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    MUTATIONS OF THE PIK3CA GENE IN HUMAN CANCERS
    1.
    发明申请
    MUTATIONS OF THE PIK3CA GENE IN HUMAN CANCERS 审中-公开

    公开(公告)号：US20200024671A1

    公开(公告)日：2020-01-23

    申请号：US16595055

    申请日：2019-10-07

    申请人： The Johns Hopkins University

    发明人： Yardena Samuels ,  Victor E. Velculescu ,  Kenneth W. Kinzler ,  Bert Vogelstein

    IPC分类号： C12Q1/6886

    摘要： Phosphatidylinositol 3-kinases (PI3Ks) are known to be important regulators of signaling pathways. To determine whether PI3Ks are genetically altered in cancers, we analyzed the sequences of the PI3K gene family and discovered that one family member, PIK3CA, is frequently mutated in cancers of the colon and other organs. The majority of mutations clustered near two positions within the PI3K helical or kinase domains. PIK3CA represents one of the most highly mutated oncogenes yet identified in human cancers and is useful as a diagnostic and therapeutic target.

    MUTATIONS OF THE PIK3CA GENE IN HUMAN CANCERS
    5.
    发明申请
    MUTATIONS OF THE PIK3CA GENE IN HUMAN CANCERS 审中-公开

    公开(公告)号：US20200248275A1

    公开(公告)日：2020-08-06

    申请号：US16853230

    申请日：2020-04-20

    申请人： The Johns Hopkins University

    发明人： Yardena Samuels ,  Victor E. Velculescu ,  Kenneth W. Kinzler ,  Bert Vogelstein

    IPC分类号： C12Q1/6886 ,  A61K48/00

    摘要： Phosphatidylinositol 3-kinases (PI3Ks) are known to be important regulators of signaling pathways. To determine whether PI3Ks are genetically altered in cancers, we analyzed the sequences of the PI3K gene family and discovered that one family member, PIK3CA, is frequently mutated in cancers of the colon and other organs. The majority of mutations clustered near two positions within the PI3K helical or kinase domains. PIK3CA represents one of the most highly mutated oncogenes yet identified in human cancers and is useful as a diagnostic and therapeutic target.

    Response to EGFR blockade
    7.
    发明授权
    Response to EGFR blockade 有权

    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.

    GENOMIC ALTERATIONS IN THE TUMOR AND CIRCULATION OF PANCREATIC CANCER PATIENTS
    8.
    发明申请
    GENOMIC ALTERATIONS IN THE TUMOR AND CIRCULATION OF PANCREATIC CANCER PATIENTS 有权

    公开(公告)号：US20210108256A1

    公开(公告)日：2021-04-15

    申请号：US17080201

    申请日：2020-10-26

    申请人： The Johns Hopkins University

    发明人： Victor E. Velculescu ,  Mark Sausen ,  Vilmos Adleff ,  Jillian A. Phallen

    IPC分类号： C12Q1/6827 ,  C12Q1/6886 ,  C12Q1/6816

    摘要： Pancreatic adenocarcinoma has the worst overall mortality of any solid tumor, with only 7% of patients surviving after 5 years. To evaluate the clinical implications of genomic alterations in this low cellularity tumor type, we deeply sequenced the genomes of 101 enriched pancreatic adenocarcinomas from patients who underwent potentially curative resections and used non-invasive approaches to examine tumor specific mutations in the circulation of these patients. These analyses revealed somatic mutations in chromatin regulating genes including MLL and ARID1A in 20% of patients that were associated with improved survival. Liquid biopsy analyses of cell free plasma DNA revealed that 43% of patients with localized disease had detectable circulating tumor DNA (ctDNA) in their blood at the time of diagnosis. Detection of ctDNA after resection predicted clinical relapse and poor outcome, and disease recurrence by ctDNA was detected 6.5 months earlier than with standard CT imaging.