Targeting RAS in Pediatric Cancer

靶向 RAS 治疗儿童癌症

• 批准号: 10487040
• 负责人: Marielle Yohe
• 金额: $ 22.23万
• 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/10487040
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Antisense Oligonucleotides; BCL1 Oncogene; 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; Hematologic Neoplasms; Human; Juvenile Myelomonocytic Leukemia; KRAS2 gene; MEKs; Malignant - descriptor; Malignant Childhood Neoplasm; Manuscripts; Medicine; Mutate; Mutation; Natural History; Neuroblastoma; Neurofibromatosis 1; Neurofibrosarcoma; Nevus; Oncogenic; 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; in vivo; 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, revealed disappointing efficacy of the combination in vivo. 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. 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 pediatric cancer (collaboration with Meredith Irwin and Christine Pratilas). 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. This protocol has so far enrolled 3 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 RMS and NB. Disappointing efficacy of a combination of tipifarnib and trametinib has been observed in RMS. 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. 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. 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).

这个项目将是实验室未来发展的主要焦点。关于这个项目，我们已经启动了几个子项目；这些子项目的目标和成就如下：NCATS资助的一个项目是鉴定RAS突变神经母细胞瘤的协同药物组合，该项目鉴定了一种MEK抑制剂和一种小脑调节剂的新组合。工作已经开始验证协同作用并建立机制（与Carol Thiele和Craig Thomas合作）一个评估罗米地新和双BRD4/PI3K抑制剂SF2523联合治疗ras驱动的儿科癌症的项目由CAPR资助，该项目已经开始工作。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，目前已经完成（与Rob Robey合作）。该项目的第二个目标是在RMS中评估联合治疗的疗效，结果显示该联合治疗在体内的疗效令人失望。评估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和一个被ComboMATCH批准用于临床翻译的概念。评估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SHP2抑制剂在儿童癌症中的联合应用（与Meredith Irwin和Christine Pratilas合作）。我将担任CTEP-COG儿科MATCH试验APEC1621M分支的副主席，该试验将评估蒂法尼对hras突变儿童癌症的疗效。到目前为止，该方案已招募了3名参与者。此外，我正在与Christine Pratilas合作评估蒂法尼对HRAS突变RMS的临床前治疗效果。我正在与Rob Kortum合作评估替法尼在RMS和NB中的组合。在RMS中观察到替法尼和曲美替尼联合使用的疗效令人失望。我们已经开始评估KRAS G12C抑制剂在神经母细胞瘤中的疗效（ARS-1620, AMG 510, AZD1569, MRTX849）。有趣的是，在与Kent Rossman博士的合作中，我们已经能够在HRAS和NRAS G12C细胞中显示这些抑制剂的功效。MCRADA用于评估儿童癌症中的KRAS反义寡核苷酸（AZD4785，现为Ionis）。我们有一个新的MCRADA与革命药物评估SHP2抑制剂在RMS和RASopathies。最后，我们还将评估一种新型开关I/II口袋粘合剂BI 2852。我们最近也开始与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）中产生的黑色素瘤。