Targeting RAS in Pediatric Cancer

靶向 RAS 治疗儿童癌症

• 批准号: 10262526
• 负责人: Marielle Yohe
• 金额: $ 15.12万
• 依托单位: DIVISION OF BASIC 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/10262526
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Antisense Oligonucleotides; BCL1 Oncogene; BRAF gene; Benign; CBL gene; Cancer Therapy Evaluation Program; Childhood; Childhood Melanoma; Clinical; Clinical Trials; Collaborations; Drug Combinations; Embryonal Rhabdomyosarcoma; Eosinophilic Granuloma; Funding; Genomics; Hematologic Neoplasms; Human; Juvenile Myelomonocytic Leukemia; KRAS2 gene; MEKs; Malignant - descriptor; Malignant Childhood Neoplasm; Medicine; Mutate; Mutation; Neuroblastoma; Neurofibromatosis 1; Neurofibrosarcoma; Nevus; Oncogenic; PTPN11 gene; 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; driver mutation; efficacy evaluation; inhibitor/antagonist; loss of function mutation; mutant; novel; novel drug combination; pre-clinical; ras GTPase-Activating Proteins; synergism; targeted agent; tumor

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: 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) 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, is ongoing. Evaluating the efficacy of the combination of a MEK inhibitor and pan-RAF inhibitor in RMS (collaboration with Angelina Vaseva). Evaluating the efficacy of the combination of a MEK inhibitor and a BCL-XL inhibitor in RMS (collaboration with Ben Braun). Evaluating the combination of a MEK inhibitor and a SHP2 inhibitor in NB (collaboration with Meredith Irwin). I will serve as 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 (protocol now open). 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 RMS and NB. We have begun to evaluate the efficacy of KRAS G12C inhibitors in neuroblastoma (ARS-1620, AMG 510, AZD1569, MRTX849). MCRADA in place to evaluate KRAS antisense oligonucleotide in pediatric cancers (AZD4785, now Ionis). We have a new MCRADA with Revolution Medicines to evaluate SHP2 inhibitors in RMS and RASopathies. Finally, we will also evaluate a novel switch I/II pocket binder BI 2852.

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这个项目的几个子项目;这些子项目的目标和成就如下所示：NCATS资助了一个项目，以确定RAS突变神经母细胞瘤的协同药物组合，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）一个评估罗米地辛和双重BRD 4/PI 3 K抑制剂SF 2523组合治疗RAS驱动的儿科癌症的项目由CAPR资助，该项目的工作已经开始。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联合用药在RMS中的疗效，目前正在进行中。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）。评价MEK抑制剂和BCL-XL抑制剂联合治疗RMS的疗效（与Ben Braun合作）。评估MEK抑制剂和SHP 2抑制剂在NB中的组合（与Meredith欧文合作）。我将担任CTEP-COG儿科MATCH试验的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（方案现已开放）。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tipifarnib在RMS和NB中的组合。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。MCRADA到位，以评估儿科癌症中的KRAS反义寡核苷酸（AZD 4785，现为Ionis）。我们有一个新的MCRADA与革命药物，以评估SHP 2抑制剂在RMS和RASopathies。最后，我们还将评估一种新的开关I/II口袋粘合剂BI 2852。