Giotta Lucifero Alice, Luzzi Sabino, Brambilla Ilaria, Schena Lucia, Mosconi Mario, Foiadelli Thomas, Savasta Salvatore
Neurosurgery Unit, Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy.
Neurosurgery Unit, Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy; Neurosurgery Unit, Department of Surgical Sciences, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Acta Biomed. 2020 Jun 30;91(7-S):61-78. doi: 10.23750/abm.v91i7-S.9956.
The tailored targeting of specific oncogenes represents a new frontier in the treatment of high-grade glioma in the pursuit of innovative and personalized approaches. The present study consists in a wide-ranging overview of the target therapies and related translational challenges in neuro-oncology.
A review of the literature on PubMed/MEDLINE on recent advances concerning the target therapies for treatment of central nervous system malignancies was carried out. In the Medical Subject Headings, the terms "Target Therapy", "Target drug" and "Tailored Therapy" were combined with the terms "High-grade gliomas", "Malignant brain tumor" and "Glioblastoma". Articles published in the last five years were further sorted, based on the best match and relevance. The ClinicalTrials.gov website was used as a source of the main trials, where the search terms were "Central Nervous System Tumor", "Malignant Brain Tumor", "Brain Cancer", "Brain Neoplasms" and "High-grade gliomas".
A total of 137 relevant articles and 79 trials were selected. Target therapies entailed inhibitors of tyrosine kinases, PI3K/AKT/mTOR pathway, farnesyl transferase enzymes, p53 and pRB proteins, isocitrate dehydrogenases, histone deacetylases, integrins and proteasome complexes. The clinical trials mostly involved combined approaches. They were phase I, II, I/II and III in 33%, 42%, 16%, and 9% of the cases, respectively.
Tyrosine kinase and angiogenesis inhibitors, in combination with standard of care, have shown most evidence of the effectiveness in glioblastoma. Resistance remains an issue. A deeper understanding of the molecular pathways involved in gliomagenesis is the key aspect on which the translational research is focusing, in order to optimize the target therapies of newly diagnosed and recurrent brain gliomas.
针对特定癌基因的精准靶向治疗是高级别胶质瘤治疗领域追求创新和个性化治疗方法的新前沿。本研究全面概述了神经肿瘤学中的靶向治疗及相关转化挑战。
对PubMed/MEDLINE上有关中枢神经系统恶性肿瘤靶向治疗最新进展的文献进行综述。在医学主题词中，将“靶向治疗”“靶向药物”和“精准治疗”与“高级别胶质瘤”“恶性脑肿瘤”和“胶质母细胞瘤”等术语相结合。根据最佳匹配度和相关性，对过去五年发表的文章进行进一步筛选。ClinicalTrials.gov网站被用作主要试验的来源，搜索词为“中枢神经系统肿瘤”“恶性脑肿瘤”“脑癌”“脑肿瘤”和“高级别胶质瘤”。
共筛选出137篇相关文章和79项试验。靶向治疗包括酪氨酸激酶抑制剂、PI3K/AKT/mTOR通路抑制剂、法尼基转移酶、p53和pRB蛋白、异柠檬酸脱氢酶、组蛋白去乙酰化酶、整合素和蛋白酶体复合物的抑制剂。临床试验大多采用联合治疗方法。其中I期、II期、I/II期和III期试验分别占33%、42%、16%和9%。
酪氨酸激酶和血管生成抑制剂与标准治疗相结合，在胶质母细胞瘤治疗中显示出最有力的有效性证据。耐药性仍然是一个问题。深入了解胶质瘤发生过程中涉及的分子途径是转化研究的关键重点，以便优化新诊断和复发性脑胶质瘤的靶向治疗。
