Targeting RAS in Pediatric Cancer

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评估RMS联合治疗的疗效，目前正在进行中。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）。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NB中的联合应用（与Meredith Irwin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尼在hras突变型儿童癌症中的疗效（方案现已开放）。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。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）。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。

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.