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Molecular targeting of renal cell carcinoma by an oral combination.
Oncogenesis ( IF 6.2 ) Pub Date : 2020-05-19 , DOI: 10.1038/s41389-020-0233-0
Andre R Jordan 1, 2 , Jiaojiao Wang 1 , Travis J Yates 2, 3 , Sarrah L Hasanali 1 , Soum D Lokeshwar 4 , Daley S Morera 1 , Nagarajarao Shamaladevi 5 , Charles S Li 1 , Zachary Klaassen 6 , Martha K Terris 6 , Muthusamy Thangaraju 1 , Amar B Singh 7 , Mark S Soloway 8 , Vinata B Lokeshwar 1
Affiliation  

The 5-year survival rate of patients with metastatic renal cell carcinoma (mRCC) is <12% due to treatment failure. Therapeutic strategies that overcome resistance to modestly effective drugs for mRCC, such as sorafenib (SF), could improve outcome in mRCC patients. SF is terminally biotransformed by UDP-glucuronosyltransferase-1A9 (A9) mediated glucuronidation, which inactivates SF. In a clinical-cohort and the TCGA-dataset, A9 transcript and/or protein levels were highly elevated in RCC specimens and predicted metastasis and overall-survival. This suggested that elevated A9 levels even in primary tumors of patients who eventually develop mRCC could be a mechanism for SF failure. 4-methylumbelliferone (MU), a choleretic and antispasmodic drug, downregulated A9 and inhibited SF-glucuronidation in RCC cells. Low-dose SF and MU combinations inhibited growth, motility, invasion and downregulated an invasive signature in RCC cells, patient-derived tumor explants and/or endothelial-RCC cell co-cultures; however, both agents individually were ineffective. A9 overexpression made RCC cells resistant to the combination, while its downregulation sensitized them to SF treatment alone. The combination inhibited kidney tumor growth, angiogenesis and distant metastasis, with no detectable toxicity; A9-overexpressing tumors were resistant to treatment. With effective primary tumor control and abrogation of metastasis in preclinical models, the low-dose SF and MU combinations could be an effective treatment option for mRCC patients. Broadly, our study highlights how targeting specific mechanisms that cause the failure of "old" modestly effective FDA-approved drugs could improve treatment response with minimal alteration in toxicity profile.

中文翻译:

通过口服组合对肾细胞癌的分子靶向。

由于治疗失败,转移性肾细胞癌(mRCC)患者的5年生存率<12%。克服对mRCC的中度有效药物如索拉非尼(SF)产生耐药性的治疗策略,可以改善mRCC患者的预后。SF通过UDP-葡萄糖醛酸转移酶-1A9(A9)介导的葡萄糖醛酸苷化最终被生物转化,从而使SF失活。在临床队列和TCGA数据集中,RCC标本中的A9转录本和/或蛋白质水平高度升高,并预测了转移和整体生存。这表明即使在最终发展为mRCC的原发性肿瘤中,A9水平升高也可能是SF衰竭的机制。4-甲基伞形酮(MU)是一种抗胆碱药和抗痉挛药,下调R9细胞中的A9并抑制SF-葡萄糖醛酸苷化。低剂量的SF和MU组合抑制RCC细胞,患者来源的肿瘤外植体和/或内皮-RCC细胞共培养物中的生长,运动,侵袭并下调侵袭性标记;但是,两种药物均无效。A9过度表达使RCC细胞对该组合产生抗性,而其下调则使它们仅对SF治疗敏感。联合使用可抑制肾脏肿瘤的生长,血管生成和远处转移,且无可检测的毒性。过表达A9的肿瘤对治疗有抗性。通过在临床前模型中有效控制原发肿瘤并消除转移,低剂量SF和MU组合可能成为mRCC患者的有效治疗选择。从广义上讲,我们的研究突出了如何针对导致“旧”失败的特定机制
更新日期:2020-05-19
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