The United States of America As Represented by the Department of Health

Van Andel Research Institute

National Institutes of Health, a Component of the US Dept. of Health & Human Services

Fred Hutchinson Cancer Center

Fred Hutchinson Cancer Research Center

George F Vande Woude

Nicholas S Duesbery

Nariyoshi Shinomiya

Yu-Wen Zhang

Thomas E Kmiecik

Beatrice S Knudsen

Donna Faletto

Stuart A Aaronson

Stephen H Leppla

Donald P Bottaro

Craig P Webb

Donald G Blair

Boliang Cao

Marianne Oskarsson

Andrew M-l Chan

Iafa Keydar

James H Resau

Boliang Cao (Brian)

Ilan Tsarfaty

Nicholas Schulz

Ira Daar

Renping Zhou

Han-Mo Koo

Eunmi (Kay) Koo, Legal Representative

Jeffery S Rubin

Anne Monks

Marianne K Oskarsson

William L McClements

Ping Xu Zhao

Disruption of mitogen inducible gene 6 (Mig-6) in mice by homologous recombination (KO mice) led to early onset osteoarthritis (OA) as revealed by simultaneous enlargement and deformity of multiple joints, degradation of articular cartilage and the development of bony outgrowths or osteophytes within the joint space. Because of the striking similarity to human OA, Mig-6 KO mice are a useful animal model for studying the mechanism of this disease and for testing new drugs or therapies for treating OA. These KO mice also developed epithelial hyperplasia, adenoma, and adenocarcinoma in organs such as lung, gallbladder, and bile duct. Mig-6 is therefore a tumor suppressor gene and is a candidate gene for the frequent Ip36 genetic alterations found in lung cancer. It can be used as a tumor biomarker as well as a target for cancer therapy.

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In a wide variety of human solid tumors, an aggressive, metastatic phenotype and poor clinical prognosis are associated with expression of the receptor tyrosine kinase Met. Disclosed herein are (a) a monoclonal antibody named Met4, which antibody is specific for Met, and (b) a hybridoma cell line that produces Met4. The Met4 antibody is particularly useful for detecting Met in formalin-fixed tissue. Methods of using the Met4 antibody for detection, diagnosis, prognosis, and evaluating therapeutic efficacy are provided.

Monoclonal antibody which binds cMet (HGFR) in formalin-fixed and paraffin-embedded tissues and related methods

A transgenic animal model for evaluating growth, survival and/or metastasis of xenotransplanted normal or tumor cells or tissue is disclosed, in which a human growth factor, hHGF stimulates growth in vivo of human cells or tissue. A strain of Tg mice on the C3H background that is immunocompromised as a result of a homozygous scid gene has been bred which express a nucleic acid encoding hHGF/SE The ectopically expressed hHGF/SF ligand significantly enhances growth of human tumor cell lines and explanted tumor cells or tissue that express the Met receptor for hHGF. Such animals also have an enlarged normal livers and greater than normal liver regenerative capacity. Any Met-expressing hHGF-dependent human cells, including hepatocytes and various stem cells can survive and grow in such animals.

Immune-compromised transgenic mice expressing human hepatocyte growth factor (hHGF)

Suppression of the Hepatocyte growth factor/scatter factor (HGF/SF)-Met signaling pathway by targeting the Met protein tyrosine kinase was tested as strategy for suppressing tumor growth. Using RNA interference (RNAi) technology and adenoviruses carrying siRNA (Ad Met siRNA) target sequences dramatically reduced Met expression in mouse, dog and human tumor cells. Met was suppressed using Ad Met siRNA in mouse mammary tumor (DA3) cells and Met-transformed (NIH3T3 (M114) cells as well as human prostate cancer, sarcoma, glioblastoma, gastric and ovarian cancer cells. Furthermore, the Ad Met siRNA infection reversed transformed cell morphology. Ad Met siRNA killed cancer cells by inducing apoptosis. RNAi targeting Met suppressed HGF/SF-mediated scattering as well as ligand-mediated invasion activity and growth of tumor cells. Met siRNA infection also abrogated downstream Met signaling to molecules such as Akt and p44/42 MAPK. Importantly, the Met siRNA triggered apoptosis was correlated to suppressed tumorigenicity in vivo. Intro-tumoral infection with c-met siRNA adenovirus vectors produced significant reduction in tumor growth. Thus Met RNAi is an effective weapon for targeting Met expression and for treating c-Metcancers.

c-met siRNA adenovirus vectors inhibit cancer cell growth, invasion and tumorigenicity

Inhibitors of the MAPK pathway, including MEK-directed proteases and small molecule inhibitors, are cytotoxic to human melanoma cells in vitro and in vivo via apoptotic mechanisms. These compounds are used to kill melanoma cells and to treat subjects with melanoma, either alone or in combination with other therapeutic modalities.

Inhibition of mitogen-activated protein kinase (MAPK) pathway: a selective therapeutic strategy against melanoma

The present invention relates to in vitro and ex vivo methods of screening for modulators, homologues, and mimetics of lethal factor mitogen activated protein kinase kinase (MAPKK) protease activity, as well as methods of treating cancer by administering LF to transformed cells.

Anthrax lethal factor is a MAPK kinase protease

A method for predicting breast tumor metastasis entails determining the amount of met protein in tumor tissue relative to normal breast duct tissue.

Met proto-oncogene and a method for predicting breast cancer progression

A pharmaceutical composition comprising an effective cancerous cell growth inhibiting amount of paclitaxel, or a paclitaxel derivative, and an effective cancerous cell growth inhibiting amount of an active agent which inhibits cancerous cell growth by exerting an effect on mammalian cell cycle during G.sub.1 or S-phase of the cell division cycle to inhibit said cancerous cell growth and methods of using same.

Methods for the treatment of cancer

The present invention relates to a complex comprising hepatocyte growth factor (HGF) and met proto-oncogene protein. The present invention also relates to methods for detecting the presence of HGF ligand, met proto-oncogene receptor and methods for isolating either the ligand or receptor or complex comprising both. The present invention further relates to methods of diagnostic proliferative disorders and diseases such as hepatitis or hepatocarcinogenesis by detecting these ligand-receptor pairs.

Method of stimulating bone marrow regeneration

Hepatic growth factor receptor is the MET proto-oncogene

The present invention involves a method of identifying drugs which selectively inhibit the growth of particular cancer cells, which method comprises: (a) contacting with the drug at least two cancer cells derived from the same type of biological material, wherein the cancer cells differ as to the presence of a particular DNA sequence, (b) measuring the effect of the drug on the growth of the cancer cells, and (c) determining whether there is a correlation between the effect of the drug on the cancer cells and the presence or absence of the DNA sequence in the cancer cells. The present invention further involves the use of such drugs.

Methods of identifying drugs with selective effects against cancer cells

Methods for stimulating hematopoietic progenitors using hepatocyte

The production of vectors composed of portions of retrovirus, particularly of Moloney sarcoma virus DNA including the 'LTR' sequence which can activate genes and additional viral sequences which can 'rescue' these genes into a replicating virus particle.

LTR-Vectors

Growing community of inventors

Ada, MI, United States of America

George F Vande Woude