Oncoheroes Biosciences S.L., Barcelona, Spain; Grup d'Enginyeria de Materials, Institut Químic de Sarrià, Universitat Ramon Llull, Barcelona, 08017, Spain.
Oncoheroes Biosciences S.L., Barcelona, Spain.
SLAS Discov. 2024 Mar;29(2):100147. doi: 10.1016/j.slasd.2024.100147. Epub 2024 Feb 12.
Pediatric brain tumors (PBTs) represent about 25 % of all pediatric cancers and are the most common solid tumors in children and adolescents. Medulloblastoma (MB) is the most frequently occurring malignant PBT, accounting for almost 10 % of all pediatric cancer deaths. MB Group 3 (MB G3) accounts for 25-30 % of all MB cases and has the worst outcome, particularly when associated with MYC amplification. However, no targeted treatments for this group have been developed so far. Here we describe a unique high throughput screening (HTS) platform specifically designed to identify new therapies for MB G3. The platform incorporates optimized and validated 2D and 3D efficacy and toxicity models, that account for tumor heterogenicity, limited efficacy and unacceptable toxicity from the very early stage of drug discovery. The platform has been validated by conducting a pilot HTS campaign with a 1280 lead-like compound library. Results showed 8 active compounds, targeting MB reported targets and several are currently approved or in clinical trials for pediatric patients with PBTs, including MB. Moreover, hits were combined to avoid tumor resistance, identifying 3 synergistic pairs, one of which is currently under clinical study for recurrent MB and other PBTs.
小儿脑肿瘤（PBT）约占所有儿科癌症的 25%，是儿童和青少年中最常见的实体肿瘤。髓母细胞瘤（MB）是最常见的恶性 PBT，占所有儿科癌症死亡人数的近 10%。MB 组 3（MB G3）占所有 MB 病例的 25-30%，其预后最差，特别是与 MYC 扩增相关时。然而，到目前为止，尚未针对该组开发出靶向治疗方法。在这里，我们描述了一个独特的高通量筛选（HTS）平台，专门用于为 MB G3 寻找新的治疗方法。该平台结合了经过优化和验证的 2D 和 3D 疗效和毒性模型，这些模型考虑到了肿瘤异质性、早期药物发现阶段疗效有限和不可接受的毒性。该平台通过对一个 1280 个类似先导化合物库进行试点 HTS 活动得到了验证。结果显示了 8 种针对 MB 报告靶点的活性化合物，其中一些目前已被批准或正在儿科患者 PBT 临床试验中，包括 MB。此外，通过组合命中化合物以避免肿瘤耐药性，确定了 3 种协同对，其中一种目前正在用于复发性 MB 和其他 PBT 的临床研究。
