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    MUTANT SMOOTHENED AND METHODS OF USING THE SAME
    3.
    发明申请
    MUTANT SMOOTHENED AND METHODS OF USING THE SAME 审中-公开
    MUTANT SMOOTHENED及其使用方法

    公开(公告)号：US20170044232A1

    公开(公告)日：2017-02-16

    申请号：US15116798

    申请日：2015-02-04

    Applicant: GENENTECH, INC. ,  CURIS, INC.

    Inventor： Frederic J. de Sauvage ,  Robert L. Yauch ,  Gerrit J.P. Dijkgraaf ,  Hayley Sharpe

    IPC: C07K14/705 ,  C12Q1/68 ,  A61K31/5377 ,  C07K16/28 ,  A61K31/498

    CPC classification number: C07K14/705 ,  A61K31/498 ,  A61K31/5377 ,  A61K31/551 ,  A61K31/5513 ,  A61K47/6849 ,  C07K16/28 ,  C07K2317/34 ,  C12Q1/6886 ,  C12Q2600/156 ,  G01N33/574 ,  G01N2333/4704

    Abstract: 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.

    Abstract translation: 在分子靶向治疗癌症患者治疗后，酪氨酸激酶突变的出现代表了获得性耐药性的主要机制。 这里描述了蛇纹石受体Smoothened（SMO）中的突变，其导致对Hedgehog（Hh）通路抑制剂的抗性，例如成神经管细胞瘤。 SMO的保守残基中的氨基酸取代保持Hh信号传导，但导致Hh途径抑制剂GDC-0449不能结合SMO并抑制途径。 在一些实施方案中，本公开提供新的突变SMO蛋白质和核酸以及用于筛选检测SMO突变的方法和筛选特异性调节显示耐药性的突变SMO的药物的方法。

    Mutant smoothened and methods of using the same
    5.
    发明授权
    Mutant smoothened and methods of using the same 有权

    公开(公告)号：US09910050B2

    公开(公告)日：2018-03-06

    申请号：US15130223

    申请日：2016-04-15

    Applicant: Curis, Inc. ,  Genentech, Inc.

    Inventor： Frederic J. de Sauvage ,  Gerrit J. P. Dijkgraaf ,  Thomas Januario ,  Robert L. Yauch

    IPC: C07K14/705 ,  C07K16/28 ,  G01N33/15 ,  G01N33/50 ,  G01N33/74

    CPC classification number: G01N33/74 ,  C07K14/705 ,  G01N2333/726 ,  G01N2500/10

    Abstract: 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.

    MUTANT SMOOTHENED AND METHODS OF USING THE SAME
    7.
    发明申请
    MUTANT SMOOTHENED AND METHODS OF USING THE SAME 有权
    MUTANT SMOOTHENED及其使用方法

    公开(公告)号：US20160313354A1

    公开(公告)日：2016-10-27

    申请号：US15130223

    申请日：2016-04-15

    Applicant: Curis, Inc. ,  Genentech, Inc.

    Inventor： Frederic J. de Sauvage ,  Gerrit J.P. Dijkgraaf ,  Thomas Januario ,  Robert L. Yauch

    IPC: G01N33/74

    CPC classification number: G01N33/74 ,  C07K14/705 ,  G01N2333/726 ,  G01N2500/10

    Abstract: 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.

    Abstract translation: 在分子靶向治疗癌症患者治疗后，酪氨酸激酶突变的出现代表了获得性耐药性的主要机制。 在这里，我们描述了蛇纹石受体Smoothened（SMO）中的突变，其导致对成神经管细胞瘤中的Hedgehog（Hh）通路抑制剂的抗性。 SMO的保守天冬氨酸残基中的单个氨基酸取代保持Hh信号传导，但导致Hh通路抑制剂GDC-0449不能结合SMO并抑制途径。 这种突变不仅在成神经管细胞瘤的GDC-0449抗性小鼠模型中获得，而且在GDC-0449复发后在成神经管细胞瘤患者中鉴定。 本发明提供了检测SMO突变的筛选方法和筛选特异性调节显示耐药性的突变SMO的药物的方法。

    E518A/K mutant smoothened and methods of using the same
    8.
    发明授权
    E518A/K mutant smoothened and methods of using the same 有权
    E518A / K突变体平滑化及其使用方法

    公开(公告)号：US09096686B2

    公开(公告)日：2015-08-04

    申请号：US13935129

    申请日：2013-07-03

    Applicant: Genentech, Inc. ,  Curis, Inc.

    Inventor： Frederic J. de Sauvage ,  Gerrit J. P. Dijkgraaf

    IPC: C07K14/00 ,  G01N33/566 ,  C07K14/705 ,  C07K14/72

    CPC classification number: C07K14/705 ,  C07K14/723

    Abstract: 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.

    Abstract translation: 在分子靶向治疗癌症患者治疗后，酪氨酸激酶突变的出现代表了获得性耐药性的主要机制。 在这里，我们描述了蛇纹石受体Smoothened（SMO）中的突变，其导致对成神经管细胞瘤中的Hedgehog（Hh）通路抑制剂的抗性。 在SMO的保守谷氨酸残基中单个氨基酸取代保持Hh信号传导，但导致Hh通路抑制剂GDC-0449不能结合SMO并抑制途径。 本发明提供了检测SMO突变的筛选方法和筛选特异性调节显示耐药性的突变SMO的药物的方法。

    MUTANT SMOOTHENED AND METHODS OF USING THE SAME
    9.
    发明申请
    MUTANT SMOOTHENED AND METHODS OF USING THE SAME 有权
    MUTANT SMOOTHENED及其使用方法

    公开(公告)号：US20140004535A1

    公开(公告)日：2014-01-02

    申请号：US13935129

    申请日：2013-07-03

    Applicant: Curis, Inc. ,  Genentech, Inc.

    Inventor： Frederic J. de Sauvage ,  Gerrit J.P. Dijkgraaf

    IPC: C07K14/705

    CPC classification number: C07K14/705 ,  C07K14/723

    Abstract: 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. The invention provides screening methods to detect SMO mutations and methods to screen for drugs that specifically modulate mutant SMO exhibiting drug resistance.

    Abstract translation: 在分子靶向治疗癌症患者治疗后，酪氨酸激酶突变的出现代表了获得性耐药性的主要机制。 在这里，我们描述了蛇纹石受体Smoothened（SMO）中的突变，其导致对成神经管细胞瘤中的Hedgehog（Hh）通路抑制剂的抗性。 SMO的保守天冬氨酸残基中的单个氨基酸取代保持Hh信号传导，但导致Hh通路抑制剂GDC-0449不能结合SMO并抑制途径。 本发明提供了检测SMO突变的筛选方法和筛选特异性调节显示耐药性的突变SMO的药物的方法。

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