Targeting RAS in Pediatric Cancer

这个项目将是实验室向前发展的一个主要重点。我们发起了几个 与该项目有关的子项目;这些子项目的目标和成就 在RAS突变中鉴定协同药物组合的项目 神经母细胞瘤由NCATS资助，NCATS确定了一种新的MEK抑制剂和 一种脑电波调制器。已经开始验证协同作用并建立机制的工作 （与卡罗尔·蒂勒和克雷格托马斯合作）一个项目，以评估一个组合， 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作用， 由CAPR资助，该项目的工作已经开始。该项目的第一个目标，评估PK 在罗米地辛的不同给药模式之后，已经完成（与 Rob Robey）。本项目的第二个目的是评估联合治疗的疗效， RMS，揭示了该组合在体内的令人失望的功效。疗效评价 在RMS中联合使用MEK抑制剂和泛RAF抑制剂（与Angelina合作 Vaseva）。这项工作导致了一个合作的手稿，是在重新提交和一个概念， 经ComboMATCH批准用于临床翻译。评估 MEK抑制剂和BCL-XL抑制剂在RMS中的组合（与Ben Braun合作）。 评估MEK抑制剂和SHP 2抑制剂在儿科癌症中的组合 （与梅雷迪思欧文和克莉丝汀普拉蒂拉斯合作）。我将担任副主席， CTEP-COG儿科MATCH试验的APEC 1621 M组，该试验将评价 替吡法尼治疗HRAS突变儿科癌症。该方案迄今为止已入组3例受试者。 此外，我正在与克莉丝汀Pratilas合作，评估替吡法尼在HRAS突变中的作用。 RMS临床前。我正在与Rob Kortum合作评估替吡法尼的组合， 在RMS和NB中。替吡法尼和曲美替尼的组合的令人失望的功效已经被证实是有效的。 在RMS中观察。我们已经开始评估KRAS G12 C抑制剂在以下患者中的疗效： 神经母细胞瘤（ARS-1620、AMG 510、AZD 1569、MRTX 849）。有趣的是，与博士合作。 肯特罗斯曼，我们已经能够显示这些抑制剂在HRAS细胞中的疗效， NRAS G12C。MCRADA用于评估儿科癌症中的KRAS反义寡核苷酸 （AZD 4785，现在的Ionis）。我们有一个新的MCRADA与革命药物评价SHP 2 RMS和RASopathies中的抑制剂。最后，我们还将评估一种新颖的开关I/II口袋 粘合剂BI 2852。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，特别是在大规模 先天性痣（NRAS驱动）。我们还计划在患者中测试司美替尼的疗效 巨大的先天性痣

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). We also plan to test the efficacy of selumetinib in patients with large/giant congenital nevi.