Moores Cancer Center, University of California San Diego, La Jolla, California.
Department of Surgery, Division of Surgical Oncology, University of California San Diego, San Diego, California.
Clin Cancer Res. 2022 Jan 1;28(1):187-200. doi: 10.1158/1078-0432.CCR-21-2092. Epub 2021 Aug 23.
Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract, with mutant succinate dehydrogenase () subunits (A-D) comprising less than 7.5% (i.e., 150-200/year) of new cases annually in the United States. Contrary to GISTs harboring or mutations, -mutant GISTs affect adolescents/young adults, often metastasize, and are frequently resistant to tyrosine kinase inhibitors (TKI). Lack of human models for any mutant tumors, including GIST, has limited molecular characterization and drug discovery.
We describe methods for establishing novel patient-derived -mutant (m) GIST models and interrogated the efficacy of temozolomide on these tumor models and in clinical trials of patients with m GIST.
Molecular and metabolic characterization of our patient-derived m GIST models revealed that these models recapitulate the transcriptional and metabolic hallmarks of parent tumors and SDH deficiency. We further demonstrate that temozolomide elicits DNA damage and apoptosis in our m GIST models. Translating our discovery to the clinic, a cohort of patients with -mutant GIST treated with temozolomide ( = 5) demonstrated a 40% objective response rate and 100% disease control rate, suggesting that temozolomide represents a promising therapy for this subset of GIST.
We report the first methods to establish patient-derived m tumor models, which can be readily employed for understanding patient-specific tumor biology and treatment strategies. We also demonstrate that temozolomide is effective in patients with m GIST who are refractory to existing chemotherapeutic drugs (namely, TKIs) in clinic for GISTs, bringing a promising treatment option for these patients to clinic..
胃肠道间质瘤（GIST）是胃肠道最常见的肉瘤，在美国每年新发病例中，突变琥珀酸脱氢酶（）亚基（A-D）少于 7.5%（即 150-200/年）。与携带或突变的 GIST 不同，-突变的 GIST 影响青少年/年轻人，常发生转移，并且常对酪氨酸激酶抑制剂（TKI）产生耐药性。缺乏任何突变肿瘤的人类模型，包括 GIST，限制了分子特征和药物发现。
我们描述了建立新型患者来源的 -突变（m）GIST 模型的方法，并研究了替莫唑胺对这些肿瘤模型的疗效以及 m GIST 患者临床试验中的疗效。
我们的患者来源的 m GIST 模型的分子和代谢特征表明，这些模型再现了亲本肿瘤的转录和代谢特征以及 SDH 缺陷。我们进一步证明替莫唑胺在我们的 m GIST 模型中引发 DNA 损伤和细胞凋亡。将我们的发现转化为临床，一组接受替莫唑胺治疗的 -突变 GIST 患者（n=5）显示出 40%的客观缓解率和 100%的疾病控制率，这表明替莫唑胺是该亚组 GIST 的一种有前途的治疗方法。
我们报告了建立患者来源的 m 肿瘤模型的首个方法，这些方法可用于了解患者特异性肿瘤生物学和治疗策略。我们还证明替莫唑胺在对现有化疗药物（即 TKI）耐药的 m GIST 患者中有效，为这些患者带来了有希望的治疗选择。
