# US 12,007,393 B2 · Methods based on the detection of RAD51 foci in tumor cells

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- Number: US 12,007,393 B2
- Document ID: US12007393B2
- Status: Granted
- Kind: B2
- Application number: 16/956,112
- Filed: 2018-12-21
- Published: 2020-10-08
- Granted: 2024-06-11
- Earliest claimed: 2017-12-21
- Assignees: Fundacio Privada Institut d'Investigacio Oncologica de Vall Hebron; AstraZeneca UK Limited; Xentech Co., Ltd
- Applicants: Fundació Privada Institut D'Investigació Oncològica De Vall Hebron; Astrazeneca UK Limited; Xentech SAS
- Inventors: Violeta Serra Elizalde; Judith Balmaña Gelpi; Cristina Cruz Zambrano; Alba Llop Guevara; Marta Castroviejo Bermejo; Mark J. O'Connor; Gemma Nicole Jones
- Web page: https://patentgrep.com/patent/US12007393B2

## CPC

- G01N 33/575: for cancer
- G01N 33/57545: of the ovaries
- A61K 31/166: having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
- A61K 31/407: condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
- A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/502: ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
- A61K 31/5025: ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K 31/551: having two nitrogen atoms, e.g. dilazep
- A61P 35/00: Antineoplastic agents
- G01N 33/5091: {for testing the pathological state of an organism}
- G01N 33/57515: of the breast
- G01N 33/57575: {involving oncogenic proteins}
- G01N 2333/916: acting on ester bonds (3.1), e.g. phosphatases (3.1.3), phospholipases C or phospholipases D (3.1.4)
- G01N 2800/52: Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim 1

A method for the treatment of a cancer in a subject in need thereof, the method comprising the administration to said subject of a therapeutically effective amount of a PARP inhibitor agent, wherein the subject has been identified as responder to said PARP inhibitor agent by a method for predicting the response of a subject diagnosed with cancer to the PARP inhibitor agent which comprises:
i) determining the level of cells with RAD51 foci in a sample containing tumor cells isolated from said subject wherein the subject has not received, within 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, and
ii) comparing the level obtained in step i) with a reference value, wherein:
a level of cells with RAD51 foci lower than said reference value indicates that the subject is predicted to respond to the PARP inhibitor agent, or
a level of cells with RAD51 foci equal or higher than said reference value, indicates that the subject is predicted not to respond to the PARP inhibitor agent.

### Claim 2 (depends on 1)

The method according to claim 1 wherein the PARP inhibitor agent is selected from the list consisting of olaparib, veliparib, niraparib, talazoparib, rucaparib, CEP-8983, E7016, BGB-290, and 3-aminobenzamide.

### Claim 3 (depends on 1)

The method according to claim 1 wherein the level of cells with RAD51 foci in the sample is determined as the relative level of cells with RAD51 foci with respect to:
the number of tumor cells in the sample,
the number of cells in the sample that are proliferating,
the number of cells in the sample that show DNA damage, and
the number of cells in the sample that are proliferating and that show DNA damage.

### Claim 4 (depends on 3)

The method according to claim 3 wherein the number of cells in the sample that are proliferating is determined by determining the expression of a protein selected from the list consisting of Geminin, KI-67, Proliferating cell nuclear antigen, Cyclin A2, and/or wherein the number of cells in the sample that show double strand DNA breaks is determined by the expression in the nucleus of a protein selected from the list consisting of γH2AX , replication protein A (pRPA), p53 Binding protein 1 (53BP1), double-strand break repair protein (MRE11).

### Claim 5 (depends on 4)

The method according to claim 4 wherein the number of cells in the sample that are proliferating is determined by determining the expression of Geminin, and wherein the number of cells in the sample that show double strand DNA breaks is determined by the expression in the nucleus of γH2AX .

### Claim 6 (depends on 1)

The method according to claim 1 wherein the subject from whom the sample has been isolated has received an anti-cancer treatment before the isolation of the sample, wherein the anti-cancer treatment is different from a chemotherapy selected from the group consisting of AC, FEC, ECF and navelbine/epirubicin if the patient has received the anti-cancer treatment within 24 hours prior to the isolation of the sample.

### Claim 7 (depends on 3)

The method according to claim 3, wherein the DNA damage is double strand DNA breaks.