Clinical Studies in Pediatric Solid Tumors

儿科实体瘤的临床研究

• 批准号: 9556767
• 负责人: LEE J. HELMAN
• 金额: $ 63万
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9556767
• 关键词: Adult; Antibodies; Biological; Biology; Childhood; Childhood Solid Neoplasm; Clinic; Clinical Research; Country; Dasatinib; Data; EWS-FLI1 fusion protein; Endocrinologist; Ewings sarcoma; Gastrointestinal Stromal Tumors; Genes; Genetic; Genetic Transcription; Genome; Genomics; Germ-Line Mutation; Goals; Heat-Shock Proteins 90; Hypermethylation; Immune checkpoint inhibitor; Immunologics; Institution; International; KDR gene; Laboratory Study; Lead; Mediation; Medical Oncologist; Methylation; Mutation; PARP inhibition; PDCD1LG1 gene; Patient-Focused Outcomes; Patients; Pediatric Oncologist; Pharmaceutical Preparations; Phase; Physicians; Plicamycin; Publishing; Rare Diseases; Recurrence; Renal carcinoma; Rhabdomyosarcoma; Running; Site; Surgeon; Testing; Toxic effect; United States National Institutes of Health; Work; arm; base; cancer genome; chemotherapy; childhood sarcoma; drug testing; high risk; high throughput screening; improved outcome; in vivo; inhibitor/antagonist; interest; irinotecan; kinase inhibitor; mutant; osteosarcoma; patient subsets; phase 1 study; phase 2 study; phase 3 study; predicting response; programs; promoter; response; src-Family Kinases; synergism; temozolomide; tumor; young adult

Osteosarcoma: As described above, we have written a Phase II study to test a PD L1 antibody in patients with recurrent osteosarcoma. The study will include built-in genomic and immunologic assessment of patients treated and will be performed at 4 institutions with St Jude being the lead institution. Ewings Sarcoma: Based partly on our previous finding of a study of an IGFIR antibody alone in the treatment of Ewing's sarcoma (results published several years ago), the COG has now opened a Phase III study comparing standard chemotherapy to chemotherapy plus an IGFIR Ab in high risk Ewing's sarcoma patients. We have recently established an international consortium to study PARP inhibitors in Ewings sarcoma based on published work of others and our unpublished data suggesting that Ewings tumors may be particularly sensitive to PARP inhibition. The study has almost completed accural with the combination of the PARPi, Niraparib and temozolomide, and an additional arm combining Niraparib with irinotecan. Rhabdomyosarcoma: Based upon our published work showing synergy between Src family kinase inhibitors and IGFIR inhibitors in rhabdmyosarcomas, we now have approval to test the combination of dasatinib, a SRC family kinase inhibitor, with an IGFIR Ab. Pediatric Gastrointestinal Stromal Tumors (GIST): We have continued our program to study pediatric GIST patients, a very rare disease that is biologically distinct from adult GIST patients. Our clinics at NIH bring in patients from across the country as well as physicians with interest/expertise in this rare disease from several centers across the country including surgeons, pediatric and medical oncologists as well as pediatric endocrinologists. Following up on our initial observation of germline mutations in SDH genes in sporadic pediatric GIST patients, we have now shown that the majority of tumors studied to date harbor mutations in one of the SDH A B C or D genes and it appears that around 80% of these patients harbor germline mutations in these genes. In addition, we have now shown that a number of patients with SDH deficiency but no identifiable mutation have a tumor-specific methylation of their SDHC promoter leading to silencing of SDHC expression. We have furthermore shown that all of these SDH-deficient GISTS also have global hypermethylation in the tumor genome. Based on responses of SDH mutant kidney cancers to VEGFR inhibitors such as vandetanib we opened a clinical study to test this drug in SDH mutant GIST tumors as well, but unfortunately there was no activity observed. We are currently completing a second study to test the potent DNMT inhibitor, guadecitabine in these pateints based upon the observed global hypermethylation in all SDH deficient GIST tumors and the specific SDHC promoter hypermethylation in a subset of patients.

骨肉瘤：如上所述，我们已经撰写了一项 II 期研究，以测试复发性骨肉瘤患者的 PD L1 抗体。该研究将包括对接受治疗的患者进行内置基因组和免疫学评估，并将在 4 家机构进行，其中 St Jude 是牵头机构。尤文氏肉瘤：部分基于我们之前单独使用 IGFIR 抗体治疗尤文氏肉瘤的研究结果（几年前发表的结果），COG 现已开展一项 III 期研究，比较标准化疗与化疗加 IGFIR 抗体的治疗效果。高危尤文氏肉瘤患者。我们最近建立了一个国际联盟，根据其他人已发表的工作和我们未发表的数据来研究尤文氏肉瘤中的 PARP 抑制剂，这些数据表明尤文氏肿瘤可能对 PARP 抑制特别敏感。该研究几乎完成了 PARPi、尼拉帕尼和替莫唑胺联合治疗的精确性研究，以及尼拉帕尼和伊立替康联合治疗的附加研究。横纹肌肉瘤：基于我们已发表的研究显示 Src 家族激酶抑制剂和 IGFIR 抑制剂在横纹肌肉瘤中的协同作用，我们现在已获准测试 SRC 家族激酶抑制剂达沙替尼与 IGFIR Ab 的组合。儿童胃肠道间质瘤 (GIST)：我们继续研究儿童 GIST 患者的计划，这是一种非常罕见的疾病，在生物学上与成人 GIST 患者不同。我们 NIH 的诊所吸引了来自全国各地的患者以及来自全国多个中心对这种罕见疾病感兴趣/具有专业知识的医生，包括外科医生、儿科和肿瘤内科医生以及儿科内分泌科医生。继我们对散发性儿科 GIST 患者 SDH 基因种系突变的初步观察之后，我们现在表明，迄今为止研究的大多数肿瘤都含有 SDH A B C 或 D 基因之一的突变，并且似乎其中大约 80%患者的这些基因中存在种系突变。此外，我们现在已经证明，许多 SDH 缺陷但没有可识别突变的患者的 SDHC 启动子存在肿瘤特异性甲基化，导致 SDHC 表达沉默。我们还进一步证明，所有这些 SDH 缺陷的 GISTS 的肿瘤基因组中也存在整体高甲基化。根据 SDH 突变肾癌对 VEGFR 抑制剂（如凡德他尼）的反应，我们开展了一项临床研究，在 SDH 突变 GIST 肿瘤中测试该药物，但遗憾的是没有观察到活性。我们目前正在完成第二项研究，根据在所有 SDH 缺陷 GIST 肿瘤中观察到的整体高甲基化以及一部分患者中特定的 SDHC 启动子高甲基化，在这些患者中测试强效 DNMT 抑制剂瓜地西他滨。

项目成果

Osteosarcoma: The same old drugs or more?

• DOI: 10.1200/jco.2008.17.1108
• 发表时间: 2008-06-20
• 期刊: JOURNAL OF CLINICAL ONCOLOGY
• 影响因子: 45.3
• 作者: Bielack, Stefan S.;Marina, Neyssa;Reaman, Gregory H.
• 通讯作者: Reaman, Gregory H.

Progress in the curative treatment of childhood hematologic malignancies.

儿童血液系统恶性肿瘤的治疗进展。

• DOI: 10.1093/jnci/djn306
• 发表时间: 2008
• 期刊: Journal of the National Cancer Institute
• 作者: Wayne,AlanS;Reaman,GregoryH;Helman,LeeJ
• 通讯作者: Helman,LeeJ

Dilemmas associated with congenital ewing sarcoma family tumors.

与先天性尤文肉瘤家族肿瘤相关的困境。

• DOI: 10.1097/mph.0b013e31815cf71f
• 发表时间: 2008
• 期刊: Journal of pediatric hematology/oncology
• 作者: Kim,SuYoung;Tsokos,Maria;Helman,LeeJ
• 通讯作者: Helman,LeeJ

Molecular Subtypes of KIT/PDGFRA Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Gastrointestinal Stromal Tumor Clinic.

• DOI: 10.1001/jamaoncol.2016.0256
• 发表时间: 2016-07-01
• 期刊: JAMA oncology
• 影响因子: 28.4
• 作者: Boikos SA;Pappo AS;Killian JK;LaQuaglia MP;Weldon CB;George S;Trent JC;von Mehren M;Wright JA;Schiffman JD;Raygada M;Pacak K;Meltzer PS;Miettinen MM;Stratakis C;Janeway KA;Helman LJ
• 通讯作者: Helman LJ