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Biomarkers and methods for determining sensitivity to microtubule-stabilizing agents

a microtubule stabilizing agent and biomarker technology, applied in the field of pharmaceuticals, can solve problems such as the difficulty of predicting drug sensitivity in patients

Inactive Publication Date: 2006-06-08
R PHARMA US OPERATING LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The invention provides methods for identifying which patients will respond to treatment with microtubule-stabilizing agents, such as chemotherapy, by measuring the levels of certain biomarkers in a biological sample from the patient. This information can be used to predict which patients will benefit from treatment and which patients will not. The methods involve exposing the patient to the microtubule-stabilizing agent and measuring the levels of biomarkers before and after exposure. An increase in the level of the biomarker indicates that the patient will respond to treatment. The invention also provides biomarkers that can be used to predict the effectiveness of a microtubule-stabilizing agent in treating cancer."

Problems solved by technology

The ability to predict drug sensitivity in patients is particularly challenging because drug responses reflect not only properties intrinsic to the target cells, but also a host's metabolic properties.

Method used

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  • Biomarkers and methods for determining sensitivity to microtubule-stabilizing agents

Examples

Experimental program
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Effect test

example 1

Identification of Biomarkers

Methods

[0068] Cell Lines and Cytotoxicity Assay

[0069] 23 breast cancer cell lines were assayed for their sensitivity to ixabepilone. Each cell line was exposed to ixabepilone for 72 hours, and growth inhibition was assessed by the CellTiter 96® Aqueous Non-Radioactive Cell proliferation Assay (Promega) for IC50 measurements. Then, the concentration of the ixabepilone required for 50% growth inhibition was calculated as the IC50. For each experimental condition, at least triplicate measurements were carried out for each cell line. The 23 cell lines were assayed for their IC50 measurements twice, and these two separate IC50 data sets were used for the following analysis.

[0070] Training Set Selection

[0071] For analysis, training cell lines were chosen in the following manner. The 23 cell lines were assigned into the classes “sensitive” or “resistant” using IC50 values; log(IC50) values were normalized based on the mean and the standard deviation (SD) a...

example 2

Further Evaluation of ER and Tau Biomarkers

[0091] Estrogen receptor (ER) and tau (Tau) were identified as biomarkers since their expression patterns were highly correlated with resistance to ixabepilone. In addition, it was found that the ER pathway was the most implicated biological network for resistance to ixabepilone based on the pathway analysis using preclinical candidate markers (FIGS. 9 and 10). Interestingly, Tau was recently identified as the gene most correlated with pathological complete response for T / FAC neoadjuvant treatment in breast cancer patients (M. Ayers et al, J. Clin. Oncol., 22(12):2284-93 (2004); R. Rouzier et al., P.N.A.S., Jun 7; 102(23):8315-20 (2005)). Following this report, our preclinical study on paclitaxel supported the clinical findings of Tau as a novel mediator of paclitaxel sensitivity (P. Wagner et al., Cell Cycle, Sep; 4(9):1149-52 (2005)). ER and Tau were evaluated for their predictability of response to ixabepilone in CA163-080 trial.

Metho...

example 3

Production of Antibodies Against the Biomarkers

[0105] Antibodies against the biomarkers can be prepared by a variety of methods. For example, cells expressing a biomarker polypeptide can be administered to an animal to induce the production of sera containing polyclonal antibodies directed to the expressed polypeptides. In one aspect, the biomarker protein is prepared and isolated or otherwise purified to render it substantially free of natural contaminants, using techniques commonly practiced in the art. Such a preparation is then introduced into an animal in order to produce polyclonal antisera of greater specific activity for the expressed and isolated polypeptide.

[0106] In one aspect, the antibodies of the invention are monoclonal antibodies (or protein binding fragments thereof). Cells expressing the biomarker polypeptide can be cultured in any suitable tissue culture medium, however, it is preferable to culture cells in Earle's modified Eagle's medium supplemented to contain...

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Abstract

Biomarkers that are useful for identifying a mammal that will respond therapeutically or is responding therapeutically to a method of treating cancer that comprises administering a microtubule-stabilizing agent. In one aspect, the cancer is breast cancer, and the microtubule-stabilizing agent is an epothilone or analog or derivative thereof, or ixabepilone.

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 60 / 631,993 filed Nov. 30, 2004, whose contents are hereby incorporated by reference in its entirety.SEQUENCE LISTING [0002] A compact disc labeled “Copy 1” contains the Sequence Listing as 10338 NP.ST25.txt. The Sequence Listing is 1686 KB in size and was recorded Nov. 29, 2005. The compact disk is 1 of 2 compact disks. A duplicate copy of the compact disc is labeled “Copy 2” and is 2 of 2 compact discs. [0003] The compact disc and duplicate copy are identical and are hereby incorporated by reference into the present application. FIELD OF THE INVENTION [0004] The present invention relates generally to the field of pharmacogenomics, and more specifically to methods and procedures to determine drug sensitivity in patients to allow the identification of individualized genetic profiles which will aid in treating diseases and disorders. BACKGROUND OF THE INVENTION [0005] Cancer is a disease with extensive hist...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12Q1/68G01N33/574
CPCC12Q1/6886C12Q2600/106C12Q2600/158G01N33/574G01N33/57415G01N33/57484G01N2800/52
Inventor LEE, HYERIMSHAW, PETERCLARK, EDWIN A.
Owner R PHARMA US OPERATING LLC
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