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Compositions and methods for treating and diagnosing cancer

Inactive Publication Date: 2007-05-10
RGT UNIV OF MICHIGAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0017] The present invention relates to compositions and methods for treating, characterizing, and diagnosing cancer. In particular, the present invention provides gene expression profiles and signatures associated with solid tumor stem cells, as well as novel stem cell cancer markers useful for the diagnosis, chara

Problems solved by technology

Although its mortality has not increased along with its incidence, due to earlier diagnosis and improved treatment, it is still one of the predominant causes of death in middle-aged women.
However, the currently available treatment options often prolong the disease-free state and overall survival rate, as well as increase the quality of the life.
The morphologic appearance of the tumor can also be assessed but because tumors with similar histopathologic appearance can exhibit significant clinical variability, this approach has serious limitations.
Yet these analyses, though useful, are only partially predictive of the clinical behavior of breast tumors, and there is much phenotypic diversity present in breast cancers that current diagnostic tools fail to detect.
Furthermore, although current therapies can often prolong the disease-free state and overall survival when used on high-risk patients, they are limited by their lack of specificity and the emergence of treatment-resistant cancer cells.
Because of the relatively low rate of reoccurrence, the benefit of post surgical chemotherapy in Duke' B has been harder to detect and remains controversial.
However, the Duke's B classification is imperfect as approximately 20-30% of these patients behave more like Duke's C and relapse within five years.
Indeed, mutations within a long-lived stem cell population can initiate the formation of cancer stem cells that underlie the growth and maintenance of tumors and whose presence contributes to the failure of current therapeutic approaches.
Although great strides have been made understanding the genetic changes that lead to cancer (e.g. breast cancer and colorectal cancer), the lack of reliable tumor assay for de novo human cancer cells has hindered the ability to understand the effects of these mutations at the cellular level.
Also, the lack of identified cancer markers for solid tumor stem cells has hindered the development of diagnostics and therapeutics for cancer patients (e.g. breast cancer patients).

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  • Compositions and methods for treating and diagnosing cancer
  • Compositions and methods for treating and diagnosing cancer
  • Compositions and methods for treating and diagnosing cancer

Examples

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example 1

Establishing and Analyzing a Solid Tumor Cell Xenograft Model

[0379] This example describes the generation of tumors in mice using human solid tumor cells from humans and the analysis of these tumors.

[0380] Materials and Methods

[0381] Mouse preparation. 8-week old female NOD-SCID mice were anesthetized by an intra-peritoneal injection of 0.2 ml Ketamine / Xylazine (300 mg Ketamine combined with 20 mg Xylazine in a 4 ml volume. 0.02 ml of the solution was used per 20 g mouse). Dilution to 200 μl was done using HBSS. Mice were then treated with VP-16 (etoposide) via an intra-peritoneal injection (30 mg etoposide dose per 1 kg mouse, diluted in serum-free HBSS for a final injection volume of 200 μl). At the same time, estrogen pellets were placed subcutaneously on the back of the mouse's neck using a trocar. All tumor injections / implants were done 5 days after this procedure. In the following procedures, mice were anesthetized as described above.

[0382] Primary tumor specimen implantat...

example 2

Characterizing the Wnt / β-Catenin Pathway in Human Breast Cancer Tumors Using Systems and Methods of the Present Invention

[0416] This Example provides illustrative screening methods using the sytems and methods of the present invention. This example describes, for example, how one could characterize the Wnt / β-catenin pathway in human breast cancer tumors using the xenograft model described above. The Wnt / β-catenin pathway plays a role in the proliferation and self-renewal of normal stem cells. Although a significant percentage of human breast cancers appear to have constitutive activation of this critical pathway, unlike colon cancer, it has not been definitively established what role this pathway plays in the pathology of this disease in humans (Candidus et,al., 1996, Cancer Res. 56:49-52; Sorlie et al., 1998, Hum. Mutat. 12:215; Jonsson et al., 2000, Eur. J. Cancer 36:242-8; Schlosshauer et al., 2000, Carcinogenesis 21:1453-6; Lin et al., 2000, PNAS 97:4262-6; Wong et al., 2002, J...

example 3

Localization of β-Catenin in Tumorigenic Cells

[0452] In normal hematopoietic cells, nuclear β-catenin is found only in the stem cell compartment. Reya et al. further demonstrate that β-catenin signaling is necessary for normal stem cells to self-renew. A recently completed analysis of the subcellular localization of β-catenin in tumorigenic and non-tumorigenic tumor 1 breast cancer cells further supports this notion. Normally, the subcellular distribution of β-catenin is heterogeneous in cancer cells. In some cells, the protein is located primarily in the outer membrane, while in others primarily in the nucleus. The subcellular distribution of the protein differs in the tumorigenic and non-tumorigenic cancer cells. The β-catenin is primarily located in the cytoplasm of the non-tumorigenic cancer cells, while it is primarily in the nucleus of the tumorigenic cells (FIG. 8). Since upon activation by a Wnt signal, β-catenin translocates from the cell membrane to the nucleus to activat...

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Abstract

The present invention relates to compositions and methods for treating, characterizing, and diagnosing cancer. In particular, the present invention provides gene expression profiles and signatures associated with solid tumor stem cells, as well as novel stem cell cancer markers useful for the diagnosis, characterization, prognosis and treatment of solid tumor stem cells. More particularly, the present invention identifies two profiles of cancer stem cells useful for the diagnosis, characterization, and treatment of cancer and cancer metastases. The invention also provides a variety of reagents such as stem cell gene signatures for use in the diagnosis and management of cancer.

Description

[0001] This application claims the benefit of the filing date of U.S. Provisional Appl. No. 60 / 690,001, filed Jun. 13, 2005, which is incorporated herein by reference in its entirety. [0002] U.S. application Ser. No.11 / 050,282, filed Feb. 3, 2005, U.S. Appl No. 60 / 541,527, filed Feb. 3, 2004, and U.S. application Ser. No. 10 / 864,207, filed Jun. 9, 2004, are herein incorporated by reference in their entirety.[0003] This invention was made with government support under Grant No. 5P01CA07513606 awarded by the National Institute of Health. The Government has certain rights in the invention.FIELD OF THE INVENTION [0004] The present invention relates to compositions and methods for treating, characterizing, and diagnosing cancer. In particular, the present invention provides gene expression profiles and signatures associated with solid tumor stem cells, as well as novel stem cell cancer markers useful for the diagnosis, characterization, prognosis, and treatment of solid tumor stem cells ...

Claims

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Application Information

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IPC IPC(8): C12Q1/68G01N33/574C12N5/08C12N5/09C12N5/095
CPCG01N2333/705C12N5/0693C12N5/0695C12N2501/58C12Q1/6886G01N33/57484G01N33/6887A61P35/00A61P35/02
Inventor CLARKE, MICHAEL F.WANG, XINHAOLEWICKI, JOHN A.GURNEY, AUSTIN L.
Owner RGT UNIV OF MICHIGAN
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