Genentech, Inc.

Curis, Inc.

Genetech, Inc.

Washington University

Assistance Publique-hopitaux De Paris

Université Paris Diderot-Paris 7

F. Hoffmann-la Roche Ag

Frederic J De Sauvage

Dan L Eaton

Arnon Rosenthal

Victoria Smith

Austin L Gurney

Allen J Ebens

Jo-Anne Hongo

Donna Marie Stone

Maximilien Murone

Andrew G Polson

Gretchen Frantz

Gerrit J P Dijkgraaf

William I Wood

Audrey Goddard

Robert D Klein

Hartmut Koeppen

Robert L Yauch

David A Carpenter

Wesley Chang

Heidi S Phillips

Mary Jean Sparks

Paul J Godowski

J Christopher Grimaldi

Yan Wu

Hua Tian

Robert A Lazarus

Jeffrey D Milbrandt

Paul T Kotzbauer

Eugene M Johnson

Patricia A Lampe

Wenjun Ouyang

Craig W Crowley

Suzanna J Scales

Henry R Maun

Christine Tan

Jeremy M Murray

Marie Anne Evangelista

Zheng-Zheng Shi

Charles Montgomery

Thomas E Januario

Sarah G Hymowitz

Brian Biehs

Yan Zheng

Iqbal Grewal

Nicole Basset-Seguin

Franklin Peale

Ling Ling Culbertson

Suzie J Scales

Gerrit Jp Dijkgraaf

Nico P Ghilardi

Andrew Poison

Ivan Bosanac

Hayley Sharpe

Xiaohui Wen

Jr Allen Ebens

Zora Modrusan

Cameron L Noland

Somasekar Seshagiri

Gerrit JP Dijkgraaf

Thomas Januario

Eric William Stawiski

Gerrit JP Dijkraaf

Jose F Bazan

Steffen Durinck

Yongmei Chen

Elaine Storm

Alexander R Abbas

Dimitry M Danilenko

Patricia A Valdez

Jo-Anne S Hongo

The emergence of mutations in tyrosine kinases following treatment of cancer patients with molecular-targeted therapy represents a major mechanism of acquired drug resistance. Here, mutations in the serpentine receptor, Smoothened (SMO) are described, which result in resistance to a Hedgehog (Hh) pathway inhibitor, such as in medulloblastoma. Amino acid substitutions in conserved residues of SMO maintain Hh signaling, but result in the inability of the Hh pathway inhibitor, GDC-0449, to bind SMO and suppress the pathway. In some embodiments, the disclosure provides for novel mutant SMO proteins and nucleic acids and for screening methods to detect SMO mutations and methods to screen for drugs that specifically modulate mutant SMO exhibiting drug resistance.

Mutant smoothened and methods of using the same

Provided herein are methods of using anti-LGR5 antibodies, for example, for treating a hedgehog-related disease including basal cell carcinoma.

Methods of treating hedgehog-related diseases with an anti-LGR5 antibody

The emergence of mutations in tyrosine kinases following treatment of cancer patients with molecular-targeted therapy represents a major mechanism of acquired drug resistance. Here, we describe a mutation in the serpentine receptor, Smoothened (SMO), which results in resistance to a Hedgehog (Hh) pathway inhibitor in medulloblastoma. A single amino acid substitution in a conserved aspartic acid residue of SMO maintains Hh signaling, but results in the inability of the Hh pathway inhibitor, GDC-0449, to bind SMO and suppress the pathway. This mutation was not only acquired in a GDC-0449-resistant mouse model of medulloblastoma, but was identified in a Medulloblastoma patient following relapse on GDC-0449. The invention provides screening methods to detect SMO mutations and methods to screen for drugs that specifically modulate mutant SMO exhibiting drug resistance.

The emergence of mutations in tyrosine kinases following treatment of cancer patients with molecular-targeted therapy represents a major mechanism of acquired drug resistance. Here, we describe a mutation in the serpentine receptor, Smoothened (SMO), which results in resistance to a Hedgehog (Hh) pathway inhibitor in medulloblastoma. A single amino acid substitution in a conserved glutamic acid residue of SMO maintains Hh signaling, but results in the inability of the Hh pathway inhibitor, GDC-0449, to bind SMO and suppress the pathway. The invention provides screening methods to detect SMO mutations and methods to screen for drugs that specifically modulate mutant SMO exhibiting drug resistance.

E518A/K mutant smoothened and methods of using the same

The present invention is directed to compositions of matter useful for the treatment of hematopoietic tumor in mammals and to methods of using those compositions of matter for the same.

Compositions and methods for the treatment of tumor of hematopoietic origin

The present invention provides for a method of using BOC/CDO hedgehog antagonists to inhibit hedgehog signaling, as well as treating and diagnosing disorders relating to hedgehog signaling or overexpression of hedgehog, including cancer, cell proliferative disorders, and angiogenesis, neurological disorders, as well as other conditions affected by hedgehog signaling such as hair growth, neural stem cell differentiation, chondrogenesis and osteogenesis, lung surfactant production, formation of lamellated bodies in lung cells.

Method of diagnosing the presence of a tumor in a mammal by assessing CDO expression levels

Isolated mpl ligand, isolated DNA encoding mpl ligand, and recombinant methods of preparing mpl ligand are disclosed. These mpl ligands are shown to influence the replication, differentiation or maturation of blood cells, especially megakaryocyte progenitor cells. Accordingly, these compounds are used for treatment of thrombocytopenia.

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The present invention relates to nucleotide sequences, including expressed sequence tags (ESTs), oligonucleotide probes, polypeptides, vectors and host cells expressing, immunoadhesins, agonists and antagonists (including antibodies) to human & vertebrate fused.

Nucleic acid encoding fused

Isolated thrombopoietin (TPO), isolated DNA encoding TPO, and recombinant or synthetic methods of preparing and purifying TPO are disclosed. Various forms of TPO are shown to influence the replication, differentiation or maturation of blood cells, especially megakaryocytes and megakaryocyte progenitor cells. Accordingly, these compounds may be used for treatment of thrombocytopenia.

Monoclonal antibody to human thrombopoietin

Isolated mpl ligand, isolated DNA encoding mpl ligand, and recombinant or synthetic methods of preparing mpl ligand are disclosed. These mpl ligands are shown to influence the replication, differentiation or maturation of blood cells, especially megakaryocytes and megakaryocyte progenitor cells. Accordingly, these compounds may be used for treatment of thrombocytopenia.

Nucleic acids encoding MPL ligand (thrombopoietin), variants, and fragments thereof

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Foster City, CA, United States of America

Frederic J De Sauvage