PO.PR02.01 · 预防研究

TRAIL诱导药物ONC201在转基因KRAS G12V小鼠肺癌模型中预防腺癌

TRAIL inducing drug, ONC201 prevents adenocarcinoma in transgenic KRAS G12V mouse lung cancer model

编号 948 展板 7 时间 4/19 02:00–05:00 区域 Section 37 主讲 Karthikkumar Venkatachalam, PhD

分会场 Experimental Chemoprevention and Interception: Data and Tools

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作者与单位 Authors & Affiliations

Karthikkumar Venkatachalam¹, Gopal Pathuri¹, Nicole Stratton¹, Anil Singh¹, Nandini Kumar¹, Shizuko Sei², Vignesh Gunasekharan², Chinthalapally V. Rao¹, Venkateshwar Madka¹

¹Center for Cancer Prevention and Drug Development, Stephenson Cancer Center, Department of Medicine, University of Oklahoma HSC, Oklahoma City, OK,²Division of Cancer Prevention, National Cancer Institue, Rockville, MD

摘要 Abstract

中文摘要

肺癌是全球主要癌症之一。2025年美国将有约226,000人被诊断为肺癌。在所有肺癌中，近四分之一为KRAS突变型肿瘤，此类肿瘤治疗极具挑战性且预后不良。肺癌的阻断对于减轻疾病负担和死亡率至关重要。然而，目前尚无FDA批准的阻断药物。TCGA数据库揭示，介导凋亡的TRAIL表达在肺肿瘤进展阶段中丧失。ONC201（Dordaviprone）是一种口服有效的TRAIL诱导小分子化合物，已被证实具有临床前疗效，并正在针对多种癌症进行临床评估。我们此前报道了ONC201在NNK诱导的A/J小鼠肺癌模型中的癌症预防潜力。在此，我们评估了ONC201在侵袭性KRAS G12V肺肿瘤小鼠模型中的疗效。通过内部繁育培育出雄性和雌性KRAS G12V小鼠。六周龄小鼠被随机分组（n=20/性别）为安慰剂组和阻断组。自8周龄（早期腺瘤阶段）开始，小鼠经灌胃给予其中一种剂量的ONC201（0、25、50、100 mg/kg，PBS载体），每周两次，持续28周。所有小鼠在36周龄时被安乐死，评估肺部以确定肿瘤发生率和多发性。安慰剂组中雄性和雌性KRAS G12V小鼠均发生肺肿瘤（发生率约100%），平均肿瘤多发性为每只小鼠12.2±1.5个（雄性）和11.7±0.8个（雌性）。与各自对照组相比，ONC201处理以剂量依赖方式显著降低了雄性（减少34%-63%；p<0.05-p<0.0001）和雌性（减少33%-55%；p<0.001-p<0.0001）小鼠的肺肿瘤总多发性。H&E染色的肺肿瘤切片经组织学分类为腺瘤（AD）和腺癌（ADCA）。安慰剂组雄性小鼠的多发性为9.3±1.3个ADCA、12±1.2个AD+ADCA；雌性小鼠为8.3±0.6个ADCA、11.61±0.87个AD+ADCA。组织病理学结果表明，与各自对照小鼠相比，ONC201处理的雄性（53%-86%；p<0.001-p<0.0001）和雌性小鼠（54%-79%；p<0.0001）的ADCA多发性呈剂量依赖性降低。在雄性和雌性小鼠所测试的全部三个剂量中均未观察到毒性临床体征。免疫印迹和IHC结果显示，TRAIL诱导剂ONC201触发下游信号分子（TRAIL、DR5、FADD、Apaf1），升高凋亡标志物（Caspases），同时降低增殖标志物（PCNA、Cyclin D1、EGFR、Ki67）。总之，ONC201在两个临床前小鼠模型中展现出强效的肺癌预防作用，值得进一步开展临床开发，用于高风险人群的肺肿瘤预防。（本项目由NCI、NIH、DHHS的联邦资金100%资助，合同号75N91019D00020_75N91022F00003）

查看英文原文 English abstract

Lung cancer is one of the leading cancers worldwide. Around 226,000 people will be diagnosed with lung cancer in the US during 2025. Almost one-fourth of all lung cancers are KRAS-mutated tumors, which are very challenging to treat and have poor prognosis. Interception of lung cancer is of utmost importance to reduce the burden and mortality. However, there are currently no interception agents approved by FDA. TCGA database revealed that the apoptosis mediating TRAIL expression is lost during the progression of lung tumor stages. ONC201 (Dordaviprone) is an orally active TRAIL inducing small molecule compound with proven preclinical efficacy and is being clinically evaluated against multiple cancers. Previously we reported the cancer prevention potential of ONC201 in an NNK-induced lung cancer model in A/J mice. Here, we evaluated the efficacy of ONC201 in an aggressive KRAS G12V lung tumor mouse model. Male and female KRAS G12V mice were generated by inhouse breeding. Six-week aged mice were randomized (n=20/sex) into placebo and interception groups. Beginning at 8 weeks of age (early adenoma stage) mice were gavaged one of the doses of ONC201 (0, 25, 50, 100mg/kg in PBS vehicle) twice weekly for 28 weeks. All mice were euthanized at 36 weeks of age, and lungs were evaluated to determine tumor incidence and multiplicity. Both the male and female KRAS G12V mice in placebo group developed lung tumors (~100% incidence) with average tumor multiplicity of 12.2±1.5 (male) and 11.7±0.8 (female) per mouse. ONC201 treatment resulted in significant reduction in total lung tumors multiplicity in both male (34%-63% less; p<0.05-p<0.0001) and female (33%-55% less; p<0.001-p<0.0001) mice in a dose dependent-manner as compared to their control group. H&E stained lung tumor sections were histologically classified as adenomas (AD), and adenocarcinomas (ADCA). Placebo mice showed multiplicity of 9.3±1.3 ADCA, and 12±1.2 AD+ADCA in male; 8.3±0.6 ADCA, and 11.61±0.87 AD+ADCA in female mice. Histopathology results indicated dose-dependent reduction in ADCA multiplicity in ONC201 treated mice in male (53%-86%; p<0.001 - p<0.0001) and female mice (54%-79%; p<0.0001) when compared to their respective control mice. There was no clinical sign of toxicities observed in all three doses tested in both male and female mice. Immunoblotting and IHC results revealed that TRAIL inducing ONC201 triggering the downstream signaling molecules (TRAIL, DR5, FADD, Apaf1), elevated apoptosis markers (Caspases), concurrently reduces the proliferation markers (PCNA, Cyclin D1, EGFR, Ki67). In conclusion, ONC201 demonstrated strong efficacy in preventing lung cancer in two preclinical mouse models and warrants further clinical development for the prevention of lung tumor in high risk populations. (Project funded 100% with Federal funds from NCI, NIH, DHHS, under Contract 75N91019D00020_75N91022F00003)

利益披露 Disclosure

K. Venkatachalam, None.. G. Pathuri, None.. N. Stratton, None.. A. Singh, None.. N. Kumar, None.. S. Sei, None.. V. Gunasekharan, None.. C. V. Rao, None.. V. Madka, None.

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