公开(公告)号：US08623592B2

公开(公告)日：2014-01-07

申请号：US13058687

申请日：2009-08-17

Applicant: Birgit Schoeberl ,  Brian Harms ,  Francis David Gibbons ,  Jonathan Basil Fitzgerald ,  Matthew David Onsum ,  Ulrik Nielsen ,  William Kubasek

Inventor： Birgit Schoeberl ,  Brian Harms ,  Francis David Gibbons ,  Jonathan Basil Fitzgerald ,  Matthew David Onsum ,  Ulrik Nielsen ,  William Kubasek

IPC: C12Q1/00 ,  C12Q1/68 ,  G01N33/574

CPC classification number: G01N33/6893 ,  A61K2039/505 ,  C07K16/2863 ,  C07K16/32 ,  C07K2317/31 ,  C12Q1/6809

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 predicted124 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.

Abstract translation: 本发明提供了治疗患者的方法，所述方法包括用于预测细胞如肿瘤细胞的应答的方法用于治疗剂的治疗。 这些方法包括在细胞样本中测量细胞网络的一个或多个组分的水平，然后使用细胞的计算模型计算细胞的网络激活状态（NAS）或网络抑制状态（NIS） 网络。 然后基于已经计算的NAS或NIS值来预测细胞对治疗的反应124。 本发明还包括用于细胞反应性的预测方法，其中使用统计分类算法将细胞（例如，肿瘤细胞）的NAS或NIS值的计算结合在一起。 还提供了用于预测用靶向ErbB信号通路中的组分的治疗剂对治疗的反应性的生物标志物。

公开(公告)号：US20110159513A1

公开(公告)日：2011-06-30

申请号：US13058687

申请日：2009-08-17

Applicant: Birgit Schoeberl ,  Brian Harms ,  Francis David Gibbons ,  Jonathan Basil Fitzgerald ,  Matthew David Onsum ,  Ulrik Nielsen ,  William Kubasek

Inventor： Birgit Schoeberl ,  Brian Harms ,  Francis David Gibbons ,  Jonathan Basil Fitzgerald ,  Matthew David Onsum ,  Ulrik Nielsen ,  William Kubasek

IPC: C12Q1/68 ,  G01N33/574

CPC classification number: G01N33/6893 ,  A61K2039/505 ,  C07K16/2863 ,  C07K16/32 ,  C07K2317/31 ,  C12Q1/6809

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.

Abstract translation: 本发明提供了治疗患者的方法，所述方法包括用于预测细胞如肿瘤细胞的应答的方法用于治疗剂的治疗。 这些方法包括在细胞样本中测量细胞网络的一个或多个组分的水平，然后使用细胞的计算模型计算细胞的网络激活状态（NAS）或网络抑制状态（NIS） 网络。 然后基于已经计算的NAS或NIS值来预测细胞对治疗的反应。 本发明还包括用于细胞反应性的预测方法，其中使用统计分类算法将细胞（例如，肿瘤细胞）的NAS或NIS值的计算结合在一起。 还提供了用于预测用靶向ErbB信号通路中的组分的治疗剂对治疗的反应性的生物标志物。

公开(公告)号：US20150231238A1

公开(公告)日：2015-08-20

申请号：US14004848

申请日：2012-03-15

Applicant: Gabriela Garcia ,  William Kubasek ,  Maria Johanna Lahdenranta ,  Gavin MacBeath ,  Charlotte McDonagh ,  Victor Moyo ,  Matthew David Onsum ,  Birgit Schoeberl ,  Mark Sevecka ,  Marisa Wainszelbaum ,  Bo Zhang

Inventor： Gabriela Garcia ,  William Kubasek ,  Maria Johanna Lahdenranta ,  Gavin MacBeath ,  Charlotte McDonagh ,  Victor Moyo ,  Matthew David Onsum ,  Birgit Schoeberl ,  Mark Sevecka ,  Marisa Wainszelbaum ,  Bo Zhang

IPC: A61K39/395 ,  A61K45/06 ,  A61K31/138 ,  A61K31/337

CPC classification number: A61K39/39558 ,  A61K31/138 ,  A61K31/337 ,  A61K31/513 ,  A61K31/517 ,  A61K31/7068 ,  A61K33/24 ,  A61K45/06 ,  A61K2039/505 ,  A61K2039/507 ,  A61K2039/55 ,  C07K16/2863 ,  C07K16/32 ,  C07K2317/31 ,  C07K2317/73 ,  C07K2317/76 ,  A61K2300/00

Abstract: Provided are methods for overcoming resistance to an ErbB pathway inhibitor, such as an EGFR inhibitor or a HER2 inhibitor. The resistance may be acquired resistance to an EGFR inhibitor, such as acquired resistance to gefitinib. In the methods provided, a subject exhibiting resistance to an ErbB pathway inhibitor is selected and both an ErbB 3 inhibitor and a second ErbB pathway inhibitor are administered to the subject, such as an EGFR inhibitor or a HER2 inhibitor. Also provided are methods for inhibiting the growth of a tumor comprising a T790M EGFR mutation by contacting the tumor with an ErbB3 inhibitor and an EGFR inhibitor. Compositions for overcoming resistance to an ErbB pathway inhibitor, comprising both an ErbB 3 inhibitor and a second ErbB pathway inhibitor, such as an EGFR inhibitor or a HER2 inhibitor, are also provided.

Abstract translation: 提供了克服对ErbB途径抑制剂如EGFR抑制剂或HER2抑制剂的抗性的方法。 抗性可能是对EGFR抑制剂的获得性抗性，如对吉非替尼的获得性抗性。 在所提供的方法中，选择表现出对ErbB途径抑制剂的抗性的受试者，并且对受试者，例如EGFR抑制剂或HER2抑制剂施用ErbB 3抑制剂和第二ErbB途径抑制剂。 还提供了通过使肿瘤与ErbB3抑制剂和EGFR抑制剂接触来抑制包含T790M EGFR突变的肿瘤的生长的方法。 还提供了克服对ErbB通路抑制剂的抗性的组合物，其包含ErbB 3抑制剂和第二ErbB途径抑制剂，例如EGFR抑制剂或HER2抑制剂。

公开(公告)号：US20140234317A1

公开(公告)日：2014-08-21

申请号：US14116061

申请日：2012-05-04

Applicant: Matthew David Onsum ,  Clet Niyikiza ,  Victor Moyo ,  William Kubasek ,  Akos Czibere

Inventor： Matthew David Onsum ,  Clet Niyikiza ,  Victor Moyo ,  William Kubasek ,  Akos Czibere

IPC: C07K16/32 ,  A61K39/395 ,  A61K31/517 ,  A61K31/5377

CPC classification number: C07K16/32 ,  A61K31/517 ,  A61K31/5377 ,  A61K38/005 ,  A61K38/16 ,  A61K38/17 ,  A61K39/395 ,  A61K39/39558 ,  A61K45/06 ,  A61K2039/505 ,  A61K2039/545 ,  C07K2317/90 ,  A61K2300/00

Abstract: Methods are disclosed for preventing toxic drug-drug interactions during combination cancer therapy with a drug that is an anti-ErbB3 agent, such as an anti-ErbB3 antibody, together with a drug that is a tyrosine kinase inhibitor and/or a drug that binds to alpha-1 acid glycoprotein (e.g., erlotinib). Health care practitioners obtaining any one of the drugs are warned that when co-administering the drug that is an anti-ErbB3 agent with either or both of a drug that is a tyrosine kinase inhibitor and a drug that binds to alpha-1 acid glycoprotein, at least one of the co-administered drugs should be administered using a reduced dosage to prevent toxicity. In a reduced dosage, the amount of drug administered per unit time is reduced as compared to a dose that would be administered if the drug was administered as monotherapy. The reduced dosage can be, for example, a reduced drug dose or a reduced drug dosing frequency, or both. Compositions useful in practicing the disclosed methods are also provided.

Abstract translation: 公开了用于防止组合癌症治疗期间与作为抗ErbB3抗体的药物如抗ErbB3抗体以及与酪氨酸激酶抑制剂和/或药物结合的药物的有毒药物 - 药物相互作用的方法 到α-1酸性糖蛋白（例如，厄洛替尼）。 警告提供任何一种药物的卫生保健从业人员，当与作为酪氨酸激酶抑制剂的药物或与α-1酸性糖蛋白结合的药物中的任一种或两者共同施用作为抗ErbB3药物的药物时， 共同施用的药物中的至少一种应当使用减少的剂量来施用以防止毒性。 在减少的剂量中，与如果药物作为单一疗法施用时将施用的剂量相比，每单位时间给药的药物的量减少。 减少的剂量可以是例如降低的药物剂量或降低的药物给药频率，或两者。 还提供了在实践所公开的方法中有用的组合物。

公开(公告)号：US20110027291A1

公开(公告)日：2011-02-03

申请号：US12707521

申请日：2010-02-17

Applicant: Birgit SCHOEBERL ,  Brian HARMS ,  Francis David GIBBONS ,  Jonathan Basil FITZGERALD ,  Matthew David ONSUM ,  Ulrik NIELSEN ,  William KUBASEK

Inventor： Birgit SCHOEBERL ,  Brian HARMS ,  Francis David GIBBONS ,  Jonathan Basil FITZGERALD ,  Matthew David ONSUM ,  Ulrik NIELSEN ,  William KUBASEK

IPC: A61K39/395 ,  G01N33/566 ,  A61P35/00 ,  G06F7/60 ,  G06F19/00

CPC classification number: G01N33/6893 ,  A61K2039/505 ,  C07K16/2863 ,  C07K16/32 ,  C07K2317/31 ,  C12Q1/6809

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.

Abstract translation: 本发明提供了治疗患者的方法，所述方法包括用于预测细胞如肿瘤细胞的应答的方法用于治疗剂的治疗。 这些方法包括在细胞样本中测量细胞网络的一个或多个组分的水平，然后使用细胞的计算模型计算细胞的网络激活状态（NAS）或网络抑制状态（NIS） 网络。 然后基于已经计算的NAS或NIS值来预测细胞对治疗的反应。 本发明还包括用于细胞反应性的预测方法，其中使用统计分类算法将细胞（例如，肿瘤细胞）的NAS或NIS值的计算结合在一起。 还提供了用于预测用靶向ErbB信号通路中的组分的治疗剂对治疗的反应性的生物标志物。