ABCB1 genotyping to predict microtubule-stabilizing-agent-induced toxicity
Inventors
Figg, William D. • Mross, Klaus • Behringer, Dirk • Sparreboom, Alex • Sissung, Tristan • Mielke, Stephan
Assignees
ZFT UNIVERSITAET FREIBURG • ZFT UNIVERSITAT FREIBURG • Universitaetsklinikum Freiburg • US Department of Health and Human Services
Publication Number
US-8835115-B2
Publication Date
2014-09-16
Expiration Date
2027-07-13
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Abstract
The present disclosure provides methods of identifying subjects having an increased likelihood of developing one or more adverse side effects resulting from administration of a microtubule-stabilizing agent. In particular examples, the method includes determining whether the subject has an ABCB1 predictive polymorphism for microtubule-stabilizing agent-induced toxicity, wherein the presence of such a polymorphism indicates that the subject has an increased risk of developing microtubule-stabilizing agent induced adverse effects. Examples of ABCB1 predictive polymorphisms include 2677G>T/A and 3435C>T. Also provided are methods of modifying microtubule-stabilizing agent therapy in a subject identified as having one or more ABCB1 predictive polymorphisms. Kits and isolated nucleic acid molecules that can be used in the disclosed methods are also provided.
Core Innovation
The invention provides methods for identifying subjects who have an increased likelihood of developing adverse side effects, such as neutropenia and peripheral neuropathy, resulting from the administration of microtubule-stabilizing agents, including taxanes and epothilones. This is achieved by determining the presence of predictive polymorphisms in the ABCB1 gene, such as 2677G>T/A and 3435C>T, where the presence of these polymorphisms indicates an increased risk of adverse effects. The methods also include modifying microtubule-stabilizing agent therapy in subjects identified with these polymorphisms to reduce the occurrence or severity of side effects.
The problem being addressed is the significant adverse effects caused by taxane treatment, including severe hypersensitivity reactions, neutropenia, and peripheral neuropathy, which remain challenges to optimal treatment despite optimized dosing and premedication. Since ABCB1 plays a key role in drug elimination and distribution and is expressed in tissues including those that protect peripheral nerves, polymorphisms in ABCB1 may affect drug toxicity. Therefore, there is a need for methods to identify individuals at increased risk for these side effects prior to commencement of treatment to improve safety and efficacy.
Claims Coverage
The claims include two independent methods focused on ABCB1 genotyping to identify subjects at increased risk of microtubule-stabilizing-agent-induced adverse effects and methods to decrease these adverse effects by modifying treatment accordingly. There are 14 inventive features extracted from these claims.
Method for identifying increased risk of adverse effects based on ABCB1 polymorphisms
A method of amplifying DNA from a subject with a tumor treatable by microtubule-stabilizing agents, determining if the subject has both the 2677G>T (Ala893Ser) and 3435C>T predictive polymorphisms in the ABCB1 gene using specified primer sequences, and identifying the subject as at increased risk for neutropenia and peripheral neuropathy compared to subjects lacking these polymorphisms.
Identification of microtubule-stabilizing agent classes linked to risk
The microtubule-stabilizing agent used in the identification method can be an epothilone, specifically ixabepilone, or a taxane, including paclitaxel, docetaxel, or a paclitaxel analog.
Determination of subject disease sensitivity and administration of treatment
The subject has a disease sensitive to effective amounts of microtubule-stabilizing agents, and the method may include administrating a therapeutically effective amount of such agents, potentially less than 100 mg/m2.
Sample source for DNA isolation
The method includes obtaining a blood or plasma sample from the subject and isolating DNA from it for determination of ABCB1 polymorphisms.
Method for decreasing occurrence of adverse effects based on ABCB1 genotype
A method of amplifying DNA and determining if a subject has the 2677G>T (Ala893Ser) and 3435C>T polymorphisms and modifying the administration of a microtubule-stabilizing agent to decrease neutropenia and peripheral neuropathy in the subject.
Modifications to microtubule-stabilizing agent administration to reduce adverse effects
The administration modification includes decreasing the amount of agent given, increasing the interval between doses, increasing the dosing schedule duration, administering a therapeutically effective amount of a colony-stimulating factor, or combinations thereof.
Use of colony-stimulating factors to mitigate neutropenia
The colony-stimulating factor can be granulocyte colony-stimulating factor (G-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF).
Alterations to dosage and timing for treatment optimization
Treatment modifications include decreasing dosage, altering timing of administration, increasing dosing schedule, or combinations thereof to reduce adverse effects.
The claims cover methods for genotyping ABCB1 polymorphisms 2677G>T and 3435C>T in subjects to identify increased risk of microtubule-stabilizing-agent-induced neutropenia and peripheral neuropathy, use of this information to modify treatment regimens including dose and schedule adjustments, and administration of colony-stimulating factors to reduce toxicity.
Stated Advantages
Enables identification of subjects at increased risk for adverse effects from microtubule-stabilizing agents prior to treatment.
Allows modification of treatment regimens to reduce incidence and severity of adverse effects such as neutropenia and peripheral neuropathy.
Documented Applications
Screening human subjects who are candidates for treatment with microtubule-stabilizing agents to identify increased risk of drug-induced adverse effects.
Modifying chemotherapy regimens including dose reduction, altered scheduling, or adjunct CSF administration based on ABCB1 genotype to minimize adverse effects.
Use with various microtubule-stabilizing agents such as taxanes (paclitaxel, docetaxel) and epothilones (ixabepilone) in treating cancers including breast, ovarian, lung, prostate, bladder, esophageal, head and neck, and kidney cancers.
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