Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Molecular Therapeutics Program and Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
NexusPharma, Inc., Philadelphia, PA, USA.
J Exp Clin Cancer Res. 2018 Jan 22;37(1):11. doi: 10.1186/s13046-018-0671-0.
Small molecule ONC201 is an investigational anti-tumor agent that upregulates intra-tumoral TRAIL expression and the integrated stress response pathway. A Phase I clinical trial using ONC201 therapy in advanced cancer patients has been completed and the drug has progressed into Phase II trials in several cancer types. Colorectal cancer (CRC) remains one of the leading causes of cancer worldwide and metastatic disease has a poor prognosis. Clinical trials in CRC and other tumor types have demonstrated that therapeutics targeting the vascular endothelial growth factor (VEGF) pathway, such as bevacizumab, are effective in combination with certain chemotherapeutic agents.
We investigated the potential combination of VEGF inhibitors such as bevacizumab and its murine-counterpart; along with other anti-angiogenic agents and ONC201 in both CRC xenograft and patient-derived xenograft (PDX) models. We utilized non-invasive imaging and immunohistochemistry to determine potential mechanisms of action.
Our results demonstrate significant tumor regression or complete tumor ablation in human xenografts with the combination of ONC201 with bevacizumab, and in syngeneic MC38 colorectal cancer xenografts using a murine VEGF-A inhibitor. Imaging demonstrated the impact of this combination on decreasing tumor growth and tumor metastasis. Our results indicate that ONC201 and anti-angiogenic agents act through distinct mechanisms while increasing tumor cell death and inhibiting proliferation.
With the use of both a murine VEGF inhibitor in syngeneic models, and bevacizumab in human cell line-derived xenografts, we demonstrate that ONC201 in combination with anti-angiogenic therapies such as bevacizumab represents a promising approach for further testing in the clinic for the treatment of CRC.
小分子 ONC201 是一种研究性抗肿瘤药物，可上调肿瘤内 TRAIL 表达和整体应激反应途径。一项使用 ONC201 治疗晚期癌症患者的 I 期临床试验已经完成，该药物已在几种癌症类型中进入 II 期试验。结直肠癌（CRC）仍然是全球癌症的主要原因之一，转移性疾病预后不良。CRC 和其他肿瘤类型的临床试验表明，靶向血管内皮生长因子（VEGF）途径的治疗方法，如贝伐珠单抗，与某些化疗药物联合使用在治疗上是有效的。
我们研究了 VEGF 抑制剂（如贝伐珠单抗及其鼠类对应物）与 ONC201 联合在 CRC 异种移植和患者来源异种移植（PDX）模型中的潜在组合。我们利用非侵入性成像和免疫组织化学来确定潜在的作用机制。
我们的结果表明，ONC201 与贝伐珠单抗联合使用，在人异种移植中，以及在使用鼠类 VEGF-A 抑制剂的同源 MC38 结直肠癌细胞异种移植中，肿瘤显著消退或完全消融。成像表明，这种联合用药对降低肿瘤生长和肿瘤转移有影响。我们的结果表明，ONC201 和抗血管生成药物通过不同的机制发挥作用，同时增加肿瘤细胞死亡和抑制增殖。
我们使用鼠类 VEGF 抑制剂在同源模型中，以及贝伐珠单抗在人细胞系衍生的异种移植中，证明了 ONC201 与抗血管生成疗法（如贝伐珠单抗）联合使用是一种很有前途的方法，值得进一步在临床上进行测试，以治疗 CRC。
