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Targeting RAS in Pediatric Cancer

靶向 RAS 治疗儿童癌症

基本信息

批准号：
10926381
负责人：
Marielle Yohe
金额：
$ 23.8万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
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/10926381
关键词：
Acute Lymphocytic Leukemia Acute Myelocytic Leukemia BRAF gene Benign CBL gene Cancer Therapy Evaluation Program Cells Childhood Childhood Melanoma Clinical Clinical Trials Collaborations Division of Cancer Epidemiology and Genetics Drug Combinations Embryonal Rhabdomyosarcoma Enrollment Eosinophilic Granuloma Funding Genomics Glues Grant Hematologic Neoplasms Human Juvenile Myelomonocytic Leukemia KRAS2 gene MEKs Malignant - descriptor Malignant Childhood Neoplasm Malignant neoplasm of thyroid Manuscripts Molecular Mutate Mutation NF1 gene National Center for Advancing Translational Sciences Natural History Neuroblastoma Neurofibromatosis 1 Neurofibrosarcoma Nevus Oncogenic PIK3CG gene PTPN11 gene Participant Patients Pediatric Hematology Pediatric Neoplasm Pilocytic Astrocytoma Plexiform Neurofibroma Protein Isoforms Protocols documentation RAS genes Ras/Raf Relapse Rhabdomyosarcoma Signal Transduction Somatic Mutation Testing Tipifarnib Work arm clinical translation driver mutation efficacy evaluation efficacy testing giant congenital nevus in vivo inhibitor loss of function mutation mutant novel novel drug combination pre-clinical ras GTPase-Activating Proteins synergism targeted agent tumor

项目摘要

This project will be a major focus of the lab moving forward. We have initiated several subprojects with respect to this project; the aims and accomplishments in these subprojects are listed below: 1) A project to identify synergistic drug combinations in RAS mutated neuroblastoma was funded by NCATS, which identified a novel combination of a MEK inhibitor and a cereblon modulator. Work has begun to validate the synergy and establish a mechanism (collaboration with Carol Thiele and Craig Thomas) 2) A project to evaluate a combination of romidepsin and the dual BRD4/PI3K inhibitor, SF2523, in RAS-driven pediatric cancers was funded by CAPR and work has begun on this project. The first aim of the project, evaluating PK after different modes of administration of romidepsin, has been completed (collaboration with Rob Robey). The second aim of this project, evaluation of the efficacy of the combination in RMS, revealed disappointing efficacy of the combination in vivo. 3) Evaluating the efficacy of the combination of a MEK inhibitor and pan-RAF inhibitor in RMS (collaboration with Angelina Vaseva). This work led to a collaborative manuscript that is in resubmission and a concept that was approved by ComboMATCH for clinical translation. The protocol (EAY191-C1) will be open in Q3 with Dr. Yohe as chair. 4) Evaluating the efficacy of tipifarnib in HRAS mutant RMS. I am the vice-chair of the APEC1621M arm of the CTEP-COG Pediatric MATCH trial, which will evaluate the efficacy of tipifarnib in HRAS-mutant pediatric cancers. This protocol has so far enrolled 5 participants. In addition, I am collaborating with Christine Pratilas to evaluate tipifarnib in HRAS mutated RMS preclinically. I am collaborating with Rob Kortum to evaluate combinations of tipifarnib in thyroid cancer. 5) Evaluating the efficacy of the molecular glue VS-6766 in rhabdomyosarcoma and neuroblastoma (collaboration with Angelina Vaseva). Additionally Drs. Vaseva, Pratilas and I have received a Rally grant for our collaborative work targeting RAS in rhabdomyosarcoma. 6) We have begun to evaluate the efficacy of KRAS G12C inhibitors in neuroblastoma (ARS-1620, AMG 510, AZD1569, MRTX849). Interestingly, in collaboration with Dr. Kent Rossman, we have been able to show efficacy of these inhibitors in cells with HRAS and NRAS G12C. 7) We have also recently started a collaboration with Dr. Michael Sargen in DCEG to study the natural history of pediatric melanoma, particularly that arising in large congenital nevi (NRAS driven). We also plan to test the efficacy of selumetinib in patients with large/giant congenital nevi. This trial has undergone SRC review.

这个项目将是实验室向前发展的一个主要重点。我们已经启动了关于该项目的几个子项目;这些子项目的目标和成就如下所示：1）NCATS资助了一个确定RAS突变神经母细胞瘤协同药物组合的项目，该项目确定了MEK抑制剂和cereblon调节剂的新型组合。已经开始验证协同作用并建立机制的工作（与Carol Thiele和克雷格托马斯合作）2）评估罗米地辛和双重BRD 4/PI 3 K抑制剂SF 2523在RAS驱动的儿科癌症中的组合的项目由CAPR资助，并且已经开始该项目的工作。该项目的第一个目标是评估罗米地辛不同给药模式后的PK，已经完成（与Rob Robey合作）。该项目的第二个目的是评价该组合在RMS中的疗效，结果显示该组合在体内的疗效令人失望。3)评价MEK抑制剂和泛RAF抑制剂联合治疗RMS的疗效（与Angelina Vaseva合作）。这项工作导致了一份正在重新提交的合作手稿，以及一个由ComboMATCH批准用于临床翻译的概念。方案（EAY 191-C1）将于第3季度开放，由Yohe博士担任主席。4)评估替吡法尼在HRAS突变型RMS中的疗效。我是CTEP-COG儿科MATCH试验APEC 1621 M组的副主席，该试验将评估tipifarnib在HRAS突变儿科癌症中的疗效。该方案迄今为止已招募了5名参与者。此外，我正在与克莉丝汀Pratilas合作，以临床前评估替吡法尼在HRAS突变RMS中的作用。我正在与Rob Kortum合作评估甲状腺癌中tipifarnib的组合。5)评价分子胶VS-6766在横纹肌肉瘤和神经母细胞瘤中的疗效（与Angelina Vaseva合作）。此外，Vaseva博士，Pratilas和我已经收到了拉力赛资助，用于我们针对横纹肌肉瘤RAS的合作工作。6)我们已开始评价KRAS G12 C抑制剂（ARS-1620、AMG 510、AZD 1569、MRTX 849）在神经母细胞瘤中的疗效。有趣的是，与肯特罗斯曼博士合作，我们已经能够在HRAS和NRAS G12 C细胞中显示这些抑制剂的疗效。7)我们最近还开始与DCEG的Michael Sargen博士合作，研究儿童黑色素瘤的自然史，特别是在大先天性痣（NRAS驱动）中出现的黑色素瘤。我们还计划测试司美替尼在大/巨大型先天性痣患者中的疗效。本试验已接受SRC审查。