公开(公告)号：US11845994B2

公开(公告)日：2023-12-19

申请号：US17225717

申请日：2021-04-08

申请人： The Johns Hopkins University ,  University of Torino

发明人： Victor E. Velculescu ,  Eniko Papp ,  Vilmos Adleff ,  Andrea Bertotti ,  Livio Trusolino

IPC分类号： C12Q1/6886 ,  A61K39/395 ,  C07K16/28 ,  C12Q1/68 ,  A61P35/00 ,  A61K39/00

CPC分类号： C12Q1/6886 ,  A61K39/395 ,  A61P35/00 ,  C07K16/2863 ,  C12Q1/68 ,  A61K2039/505 ,  A61K2039/55 ,  C07K2317/24 ,  C07K2317/76 ,  C12Q2600/106 ,  C12Q2600/156 ,  C12Q2600/158

摘要： Recent large-scale analyses have demonstrated that the genomic landscape of human cancer is complex and variable among individuals of the same tumor type. Such underlying genetic differences may in part be responsible for the varying therapeutic responses observed in cancer patients. To examine the effect of somatic genetic changes in colorectal cancer on sensitivity to a common targeted therapy, we performed complete exome sequence and copy number analyses of 129 tumors that were KRAS wild-type and analyzed their response to anti-EGFR antibody blockade in patient-derived tumorgraft models. In addition to previously identified genes, we detected mutations in ERBB2, EGFR, FGFR1, PDGFRA, and MAP2K1 as potential mechanisms of primary resistance to this therapy. Alterations in the ectodomain of EGFR were identified in patients with acquired resistance to EGFR blockade. Amplifications and sequence changes in the tyrosine kinase receptor adaptor gene IRS2 were identified in tumors with increased sensitivity to anti-EGFR therapy. Therapeutic resistance to EGFR blockade could be overcome in tumorgraft models through combinatorial therapies targeting actionable genes. These analyses provide a systematic approach to evaluate response to targeted therapies in human cancer, highlight additional mechanisms of responsiveness to anti-EGFR therapies, and provide additional avenues for intervention in the management of colorectal cancer.

公开(公告)号：US20240344136A1

公开(公告)日：2024-10-17

申请号：US18516168

申请日：2023-11-21

申请人： The Johns Hopkins University ,  University of Torino

发明人： Victor E. Velculsecu ,  Eniko Papp ,  Vilmos Adleff ,  Andrea Bertotti ,  Livio Trusolino

IPC分类号： C12Q1/6886 ,  A61K39/00 ,  A61K39/395 ,  A61P35/00 ,  C07K16/28 ,  C12Q1/68

CPC分类号： C12Q1/6886 ,  A61K39/395 ,  A61P35/00 ,  C07K16/2863 ,  C12Q1/68 ,  A61K2039/505 ,  A61K2039/55 ,  C07K2317/24 ,  C07K2317/76 ,  C12Q2600/106 ,  C12Q2600/156 ,  C12Q2600/158

摘要： Recent large-scale analyses have demonstrated that the genomic landscape of human cancer is complex and variable among individuals of the same tumor type. Such underlying genetic differences may in part be responsible for the varying therapeutic responses observed in cancer patients. To examine the effect of somatic genetic changes in colorectal cancer on sensitivity to a common targeted therapy, we performed complete exome sequence and copy number analyses of 129 tumors that were KRAS wild-type and analyzed their response to anti-EGFR antibody blockade in patient-derived tumorgraft models. In addition to previously identified genes, we detected mutations in ERBB2, EGFR, FGFR1, PDGFRA, and MAP2K1 as potential mechanisms of primary resistance to this therapy. Alterations in the ectodomain of EGFR were identified in patients with acquired resistance to EGFR blockade. Amplifications and sequence changes in the tyrosine kinase receptor adaptor gene IRS2 were identified in tumors with increased sensitivity to anti-EGFR therapy. Therapeutic resistance to EGFR blockade could be overcome in tumorgraft models through combinatorial therapies targeting actionable genes. These analyses provide a systematic approach to evaluate response to targeted therapies in human cancer, highlight additional mechanisms of responsiveness to anti-EGFR therapies, and provide additional avenues for intervention in the management of colorectal cancer.

公开(公告)号：US20210301352A1

公开(公告)日：2021-09-30

申请号：US17225717

申请日：2021-04-08

申请人： The Johns Hopkins University ,  University of Torino

发明人： Victor E. Velculescu ,  Eniko Papp ,  Vilmos Adleff ,  Andrea Bertotti ,  Livio Trusolino

IPC分类号： C12Q1/6886 ,  A61K39/395 ,  C07K16/28 ,  C12Q1/68 ,  A61P35/00

摘要： Recent large-scale analyses have demonstrated that the genomic landscape of human cancer is complex and variable among individuals of the same tumor type. Such underlying genetic differences may in part be responsible for the varying therapeutic responses observed in cancer patients. To examine the effect of somatic genetic changes in colorectal cancer on sensitivity to a common targeted therapy, we performed complete exome sequence and copy number analyses of 129 tumors that were KRAS wild-type and analyzed their response to anti-EGFR antibody blockade in patient-derived tumorgraft models. In addition to previously identified genes, we detected mutations in ERBB2, EGFR, FGFR1, PDGFRA, and MAP2K1 as potential mechanisms of primary resistance to this therapy. Alterations in the ectodomain of EGFR were identified in patients with acquired resistance to EGFR blockade. Amplifications and sequence changes in the tyrosine kinase receptor adaptor gene IRS2 were identified in tumors with increased sensitivity to anti-EGFR therapy. Therapeutic resistance to EGFR blockade could be overcome in tumorgraft models through combinatorial therapies targeting actionable genes. These analyses provide a systematic approach to evaluate response to targeted therapies in human cancer, highlight additional mechanisms of responsiveness to anti-EGFR therapies, and provide additional avenues for intervention in the management of colorectal cancer.

公开(公告)号：US10982287B2

公开(公告)日：2021-04-20

申请号：US15541521

申请日：2016-01-06

申请人： The Johns Hopkins University ,  University of Torino

发明人： Victor Velculescu ,  Eniko Papp ,  Vilmos Adleff ,  Andrea Bertotti ,  Livio Trusolino

IPC分类号： C12Q1/6886 ,  A61K39/395 ,  C07K16/28 ,  C12Q1/68 ,  A61P35/00 ,  A61K39/00

摘要： Recent large-scale analyses have demonstrated that the genomic landscape of human cancer is complex and variable among individuals of the same tumor type. Such underlying genetic differences may in part be responsible for the varying therapeutic responses observed in cancer patients. To examine the effect of somatic genetic changes in colorectal cancer on sensitivity to a common targeted therapy, we performed complete exome sequence and copy number analyses of 129 tumors that were KRAS wild-type and analyzed their response to anti-EGFR antibody blockade in patient-derived tumorgraft models. In addition to previously identified genes, we detected mutations in ERBB2, EGFR, FGFR1, PDGFRA, and MAP2K1 as potential mechanisms of primary resistance to this therapy. Alterations in the ectodomain of EGFR were identified in patients with acquired resistance to EGFR blockade. Amplifications and sequence changes in the tyrosine kinase receptor adaptor gene IRS2 were identified in tumors with increased sensitivity to anti-EGFR therapy. Therapeutic resistance to EGFR blockade could be overcome in tumorgraft models through combinatorial therapies targeting actionable genes. These analyses provide a systematic approach to evaluate response to targeted therapies in human cancer, highlight additional mechanisms of responsiveness to anti-EGFR therapies, and provide additional avenues for intervention in the management of colorectal cancer.

公开(公告)号：US20170327898A1

公开(公告)日：2017-11-16

申请号：US15596517

申请日：2017-05-16

申请人： THE JOHNS HOPKINS UNIVERSITY

发明人： Victor Velculescu ,  Eniko Papp ,  Vilmos Adleff

IPC分类号： C12Q1/68 ,  G06F19/00 ,  G06F19/18

CPC分类号： C12Q1/6886 ,  C12Q2600/112 ,  C12Q2600/118 ,  C12Q2600/156 ,  G06F19/3481 ,  G16B10/00 ,  G16B20/00 ,  G16H50/30

摘要： The evolutionary origin of high-grade serous ovarian carcinoma remains largely unknown. The vast majority of tumor-specific genomic alterations from ovarian cancers are present in fallopian tube STIC lesions (average of 55 sequence alterations per tumor), including those affecting TP53, BRCA1, BRCA2 or PTEN genes. A quantitative evolutionary analysis indicated that tumors of the fallopian tube were the likely precursors of ovarian cancer and could directly give rise to metastatic lesions. These analyses suggest that there may be less than two years between the development of a STIC and the initiation of fallopian tube tumors, ovarian tumors or other metastases. Thus there may be a short window between the development of a STIC and the initiation of ovarian tumors or other metastases, highlighting the importance of the prevention, early detection and therapeutic intervention of this disease.

公开(公告)号：US20210355545A1

公开(公告)日：2021-11-18

申请号：US17284948

申请日：2019-10-15

申请人： The Johns Hopkins University ,  The Regents of the University of California

发明人： Victor E. Velculescu ,  Robert B. Scharpf ,  Eniko Papp ,  Dorothy Hallberg ,  Dennis Slamon ,  Gottfried Konecny

IPC分类号： C12Q1/6886

摘要： This document relates to methods and materials for assessing and/or treating mammals (e.g., humans) having cancer. For example, methods and materials for identifying a mammal as being likely to respond to a particular cancer treatment, and, optionally, for treating the mammal, are provided.