Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain.
The Ramón y Cajal Health Research Institute (IRYCIS), CIBERONC, 28034 Madrid, Spain.
Int J Mol Sci. 2019 Oct 8;20(19):4949. doi: 10.3390/ijms20194949.
Despite being infrequent tumors, the incidence and prevalence of pancreatic neuroendocrine tumors (P-NETs) has been rising over the past few decades. In recent years, rigorous phase III clinical trials have been conducted, allowing the approval of several drugs that have become the standard of care in these patients. Although various treatments are used in clinical practice, including somatostatin analogues (SSAs), biological therapies like sunitinib or everolimus, peptide receptor radionuclide therapy (PRRT) or even chemotherapy, a consensus regarding the optimal sequence of treatment has not yet been reached. Notwithstanding, sunitinib is largely used in these patients after the promising results shown in SUN111 phase III clinical trial. However, both prompt progression as well as tumor recurrence after initial response have been reported, suggesting the existence of primary and acquired resistances to this antiangiogenic drug. In this review, we aim to summarize the most relevant mechanisms of angiogenesis resistance that are key contributors of tumor progression and dissemination. Furthermore, several targeted molecules acting selectively against these pathways have shown promising results in preclinical models, and preliminary results from ongoing clinical trials are awaited.
尽管胰腺神经内分泌肿瘤 (P-NETs) 较为罕见，但在过去几十年中，其发病率和患病率一直在上升。近年来，进行了严格的 III 期临床试验，批准了几种药物，这些药物已成为这些患者的标准治疗方法。尽管在临床实践中使用了各种治疗方法，包括生长抑素类似物 (SSAs)、生物疗法如舒尼替尼或依维莫司、肽受体放射性核素治疗 (PRRT) 甚至化疗，但尚未就最佳治疗顺序达成共识。尽管如此，在 III 期 SUN111 临床试验中显示出有前景的结果后，舒尼替尼在这些患者中被广泛使用。然而，据报道，初始反应后既有肿瘤快速进展，也有肿瘤复发，表明对这种抗血管生成药物存在原发性和获得性耐药。在这篇综述中，我们旨在总结血管生成耐药的最重要机制，这些机制是肿瘤进展和扩散的关键因素。此外，针对这些途径的几种靶向分子在临床前模型中显示出了有前景的结果，正在等待正在进行的临床试验的初步结果。
