Targeting RAS in Pediatric Cancer

这个项目将是实验室未来发展的主要重点。我们已经启动了与该项目相关的几个子项目；这些子项目的目标和成果如下：NCATS资助了一个确定RAS突变神经母细胞瘤的协同药物组合的项目，该项目确定了一种MEK抑制剂和脑激活素调节剂的新组合。已经开始验证协同作用并建立机制(与Carol Thiele和Craig Thomas合作)一项评估romidessin和双重BRD4/PI3K抑制剂SF2523在RAS驱动的儿童癌症中的组合的项目由CAPR资助，该项目的工作已经开始。该项目的第一个目标--在罗米迪欣不同给药模式下评估PK--已经完成(与Rob Robey合作)。该项目的第二个目标是评估联合用药在RMS中的疗效，目前正在进行中。评估MEK抑制剂和PAN-RAF抑制剂在RMS中的联合疗效(与Angelina Vaseva合作)。评估MEK抑制剂和bcl-xl抑制剂在RMS中的联合疗效(与Ben Braun合作)。评估一种MEK抑制剂和一种SHP2抑制剂在NB中的组合(与Meredith Irwin合作)。我将担任CTEP-COG儿科匹配试验APEC1621M ARM的副主席，该试验将评估替普法尼对HRAS突变的儿科癌症的疗效(方案现已开放)。此外，我正在与Christine Patilas合作，在临床前评估替法尼布治疗HRAS突变的RMS。我正在与罗布·科尔图姆合作，评估替法尼布在RMS和NB中的组合。我们已经开始评估KRAS G12C抑制剂(ARS-1620、AMG 510、AZD1569、MRTX849)治疗神经母细胞瘤的疗效。MCRADA用于评估KRAS反义寡核苷酸在儿童癌症中的应用(AZD4785，现为Ionis)。我们有一个新的MCRADA与革命药物一起评估SHP2抑制剂在RMS和Rasopathies中的作用。最后，我们还将评估一种新型的Switch I/II袖珍活页夹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.