Methods, systems and products for predicting response of tumor cells to a therapeutic agent and treating a patient according to the predicted response

a technology of tumor cells and therapeutic agents, applied in the field of methods, can solve the problems of not being able to identify such markers for all therapeutic agents, tumors that cannot guarantee the responsiveness of cetuximab, and the inability to predict the response of tumor cells to a therapeutic agent,

Inactive Publication Date: 2011-02-03
MERRIMACK PHARMACEUTICALS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

While such targeted therapies have been shown to be effective in some patients, the response rate is never 100%.
Thus, mere expression of ErbB1 (the antigen targeted by the cetuximab antibody) in a tumor does not guarantee responsiveness to cetuximab.
While such stable, “direct” markers that are predictive of responsiveness to certain therapeutic agents have been identified, it is unclear whether such markers can be identified for all therapeutic agents.
However, phosphoproteins can be very labile and the phosphorylation can dissipate quickly after surgery if the tissue sample is not immediately and rapidly frozen (or, in some cases, formalin fixed).
Therefore, while phosphoprotein profiles contain important information about the pathways driving tumor progression, such phosphoprotein profiles currently are not widely used as biomarkers for predicting responsiveness to therapeutic treatment.

Method used

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  • Methods, systems and products for predicting response of tumor cells to a therapeutic agent and treating a patient according to the predicted response
  • Methods, systems and products for predicting response of tumor cells to a therapeutic agent and treating a patient according to the predicted response
  • Methods, systems and products for predicting response of tumor cells to a therapeutic agent and treating a patient according to the predicted response

Examples

Experimental program
Comparison scheme
Effect test

example 1

Xenograft Efficacy Studies with Ab #6: Training Data Set

[0230]In this example, four xenograft tumor models were used to identify tumor cell lines that responded to treatment with the anti-ErbB3 antibody Ab #6. The four xenograft tumor models studied represent different indications: MALME3M (melanoma cancer line; ATCC No. HTB-64), ADRr (ovarian cancer cell line; NCI-60, cosmic sample ID No. 905987), ACHN (renal cancer cell line; ATCC No. CRL-1611) and DU145 (prostate cancer cell line; ATCC No. HTB-81). As described in further detail below, the MALME3M and ADRr xenografts did not show a response to treatment with Ab #6, whereas the ACHN and DU145 xenografts did show a response to Ab #6 treatment.

[0231]In the xenograft tumor models, mice (nu / nu mice: 3-4 week old female mice, T-cell deficient; outbred; Albino background; from Charles River Labs, Wilmington, Mass.) are implanted in the right flank with 3.5×106−3×108 cells / mouse (depending on cell line) in 200 μl via subcutaneous injecti...

example 2

pErbB3 Levels in Tumor Cell Line Lysates Correlate with Ab #6 Responsiveness in Xenografts

[0235]In this example, the concentration of phosphorylated ErbB3 (pErbB3) was measured in vivo in each of the four tumor cell lines studied in Example 1, MALME3M, ADRr, DU145 and ACHN, in a short term pharmacodynamic (PD) study. The OvCAR8 xenograft also was included in this experiment (this xenograft is shown to be responsive to Ab #6 treatment in Example 5 described below).

[0236]MALME3M, ADRr, DU145, OvCAR 8 and ACHN cells are grown in culture and harvested for implantation (15×15 cm plates, ˜80% confluency, total # of cells=2−4×108) and kept on ice until implantation. Cells (approximately 2×107 cells / mouse) are implanted into 20 mice (via subcutaneous injection, 200 μl cells / injection / mouse) into the right flank and then the mice are allowed to recover while being monitored for initial tumor growth. Tumors are measured (L×W) by digital caliper measurement. Once the mice reached a tumor volum...

example 3

pErbB3 and pAKT Levels Decrease as a Function of Time to Freeze

[0243]In this example, the stability of pErbB3 and pAKT was assessed, as well as the expression levels of ErbB I, ErbB2 and ErbB3, in tumor lysates as a function of time after resurrection from freezing the tumor.

[0244]Untreated ACHN and EKVX xenograft mice are euthanized by CO2 asphyxiation and tumors are dissected and cut into 4 pieces and put into liquid nitrogen at different time points: 0 min, 10 min, 30 min, and 60 min. Then, pErbB3 and pAKT levels, as well as ErbB1-3 levels, are measured in each of the samples after thawing. The results obtained using the methods described above or minor variations thereof are summarized in the bar graphs shown in FIGS. 3A-3E, with FIGS. 3A and 3B showing the levels of pErbB3 and pAKT, respectively, in the ACHN lysates and FIGS. 3C, 3D and 3E showing the levels of ErbB1, ErbB2 and ErbB3, respectively, in the EKVX lysates.

[0245]As shown in FIGS. 3A and 3B, in the 10 minute samples,...

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Abstract

The invention provides methods for treating patients which methods comprise methods for predicting responses of cells, such as tumor cells, to treatment with therapeutic agents. These methods involve measuring, in a sample of the cells, levels of one or more components of a cellular network and then computing a Network Activation State (NAS) or a Network Inhibition State (NIS) for the cells using a computational model of the cellular network. The response of the cells to treatment is then predicted based on the NAS or NIS value that has been computed. The invention also comprises predictive methods for cellular responsiveness in which computation of a NAS or NIS value for the cells (e.g., tumor cells) is combined with use of a statistical classification algorithm. Biomarkers for predicting responsiveness to treatment with a therapeutic agent that targets a component within the ErbB signaling pathway are also provided.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation-in-part of PCT Application No. PCT / US2009 / 054051, filed Aug. 17, 2009, which claims priority to U.S. Provisional Application No. 61 / 189,053, filed Aug. 15, 2008, U.S. Provisional Application No. 61 / 194,702, filed Sep. 30, 2008, U.S. Provisional Application No. 61 / 208,206, filed Feb. 20, 2009 and U.S. Provisional Application No. 61 / 170,367, filed Apr. 17, 2009.BACKGROUND OF THE INVENTION[0002]Considerable advances have been made in the development of targeted therapies for the treatment of cancer and other diseases. Such targeted therapies include monoclonal antibodies that bind to antigens that are specifically or preferentially expressed on tumor cells and small molecule drugs that specifically interfere with discrete components of signaling pathways active in tumor cells. For example, cetuximab (Erbitux®) is a monoclonal antibody that targets the epidermal growth factor receptor (EGFR, also known as Er...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395G01N33/566A61P35/00G06F7/60G06F19/00
CPCA61K2039/505C07K16/32G01N33/6893C12Q1/6809C07K16/2863C07K2317/31A61P35/00A61K39/395G01N33/53G01N33/15
Inventor SCHOEBERL, BIRGITHARMS, BRIANGIBBONS, FRANCIS DAVIDFITZGERALD, JONATHAN BASILONSUM, MATTHEW DAVIDNIELSEN, ULRIKKUBASEK, WILLIAM
Owner MERRIMACK PHARMACEUTICALS INC
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