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    C. NOVYI FOR THE TREATMENT OF SOLID TUMORS IN HUMANS
    1.
    发明公开
    C. NOVYI FOR THE TREATMENT OF SOLID TUMORS IN HUMANS 审中-公开

    公开(公告)号：EP4108248A1

    公开(公告)日：2022-12-28

    申请号：EP22171112.0

    申请日：2014-03-28

    申请人： Biomed Valley Discoveries, Inc. ,  The Johns Hopkins University

    发明人： SAHA, Saurabh ,  ZHOU, Shibin ,  VOGELSTEIN, Bert ,  KINZLER, Kenneth, W.

    IPC分类号： A61K35/66 ,  A61P35/00

    摘要： The present invention provides, inter alia, methods for treating or ameliorating an effect of a solid tumor present in a human. These methods include administering intratumorally to the human a unit dose of C. novyi, preferably C. novyi NT, colony forming units (CFUs), which contains about 1 × 10 3 -1 × 10 7 CFUs suspended in a pharmaceutically acceptable carrier or solution. Methods for debulking a solid tumor present in a human, methods for ablating a solid tumor present in a human, a method for microscopically precise excision of tumor cells in a human, methods for treating or ameliorating an effect of a solid tumor that has metastasized to one or more sites in a human, unit doses of C. novyi, preferably C. novyi NT, CFUs, and kits for treating or ameliorating an effect of a solid tumor present in a human are also provided.

    MUTATIONS OF THE PIK3CA GENE IN HUMAN CANCERS
    3.
    发明公开
    MUTATIONS OF THE PIK3CA GENE IN HUMAN CANCERS 审中-公开
    PIK3CA基因在人类癌症中的突变

    公开(公告)号：EP3296407A1

    公开(公告)日：2018-03-21

    申请号：EP17197306.8

    申请日：2005-02-18

    申请人： The Johns Hopkins University

    发明人： SAMUELS, Yardena ,  VELCULESCU, Victor ,  KINZLER, Kenneth ,  VOGELSTEIN, Bert

    IPC分类号： C12Q1/68

    CPC分类号： C12Q1/6886 ,  C12Q2600/156

    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 P13K 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 P13K 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.

    摘要翻译： 已知磷脂酰肌醇3-激酶（PI3K）是信号传导途径的重要调节剂。 为了确定PI3K是否在癌症中被遗传改变，我们分析了P13K基因家族的序列并发现一个家族成员PIK3CA在结肠和其他器官的癌症中经常发生突变。 大部分突变聚集在P13K螺旋或激酶结构域内的两个位置附近。 PIK3CA代表人类癌症中鉴定的突变最严重的癌基因之一，并且可用作诊断和治疗靶标。

    SUPPRESSION OF MYELOID DERIVED SUPPRESSOR CELLS AND IMMUNE CHECKPOINT BLOCKADE
    5.
    发明公开
    SUPPRESSION OF MYELOID DERIVED SUPPRESSOR CELLS AND IMMUNE CHECKPOINT BLOCKADE 审中-公开
    抑制髓样衍生抑制细胞和免疫检测点阻断

    公开(公告)号：EP3169326A1

    公开(公告)日：2017-05-24

    申请号：EP15822398.2

    申请日：2015-07-13

    申请人： The Johns Hopkins University

    发明人： ZHOU, Shibin ,  VOGELSTEIN, Bert ,  KINZLER, Kenneth W. ,  KIM, KiBem

    IPC分类号： A61K31/44 ,  A61K31/706 ,  A61K39/395 ,  A61P35/00

    CPC分类号： A61K39/39558 ,  A61K31/437 ,  A61K31/4406 ,  A61K31/706 ,  A61K35/742 ,  A61K39/3955 ,  A61K45/06 ,  A61K2039/505 ,  C07K16/2818 ,  C07K2317/34 ,  C07K2317/92 ,  A61K2300/00

    摘要： Impressive responses have been observed in patients treated with checkpoint inhibitory anti-PD-1 or anti-CTLA-4 antibodies. However, immunotherapy against poorly immunogenic cancers remains a challenge. Treatment with both anti-PD-1 and anti-CTLA-4 antibodies were unable to eradicate large, modestly immunogenic CT26 tumors or metastatic 4T1 tumors. However, co-treatment with epigenetic modulating drugs and checkpoint inhibitors markedly improved treatment outcomes, curing more than 80% of them. Functional studies revealed that the primary targets of the epigenetic modulators were myeloid-derived suppressor cells (MDSCs). A PI3K-inhibitor that reduced circulating MDSCs also cured 80% of mice with metastatic 4T1 tumors when combined with immune checkpoint inhibitors. Thus, cancers resistant to immune checkpoint blockade can be cured by eliminating MDSCs.

    摘要翻译： 在用检查点抑制性抗PD-1或抗CTLA-4抗体治疗的患者中观察到令人印象深刻的反应。 然而，针对免疫原性差的癌症的免疫疗法仍然是一个挑战。 用抗PD-1和抗CTLA-4抗体治疗不能根除大的，适度的免疫原性CT26肿瘤或转移性4T1肿瘤。 然而，与表观遗传调节药物和检查点抑制剂的联合治疗显着改善了治疗结果，治愈了其中80％以上。 功能研究表明，表观遗传调节剂的主要靶点是骨髓衍生抑制细胞（MDSC）。 当与免疫检查点抑制剂结合时，减少循环MDSC的PI3K抑制剂也治愈了80％具有转移性4T1肿瘤的小鼠。 因此，抵抗免疫检查点阻断的癌症可以通过消除MDSC来治愈。

    ENDOTHELIAL CELL EXPRESSION PATTERNS
    8.
    发明授权
    ENDOTHELIAL CELL EXPRESSION PATTERNS 有权
    内皮细胞表达模式

    公开(公告)号：EP1572867B1

    公开(公告)日：2014-07-23

    申请号：EP02728495.9

    申请日：2002-04-10

    申请人： The Johns Hopkins University

    发明人： CARSON-WALTER, Eleanor ,  ST. CROIX, Brad ,  KINZLER, Kenneth, W. ,  VOGELSTEIN, Bert

    IPC分类号： C07K14/705 ,  G01N33/53 ,  C07K16/30

    CPC分类号： C07K14/705 ,  A61K2039/505 ,  C07K14/4748 ,  C07K16/28 ,  G01N33/5023 ,  G01N33/68 ,  G01N2333/4703 ,  G01N2500/04 ,  G01N2800/7014 ,  G01N2800/7028

    摘要： To gain a better understanding of tumor angiogenesis, new techniques for isolating endothelial cells (ECs) and evaluating gene expression patterns were developed. When transcripts from ECs derived from normal and malignant colorectal tissues were compared with transcripts from non-endothelial cells, over 170 genes predominantly expressed in the endothelium were identified. Comparison between normal- and tumor-derived endothelium revealed 79 differentially expressed genes, including 46 that were specifically elevated in tumor-associated endothelium. Experiments with representative genes from this group demonstrated that most were similarly expressed in the endothelium of primary lung, breast, brain, and pancreatic cancers as well as in metastatic lesions of the liver. These results demonstrate that neoplastic and normal endothelium in humans are distinct at the molecular level, and have significant implications for the development of anti-angiogenic therapies in the future.

    MUTATIONS IN PANCREATIC NEOPLASMS
    9.
    发明公开
    MUTATIONS IN PANCREATIC NEOPLASMS 有权
    PANKREAS-NEOPLASMEN中的突变体

    公开(公告)号：EP2723896A2

    公开(公告)日：2014-04-30

    申请号：EP12802288.6

    申请日：2012-06-22

    申请人： The Johns Hopkins University

    发明人： VOGELSTEIN, Bert ,  KINZLER, Kenneth W. ,  WU, Jian ,  DIAZ, Luis ,  PAPADOPOULOS, Nickolas ,  MATTHAEI, Hanno ,  HRUBAN, Ralph ,  MAITRA, Anirban

    IPC分类号： C12Q1/68 ,  C12N15/11

    CPC分类号： C12Q1/6886 ,  C12Q2600/112 ,  C12Q2600/156

    摘要： To help reveal the pathogenesis of these lesions, we purified the DNA from Intraductal Papillary Mucinous Neoplasm (IPMN) cyst fluids from 19 patients and searched for mutations in 169 genes commonly altered in human cancers. We identified recurrent mutations at codon 201 of GNAS. We found that GNAS mutations were present in 66% of IPMNs and that either KRAS or GNAS mutations could be identified in 96%. In eight cases, we could investigate invasive adenocarcinomas that developed in association with IPMNs containing GNAS mutations. In seven of these eight cases, the GNAS mutations present in the IPMNs were also found in the invasive lesion. GNAS mutations were not found in other types of cystic neoplasms of the pancreas or in invasive adenocarcinomas not associated with IPMNs. These data suggest that GNAS mutations can inform the diagnosis and management of patients with cystic pancreatic lesions.

    摘要翻译： 为了揭示这些病变的发病机制，我们从19名患者的导管内乳头状粘液性肿瘤（IPMN）囊肿液中纯化了DNA，并在人类癌症中通常改变的169种基因中进行了突变检测。 我们在GNAS的201号密码子处鉴定了复发性突变。 我们发现GNAS突变存在于66％的IPMNs中，KRAS或GNAS突变可以在96％中鉴定。 在8例中，我们可以研究与含有GNAS突变的IPMN相关的侵袭性腺癌。 在这8例中有7例中，存在于IPMNs中的GNAS突变也在侵袭性损伤中发现。 在其他类型的胰腺囊性肿瘤或与IPMN无关的侵袭性腺癌中未发现GNAS突变。 这些数据表明，GNAS突变可以为囊性胰腺病变患者的诊断和治疗提供依据。

    PERSONALIZED TUMOR BIOMARKERS
    10.
    发明公开
    PERSONALIZED TUMOR BIOMARKERS 有权
    个性化肿瘤标志物

    公开(公告)号：EP2536854A2

    公开(公告)日：2012-12-26

    申请号：EP11745196.3

    申请日：2011-02-17

    申请人： The Johns Hopkins University

    发明人： VOGELSTEIN, Bert ,  KINZLER, Kenneth W. ,  VELCULESCU, Victor ,  DIAZ, Luis ,  LEARY, Rebecca J.

    IPC分类号： C12Q1/68 ,  C12N15/11 ,  C40B40/06

    CPC分类号： C12Q1/6886 ,  C12Q2600/156

    摘要： Clinical management of human cancer is dependent on the accurate monitoring of residual and recurrent tumors. We have developed a method, called personalized analysis of rearranged ends (PARE), which can identify translocations in solid tumors. Analysis of four colorectal and two breast cancers revealed an average of nine rearranged sequences (range 4 to 15) per tumor. Polymerase chain reaction with primers spanning the breakpoints were able to detect mutant DNA molecules present at levels lower than 0.001% and readily identified mutated circulating DNA in patient plasma samples. This approach provides an exquisitely sensitive and broadly applicable approach for the development of personalized biomarkers to enhance the clinical management of cancer patients.