Methods based on the detection of RAD51 foci in tumor cells
Inventors
Serra Elizalde, Violeta • BALMAÑA GELPI, Judith • CRUZ ZAMBRANO, Cristina • LLOP GUEVARA, Alba • CASTROVIEJO BERMEJO, Marta • O'Connor, Mark J. • JONES, Gemma Nicole
Assignees
Fundació Privada Institut d'Investigació Oncològica Vall-Hebron • Xentech Sas • AstraZeneca UK Ltd
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Publication Number
US-12007393-B2
Publication Date
2024-06-11
Expiration Date
Abstract
The invention provides a method allowing to determine whether a subject diagnosed with cancer is sensitive or resistant to an anti-cancer treatment, based on the level of cells with RAD51 foci in a sample containing tumor cells isolated from said subject, wherein the subject has not received at 24 hours prior to the isolation of the sample, a chemotherapy selected from the group consisting of AC, FEC, ECF and navelbine/epirubicin, and wherein the sample has not been treated with a method that induces DNA damage before determining the level of cells with RAD51 foci.
Core Innovation
The invention relates to a method for the treatment of a cancer in a subject in need thereof by administering a therapeutically effective amount of a PARP inhibitor agent. The subject is identified as a responder to the PARP inhibitor agent using a method that predicts the response of a subject diagnosed with cancer to the PARP inhibitor agent. The prediction includes determining the level of cells with RAD51 foci in a sample containing tumor cells isolated from the subject.
Prior to determining the level of cells with RAD51 foci, the subject has not received within 24 hours prior to the isolation of the sample a chemotherapy selected from AC, FEC, ECF and navelbine/epirubicin. The sample has also not been treated with a method that induces DNA damage before determining the level of cells with RAD51 foci. The level obtained is compared to a reference value to predict responder versus non-responder status.
A level of cells with RAD51 foci lower than the reference value indicates that the subject is predicted to respond to the PARP inhibitor agent, while a level of cells with RAD51 foci equal to or higher than the reference value indicates that the subject is predicted not to respond. The RAD51-foci level is used to link tumor cell RAD51 foci measurements to patient response prediction for PARP inhibitor agent treatment.
The document further refines how the RAD51-foci level is determined relative to cell-count reference groups and how proliferating cells and DNA-damage-related cells are identified using specific markers. Additional refinements specify markers such as Geminin, KI-67, Proliferating cell nuclear antigen, Cyclin A2 for proliferating cells and nuclear γH2AX, pRPA, 53BP1, MRE11 for cells showing double-strand DNA breaks. These refinements support the RAD51-foci-based comparison to reference value as the basis for treatment selection.
Claims Coverage
The document provides one independent claim, supported by dependent claims that refine the prediction and treatment method. The independent claim includes three inventive features: RAD51-foci-based prediction, constrained subject/sample conditions, and comparison of RAD51-foci level to a reference value to determine responder status prior to PARP inhibitor treatment.
Treatment guided by RAD51-foci responder prediction
A method for the treatment of a cancer in a subject comprising administration of a therapeutically effective amount of a PARP inhibitor agent, wherein the subject has been identified as responder by a method predicting response to the PARP inhibitor agent comprising determining the level of cells with RAD51 foci in a sample containing tumor cells isolated from said subject and comparing the level to a reference value.
Subject and sample constraints before RAD51-foci determination
Determining the level of cells with RAD51 foci in a sample containing tumor cells isolated from the subject wherein the subject has not received, within 24 hours prior to the isolation of the sample, a chemotherapy selected from AC, FEC, ECF and navelbine/epirubicin, and wherein the sample has not been treated with a method that induces DNA damage before determining the level of cells with RAD51 foci.
Reference-value comparison defining responder versus non-responder
Comparing the level obtained with a reference value, wherein a level of cells with RAD51 foci lower than the reference value indicates predicted response to the PARP inhibitor agent and a level of cells with RAD51 foci equal or higher than the reference value indicates predicted not to respond to the PARP inhibitor agent.
Overall claim coverage focuses on using RAD51 foci levels in tumor-cell samples under specified pre-isolation constraints and without DNA-damage induction of the sample, then classifying subjects as responders or non-responders by comparing the measured RAD51 foci level to a reference value prior to administering a PARP inhibitor agent.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Personalized therapy selection for a cancer in a subject using RAD51-foci-based identification of responders to a PARP inhibitor agent.
Patient cohort classification into predicted responders versus predicted non-responders for PARP inhibitor agent treatment based on comparing RAD51 foci levels to a reference value.
Prediction of HRR capability (HRR proficiency/deficiency) and linkage to PARPi sensitivity/resistance as supported by RAD51-foci level comparisons to a reference/cut-off described in the document.
Use of medicaments/kit incorporating RAD51-recognizing antibodies for the RAD51-foci-based prediction approach described in the document.
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