitative determination of various related oncogenic indexes.
Core Innovation
The invention provides a method of generating a curative index indicative of susceptibility to drug treatment of one or more patient specific mutations. An addressable array is formed with a first set of expression constructs harboring genes comprising one or more patient specific mutations and a second set of expression constructs of corresponding wild type genes. Viable assay cells are added to each locus under conditions enabling expression and co-expression of a Fluorescence Translocation Reporter (FTR) linked to a target gene portion.
The method compares the subcellular localization and/or translocation of the FTR in assay cells expressing the mutant genes with assay cells expressing the corresponding wild type gene to identify disparate localization/translocation results in the absence of a drug. A degree of subcellular translocation is determined for the mutant-expressing cells and normalized with respect to the degree of subcellular translocation in the corresponding wild type expressing cells to obtain a normalized activation level in the absence of a drug.
A drug is added and the normalized activation level is determined in the presence of the drug by repeating the normalization step. The method analyzes a correlation between the normalized activation level with the drug, the normalized activation level without the drug, and a clinical outcome of response to treatment. The correlation between the normalized activation level in the presence of the drug and response to treatment represents the curative index of the drug.
Claims Coverage
Independent claim clm-00001 defines the full pipeline for generating a curative index using patient-specific mutations, a Fluorescence Translocation Reporter (FTR), normalization versus corresponding wild type, and correlation with clinical response. The dependent claims refine the drug category, allow multi-drug regimens, constrain expression construct and promoter forms, restrict step ordering, and expand analyzing to machine learning and specified statistical/ML techniques.
Curative index generation by normalized FTR translocation correlation with response
Comparing subcellular localization and/or translocation of Fluorescence Translocation Reporter (FTR) in assay cells expressing patient specific mutations versus corresponding wild type genes, determining degree of translocation and normalizing to obtain a normalized activation level without drug and with drug, then analyzing a correlation between normalized activation levels and a clinical outcome of response to treatment, wherein the correlation in the presence of the drug represents the curative index of the drug.
Anti-cancer drug susceptibility curative index
The method of claim 1 in which the drug used is an anti-cancer drug.
Multi-drug regimen for curative index
The method of claim 1 comprising adding more than one drug, either concomitantly or sequentially, optionally using varying concentrations of the drug(s).
Expression constructs and promoter regulation constraints
The method of claim 1 in which the first and/or second expression constructs include double stranded linear DNA and/or use inducible or constitutive promoters.
Procedural step ordering constraint
The method of claim 1 in which step c) occurs before step a) and/or before step b).
Machine learning and named statistical/ML analysis for correlation
The method of claim 1 in which the analyzing step uses machine learning and one or more of correlation univariate analysis, multivariate analysis, support vector machines, or generalized linear models.
Overall, the claims cover generating a curative index by measuring FTR subcellular localization/translocation differences between patient-specific mutation constructs and corresponding wild type constructs, normalizing activation levels in the absence versus presence of a drug, and correlating these normalized levels with clinical response; dependent claims further narrow the drug to anti-cancer drugs, permit multi-drug and concentration-varying regimens, constrain expression construct/promoter forms, specify step ordering, and expand analysis to machine learning and specified correlation/statistical models.
Stated Advantages
Generates a curative index indicative of susceptibility to drug treatment based on correlation with clinical outcome of response to treatment.
Documented Applications
Curative index generation to indicate susceptibility to drug treatment of one or more patient specific mutations and correlate normalized activation with clinical response to the drug.
Interested in licensing this patent?