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Identification of predictive biomarkers associated with Wnt pathway inhibitors

A technology of biomarkers and inhibitors, applied in the field of cancer treatment, can solve problems such as uncontrolled proliferation

Inactive Publication Date: 2016-08-03
ONCOMED PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is believed that activation of the Wnt pathway may maintain tumor cells in an undifferentiated state and / or lead to uncontrolled proliferation

Method used

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  • Identification of predictive biomarkers associated with Wnt pathway inhibitors
  • Identification of predictive biomarkers associated with Wnt pathway inhibitors
  • Identification of predictive biomarkers associated with Wnt pathway inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0288] Identify tumors that respond to the combination of OMP-18R5 and taxol (taxol)

[0289] Breast tumor xenograft models OMP-B34, OMP-B39, OMP-B44, OMP-B59, OMP-B60, UM-T01, UM-T03 and UM-PE13 are derived from the smallest generation of tumor samples derived from patients. OncoMedPharmaceuticals or University of Michigan established. NOD / SCID mice aged six to eight weeks are injected subcutaneously with 2-4×10 4 One OMP-B34, OMP-B39, OMP-B44, OMP-B59, OMP-B60, UM-T01, UM-T03 or UM-PE13 tumor cell. Let the tumor grow until the tumor reaches an average volume of 100 to 150 mm 3 . Tumor mice were randomly divided into four groups (n=10 in each group) and were treated with control antibody 1B711 (15mg / kg), anti-FZD antibody OMP-18R5 (15mg / kg), paclitaxel (10mg / kg) or OMP-18R5 (15mg / kg) and paclitaxel (10mg / kg) combination therapy. Antibody and / or paclitaxel treatment is administered weekly. The tumor growth was monitored and the tumor volume was measured with electronic calipe...

Embodiment 2

[0295] Identify predictive biomarkers

[0296] The microarray analysis was based on untreated breast tumors OMP-B34, OMP-B39, OMP-B44, and UM-T01 that did not respond to the combination treatment of OMP-18R5 and paclitaxel ("non-responders"). The combination of 18R5 and paclitaxel was performed on untreated tumors OMP-B59, OMP-B60, UM-T03, and UM-PE13 that responded ("responders"). The RNeasy fibrous tissue mini kit (Qiagen, Valencia CA) and DNase treatment were used according to the manufacturer's instructions to isolate RNA from each tumor. The samples are stored at -80°C. The RNA was inspected on the Agilent 2100 bioanalyzer, and the integrity can be verified by the presence of intact 28S and 18S ribosomal peaks. All RNA samples have a 260 / 280 ratio> 1.8. The total RNA isolated from each tumor was amplified by Ovation RNA Amplification System V2 (NuGEN, San Carlos, CA). The amplified antisense single-stranded cDNA was segmented and biotinylated using FL-OvationcDNA biotin ...

Embodiment 3

[0306] In vivo validation of predictive biomarkers

[0307] Six additional breast cancer tumor lines were selected from the OncoMed tumor bank and were subjected to microarray analysis as described in Example 1. The six breast cancer tumors are OMP-B29, OMP-B71, OMP-B84, OMP-B90, UM-T02 and UM-T06. As described herein, the classification probability analysis using 6-gene biomarker labels is used to predict the response of each of these tumors to the combination of anti-FZD antibody OMP-18R5 and paclitaxel (see Figure 5 ). At the same time, the six tumors were evaluated in the in vivo xenograft model as described in Example 1 (see Figure 6A To F). As described in Example 1a, the "responders" in the in vivo model showed tumor growth inhibition compared with paclitaxel as a single agent, and the combination of OMP-18R5 and paclitaxel showed significantly higher tumor growth inhibition. The prediction system based on the classification probability is compared with the results of ...

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Abstract

The invention relates to identification of predictive biomarkers associated with Wnt pathway inhibitors. According to the invention, biomarkers are provided for identifying tumors likely to respond to treatment with Wnt pathway inhibitors. Also provided are methods for identifying tumors and / or patients that are likely to be responsive or non-responsive to treatment with a Wnt pathway inhibitor. Methods for treating a patient with cancer are provided, wherein the cancer is predicted to respond to a Wnt pathway inhibitor.

Description

[0001] Cross-reference of related applications [0002] This application claims the priority of U.S. Provisional Application No. 61 / 910,663 filed on December 2, 2013 and U.S. Provisional Application No. 61 / 975,339 filed on April 4, 2014. Each case is taken as a whole by reference Include here. Technical field [0003] The present invention relates to the field of cancer treatment. More particularly, the present invention provides methods for identifying tumors that may or may not respond to treatment with Wnt pathway inhibitors. In addition, the present invention provides methods for identifying, selecting, and / or treating cancer patients who may be responsive to treatment with Wnt pathway inhibitors used alone or in combination with other therapeutic agents. Background technique [0004] Cancer is one of the leading causes of death in developed countries. Approximately 1.6 million people are diagnosed with cancer each year in the United States alone and there are more than 550,00...

Claims

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Application Information

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IPC IPC(8): C12Q1/68A61K38/00
CPCA61K38/177A61P35/00C12Q1/6886C12Q2600/106C12Q2600/158
Inventor 安·M·卡保恩张春
Owner ONCOMED PHARMA
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