Dual Blockade of IGF1R and MEK synergistically inhibits pediatric cancers

IGF1R 和 MEK 的双重阻断可协同抑制儿童癌症

• 批准号: 10926334
• 负责人: Marielle Yohe
• 金额: $ 57.79万
• 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/10926334
• 关键词: Adult; Animals; BRAF gene; Cancer Therapy Evaluation Program; Cell Line; Cells; Cessation of life; Childhood Solid Neoplasm; Clinical; Clinical Trials; Collaborations; Disease; FRAP1 gene; Gene Expression; Genes; Goals; Histology; Human; IGF1 gene; IGF1R gene; IRS1 gene; Institution; Ligands; MAP Kinase Gene; MEK inhibition; MEKs; Malignant Childhood Neoplasm; Malignant Neoplasms; Modeling; Monoclonal Antibodies; Mus; Mutate; Mutation; NF-kappa B; NF1 gene; Neuroblastoma; PIK3CA gene; PIK3CG gene; PTEN gene; Pathway interactions; Pediatric Oncology Group; Pharmaceutical Preparations; Pharmacodynamics; Phase I/II Clinical Trial; Phosphorylation; Process; Proto-Oncogene Proteins c-akt; Publishing; RAS genes; Ras/Raf; Research Personnel; Resistance; Resistance development; Rhabdomyosarcoma; Testing; Therapeutic; Vincristine; Work; Xenograft Model; Xenograft procedure; anticancer research; clinical development; clinical efficacy; clinical translation; comparison control; efficacy evaluation; exceptional responders; exome sequencing; in vivo; inhibitor; knock-down; patient derived xenograft model; pediatric patients; phosphoproteomics; resistance mechanism; small molecule; standard of care; synergism; targeted agent; transcriptome sequencing; tumor

In collaboration with LASP, we conducted an in vivo study of trametinib and ganitumab in mouse xenograft models of Ras-mutated rhabdomyosarcoma. We have found that the combination of trametinib and ganitumab provided a survival advantage compared to either agent alone, and also compared to a standard of care chemotherapeutic, vincristine. We also identified that this combination provided the expected pharmacodynamic effects within the tumors, i.e. ERK phosphorylation and IGF1R expression were decreased in tumors that were treated with the combination of trametinib and ganitumab as compared to controls. We also identified that the human Ras-mutated rhabdomyosarcoma cell line, SMS-CTR, is an exceptional responder to the combination of trametinib and ganitumab. To identify why SMS-CTR responds so well to this combination, we showed that of the Ras-mutated rhabdomyosarcoma cell lines, SMS-CTR has the highest expression of IGF1R. We aimed to identify mechanisms of co-targeting the RAS-RAF-MEK-ERK pathways and the IGF1R-IRS1/2-PI3K-AKT-mTOR pathways that would be effective in cell lines that do not have high IGF1R expression, including monoclonal antibodies specific for the ligand of IGF1R, IGF1/2, and an inhibitor of IRS1/2. This work is currently ongoing. Importantly, we have also tested the combination of trametinib and ganitumab in several PDX models of RAS-mutated RMS. We show the efficacy of the combination in cell line xenograft and PDX models driven by both NRAS and HRAS. The models with relative intrinsic resistance to the combination are models that also have an alteration in genes of the PI3 kinase pathway, either PIK3CA mutation or loss of expression of PTEN. Importantly, knockdown of PTEN expression in SMS-CTR cells confers resistance to trametinib. This work was published in Clinical Cancer Research. We were in discussions with CTEP and the Children's oncology group regarding the initiation of a phase I/II clinical trial of trametinib and ganitumab in pediatric patients. We were also in discussions with ImmunityBio regarding an investigator-initiated single institution trial. Unfortunately, ganitumab is no longer available for new clinical trials. We had also been in discussions with BI regarding xentuzumab, a monoclonal antibody specific for IGF1/2 but these talks also stalled due to the lack of clinical efficacy of xentuzumab in adult malignancies. To facilitate the clinical translation of this combination, we are evaluating the efficacy of trametinib/ganitumab in other disease histologies. We have shown the efficacy of trametinib/ganitumab in two cell line xenografts of RAS-mutated neuroblastoma, and are continuing to evaluate the combination in neuroblastoma models driven by alterations in the MAPK pathway that are not RAS itself, as well as in MPNST, driven by alterations in NF1 or BRAF. In the course of the animal study of the trametinib and ganitumab combination, we created an SMS-CTR cell line that is resistant to trametinib. We are currently in the process of identifying the mechanism of resistance to trametinib in this cell line. Whole exome sequencing and whole transcriptome sequencing did not reveal a new SNV or fusion responsible for the resistance. However. gene expression and phosphoproteomic analysis have revealed that these cells modulate the Hippo and NF kappa B pathways in developing resistance to MEK inhibition. Our current work is aimed at validating these results and extending the results to other MEK inhibitor resistant RMS cell lines.

与LASP合作，我们在Ras突变横纹肌肉瘤的小鼠异种移植模型中进行了曲美替尼和ganitumab的体内研究。我们已经发现，曲美替尼和加尼妥单抗的组合与单独的任一种药物相比，以及与标准护理化疗剂长春新碱相比，提供了生存优势。我们还发现，该组合在肿瘤内提供了预期的药效学作用，即与对照相比，用曲美替尼和加尼妥单抗组合治疗的肿瘤中ERK磷酸化和IGF 1 R表达降低。我们还确定了人Ras突变的横纹肌肉瘤细胞系SMS-CTR对曲美替尼和加尼妥单抗的组合具有特殊的应答。为了确定为什么SMS-CTR对这种组合反应如此之好，我们发现在Ras突变的横纹肌肉瘤细胞系中，SMS-CTR具有最高的IGF 1 R表达。我们的目的是确定共同靶向RAS-RAF-MEK-ERK途径和IGF 1 R-IRS 1/2-PI 3 K-AKT-mTOR途径的机制，这些机制在IGF 1 R表达不高的细胞系中有效，包括对IGF 1 R配体、IGF 1/2和IRS 1/2抑制剂具有特异性的单克隆抗体。这项工作目前正在进行中。重要的是，我们还在RAS突变RMS的几种PDX模型中测试了曲美替尼和ganitumab的组合。我们在由NRAS和HRAS驱动的细胞系异种移植物和PDX模型中显示了组合的功效。具有对组合的相对内在抗性的模型是也具有PI 3激酶途径的基因改变（PIK 3CA突变或PTEN表达丧失）的模型。重要的是，SMS-CTR细胞中PTEN表达的敲低赋予对曲美替尼的抗性。这项研究发表在《临床癌症研究》上。我们正在与CTEP和儿童肿瘤学小组讨论在儿科患者中启动曲美替尼和ganitumab的I/II期临床试验。我们还与ImmunityBio讨论了一项由制药商发起的单机构试验。不幸的是，ganitumab不再用于新的临床试验。我们还与BI讨论了xentuzumab（一种IGF 1/2特异性单克隆抗体），但由于xentuzumab在成人恶性肿瘤中缺乏临床疗效，这些讨论也陷入了僵局。为了促进这种组合的临床转化，我们正在评估曲美替尼/ganitumab在其他疾病组织学中的疗效。我们已经在RAS突变的神经母细胞瘤的两种细胞系异种移植物中显示了曲美替尼/ganitumab的疗效，并且正在继续评估由MAPK通路（不是RAS本身）的改变驱动的神经母细胞瘤模型以及由NF 1或BRAF的改变驱动的MPNST中的组合。在曲美替尼和ganitumab组合的动物研究过程中，我们创建了对曲美替尼具有抗性的SMS-CTR细胞系。我们目前正在确定该细胞系对曲美替尼耐药的机制。全外显子组测序和全转录组测序没有揭示负责抗性的新SNV或融合。然而.基因表达和磷酸化蛋白质组学分析揭示了这些细胞在对MEK抑制的抗性发展中调节Hippo和NF κ B途径。我们目前的工作旨在验证这些结果，并将结果扩展到其他MEK抑制剂抗性RMS细胞系。