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Use of PARP inhibitors to treat breast or ovarian cancer patients showing a loss of heterozygosity

An inhibitor, breast cancer technology, applied in the field of genome-wide LO in ovarian cancer

Inactive Publication Date: 2016-08-31
CLOVIS ONCOLOGY INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, some types of cancer, including some lung cancers, may exhibit LOH that is primarily related to environmental factors and may be independent of genetic causes of DNA damage

Method used

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  • Use of PARP inhibitors to treat breast or ovarian cancer patients showing a loss of heterozygosity
  • Use of PARP inhibitors to treat breast or ovarian cancer patients showing a loss of heterozygosity
  • Use of PARP inhibitors to treat breast or ovarian cancer patients showing a loss of heterozygosity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Ricaparib-sensitive breast cancer cells exhibit genomic LOH

[0053] Ricaparib-sensitive cells

[0054]Sensitivity data for ricaparib in a large panel of human cancer cell lines were generated using a high-throughput growth inhibition assay. Briefly, place cells between 5 and 20x 10 3 Cells were seeded in 24-well tissue culture plates. Ricaparib was treated at concentrations ranging from 0.005 to 10 μΜ. On days 1 and 6 of ricaparib treatment, viable cells were counted using a Beckman Coulter Z2 particle counter. Growth inhibition was calculated as a function of the number of inhibited generations in the presence of ricaparib relative to the number of generations over the same time course in the absence of ricaparib. Dose response curves were generated and half maximal effective concentration (EC50) values ​​for growth inhibition were calculated for each cell line. Some of the most sensitive cell lines seen in high throughput screens were breast cancer cell lines (T...

Embodiment 2

[0069] Example 2 -Ovarian cancer patients whose tumors exhibit genomic LOH benefit from platinum-based therapy

[0070] high-grade serous ovarian neoplasms

[0071] The Cancer Genome Atlas (TCGA) project performed genomic analyzes of 316 high-grade serous ovarian tumors (Cancer Genome Atlas Research Network. Integrated genomic analyzes of ovarian carcinomas. Nature 2011;474:609-15). Samples were collected from patients newly diagnosed with ovarian serous adenocarcinoma who were undergoing surgical resection and had not received prior treatment. Patients were then treated with platinum-based chemotherapy as with standard therapy, and overall survival (interval from date of initial surgical resection to date of last known association or death) was recorded. Patients with a platinum-free interval (interval from date of last primary platinum therapy to date of progression) of 6 months or greater were identified as platinum-sensitive. Next-generation sequencing of tumors to ide...

Embodiment 3

[0083] Example 3 – Ovarian cancer patients whose tumors exhibit genomic LOH benefit from treatment with ricaparib

[0084] Next-generation sequencing of ovarian tumors from patients

[0085] Archival tumor tissue samples from patients are optionally collected for genomic analysis. To determine the maximum tolerated dose and recommended Phase II dose, patients were placed in dose escalation cohorts for continuous daily oral administration of ricaparib. The antitumor activity of ricaparib was evaluated based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. In addition, the concentration of cancer antigen-125 (CA-125) in blood was measured as a biomarker of ovarian cancer. Local BRCA1 / 2 test results are based on sequencing of the BRCA1 / 2 gene from a blood sample (peripheral blood mononuclear cells).

[0086] LOH analysis

[0087] A high-level overview of the bioinformatics analysis workflow is given in Figure 10 middle. Briefly, formalin-fixed pa...

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Abstract

In one embodiment, the subject invention relates to a method for treatment of a breast or ovarian cancer patient that includes receiving assay results stating that the patient's tumor exhibits LOH, and administering a PARP inhibitor. In one embodiment, the subject invention comprising: classifying said cancer patient, with the computer system, as being likely to respond to a PARP inhibitor if the data comprises i) one or more deleterious mutations in BRCA1 or BRCA2, or ii) a percentage of the genome having greater than 10 percent LOH as determined by the sum of the lengths of each individual LOH region divided by the total genome length, wherein an LOH region is defined as the presence of homozygosity at multiple contiguous single nucleotides, but excludes whole chromosome or chromosome arm LOH.

Description

Background of the invention [0001] In recent years, attention has turned to identifying biomarkers or other measurements in tumor tissue or blood that can predict the outcome of various therapeutic interventions. Given the importance of homologous recombination repair genes such as BRCA1 and BRCA2 in maintaining genome stability, characterizing the degree of genomic instability could lead to the identification of homologous recombination-deficient tumors. [0002] Genome-wide loss of heterozygosity and uniparental disomy in BRCA1 / 2-associated ovarian carcinomas. Clin Cancer Res 2008;14:7645-51). DNA damaging agents have been suggested as potential agents for the treatment of patients whose tumors exhibit LOH. [0003] Loss of heterozygosity (LOH) refers to the change from the heterozygous state in the normal genome to the homozygous state in the tumor genome (Beroukhim R et al. Inferringloss-of-heterozygosity from unpaired tumors using high-density oligonucleotide SNP arrays...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/68
CPCC12Q1/68C12Q2600/106C12Q2600/156C12Q1/6886A61P35/00A61K31/55C12Q2600/112G01N2800/60
Inventor K·林
Owner CLOVIS ONCOLOGY INC
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