Compositions and methods for prediction of drug sensitivity, resistance, and disease progression
Inventors
Clark, Douglas P. • SCHAYOWITZ, Adam • Cabradilla, Cirilo D.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-9766249-B2
Publication Date
2017-09-19
Expiration Date
Abstract
The present invention is based on the discovery that functional stratification and/or signaling profiles can be used for diagnosing disease status, determining drug resistance or sensitivity of cancer cells, monitoring a disease or responsiveness to a therapeutic agent, and/or predicting a therapeutic outcome for a subject. Provided herein are assays for diagnosis and/or prognosis of diseases in patients. Also provided are compositions and methods that evaluate the resistance or sensitivity of diseases to targeted therapeutic agents prior to initiation of the therapeutic regimen and to monitor the therapeutic effects of the therapeutic regimen. Also provided are methods for determining the difference between a basal level or state of a molecule in a sample and the level or state of the molecule after stimulation of a portion of the live sample with a modulator ex vivo, wherein the difference is expressed as a value which is indicative of the presence, absence or risk of having a disease. The methods of the invention may also be used for predicting the effect of an agent on the disease and monitoring the course of a subject's therapy.
Core Innovation
The invention relates to determining the difference between a basal level or state of a class of proteins in a cell sample and the level or state of the proteins after contacting with a modulator. A first portion of the sample is contacted with a modulator ex vivo within a cartridge to evoke functional signaling profiles not found in the cells in vivo prior to contacting with the modulator, and a second portion is contacted with a control ex vivo within the cartridge prior to, simultaneously with, or following a therapeutic agent, therapeutic regimen, or course of therapy.
The difference is determined by using a computer, and the difference in the basal level or state of the proteins is expressed as a value by the computer to create functional signaling profiles that stratify the samples into functional groups. The proteins are protein post-translationally modified by a kinase, a phosphatase, or a proteolytic enzyme, and the approach is positioned as generating functional signaling profiles through ex vivo modulator contact and comparison to a control portion.
The modulator is an MBK inhibitor, mTor inhibitor, EGF receptor inhibitor, BRAF inhibitor or a combination thereof. The disclosed system emphasizes computer-based expression of the basal-versus-post-contact difference value to support functional grouping of samples and identification of at least two different groups of functional signaling profiles.
Claims Coverage
The independent claim recites a method for ex vivo functional stratification by computing a basal-versus-modulator difference value for protein levels or states, generating functional signaling profiles, and stratifying samples into functional groups. The claim includes four inventive features: cartridge-based ex vivo modulator versus control contacting, computer expression of the difference as values for functional signaling profiles, protein post-translational modification by kinase/phosphatase/proteolytic enzyme, and a specified modulator class.
Cartridge-based ex vivo modulator vs control contacting to evoke functional signaling profiles
Contacting a first portion of the sample with a modulator ex vivo within a cartridge to evoke functional signaling profiles not found in the cells in vivo prior to contacting with the modulator, and contacting a second portion with a control ex vivo within the cartridge prior to, simultaneously with, or following a therapeutic agent, therapeutic regimen, or course of therapy.
Computer-expressed basal-versus-post-contact difference value to create functional signaling profiles
Determining the difference by using a computer, wherein the difference in the basal level or state of the proteins is expressed as a value by the computer and is used to create functional signaling profiles that stratify the samples into functional groups.
Protein post-translational modification by kinase, phosphatase, or proteolytic enzyme
The protein is a protein post-translationally modified by a kinase, a phosphatase, or a proteolytic enzyme.
Specified modulator class for functional signaling profiling
The modulator is an MBK inhibitor, mTor inhibitor, EGF receptor inhibitor, BRAF inhibitor or a combination thereof.
The claim coverage centers on computing a basal-versus-modulator difference for a class of protein states or levels, using that computed value to create functional signaling profiles for stratification into functional groups, where the readout protein class is post-translationally modified by kinase, phosphatase, or proteolytic enzyme and the modulator is an MBK inhibitor, mTor inhibitor, EGF receptor inhibitor, or BRAF inhibitor, or a combination.
Stated Advantages
Creates functional signaling profiles that stratify samples into functional groups.
Uses a computer to express the difference in basal level or state as a value for generating functional signaling profiles.
Documented Applications
Diagnosing or prognosing disease using functional signaling profiles stratifying samples into functional groups.
Predicting drug sensitivity or drug resistance using functional signaling profiles created from basal-versus-modulator differences.
Stratifying responders versus non-responders using functional signaling profiles.
Monitoring a therapy course using control contacting with respect to a therapeutic agent, therapeutic regimen, or course of therapy.
Generating functional signaling profiles for samples derived from tumor or cell samples, including fine needle aspiration, biopsies, and circulating tumor cells.
Interested in licensing this patent?