《癌症发现》：治疗肾透明细胞癌的新靶点

资讯作者：Perelman School of Medicine at the University of Pennsylvania

编辑翻译：奇奇

本文献于2021年8月11日发表在美国著名医学期刊《癌症发现》（Cancer Discovery）上。文中宾夕法尼亚大学佩雷尔曼医学院的研究人员发现，通过特定方法能够抑制癌细胞，这有望成为ccRCC的治疗新靶点。

根据宾夕法尼亚大学佩雷尔曼医学院的研究，肾透明细胞癌(ccRCC)的细胞可以通过抑制高密度脂蛋白胆固醇受体SCARB1的破坏，从而阻止癌细胞的增殖。

科学家们发现这些特定癌细胞和肿瘤的健康取决于胆固醇和这种受体，同时也表明了针对这种受体的药物可能会让癌细胞无法生存和扩散。研究还表明，通过饮食控制胆固醇可以减少ccRCC肿瘤的生长。研究人员表示，未来的试验可以研究用于临床上治疗ccRCC的特殊疗法和饮食。

M. Celeste Simon博士是该项研究的主导者，也是细胞与发育生物学部的MBBCh教授和艾布拉姆森家族癌症研究所科学主任。他说：“以前的研究表明，SCARB1和胆固醇都是ccRCC的一部分，但我们在这里的工作显示了其因果关系。我的同事和我都希望这些研究可以转化为有效的SCARB1抑制剂和癌症治疗方法，能够用于治疗患有这种侵袭性癌症的患者。”

在世界范围内，肾细胞癌也是一种男性和女性都较常见的癌症，去年美国有1.5万人死于肾细胞癌，其中大约70%到80%的肾细胞癌是ccRCC。许多人通过靶向和/或免疫疗法进行治疗，获得了不同程度的治疗效果。辐射也是可以用于治疗肾细胞癌的。 

这项研究中，宾夕法尼亚大学的研究人员培育了ccRCC细胞，并将它们置于具有不同程度胆固醇可用性的环境中。癌变细胞和不正常的肾细胞依靠外源性胆固醇(或外胆固醇)生长和生存，而正常的肾细胞自身能够合成胆固醇来满足典型的细胞需求。

Simon博士说:“癌细胞和普通肾脏细胞之间的差异很重要，因为这表明，如果体内可用的胆固醇受到限制，肾脏细胞自身可以产生它们所需的胆固醇。”

接下来，研究小组发现在ccRCC肿瘤中有更多的清道夫受体B1 (SCARB1)，这些是为细胞输入胆固醇的受体。这促使研究人员在体外和体内小鼠研究中敲除这些受体，并使用一种称为Block Lipid Transporter-1的分子来阻断SCARB1。如果没有SCARB1的功能，ccRCC细胞和肿瘤就无法生存。

Simon博士说：“在不久的将来，科学界可能会关注SCARB1和SCARB1抑制剂的开发，其原因是多方面的。”研究人员表示，一项1期临床试验已经开始，以探索SCARB1抑制剂ITX-5061用于治疗丙型肝炎的可能性，其他研究已经将SCARB1与SARS-CoV-2的疾病进展联系起来。

研究小组表示，尽管这些结果都很有希望，但未来的工作将需要证实使用ITX-5061等抑制剂来抑制人体内SCARB1和ccRCC的安全性和有效性。他们还表示，在过去十年中，ccRCC在男性和女性中的发病率增加，可能与西方人口中肥胖率的增加和身体质量指数(bmi)的升高有关。这项研究表明，肥胖、BMI和循环高密度脂蛋白胆固醇与ccRCC发病可能性之间存在因果关系，这种关系可以进一步研究。

英文原文

New Possible Cell Target to Treat Clear Cell Renal Cell Carcinoma

Clear cell renal cell carcinoma (ccRCC) cells can be destroyed and kept from multiplying by inhibiting the HDL cholesterol receptor SCARB1, according to research from the Perelman School of Medicine at the University of Pennsylvania.

The scientists found the health of these specific cancer cells and tumors are dependent upon cholesterol and this receptor while also showing that medication that specifically targets the receptor could make it impossible for the cancer cells to survive and spread. The research also suggests that controlling cholesterol through diet could minimize the growth of ccRCC tumors. Researchers say future trials can investigate specific therapeutics and diets that can be clinically used to treat ccRCC.

“Previous studies demonstrated that SCARB1 and cholesterol were both part of the story of ccRCC, but our work here shows a causal role,” said lead study author M. Celeste Simon, Ph.D., the Arthur H. Rubenstein, MBBCh Professor in the department of Cell and Developmental Biology and the scientific director of the Abramson Family Cancer Research Institute. “My colleagues and I hope these investigations at the bench can translate to new and successful SCARB1 inhibitors and treatments for people facing this aggressive cancer.”

Worldwide, renal cell carcinoma is a common cancer for both men and women, killing 15,000 people in the United States last year. Roughly 70 to 80 percent of renal cell carcinomas are ccRCC. Many are treated by targeted and or immune-based therapies with varying degrees of success. Radiation may also be used.

For this study, the Penn researchers cultured ccRCC cells and put them in environments with varying degrees of cholesterol availability. Cancerous cells, and not normal kidney cells, reliedon exogenous cholesterol—or outside cholesterol—in order to grow and survive whereas normal kidney cells are able to synthesize their own cholesterol fortypical cellular needs.

“That difference between cancer cells and regular kidney cells is important because it suggests that kidney cells can create cholesterol they need if cholesterol, available in the body, isrestricted,” Simon said.

Next, the team identified that there is agreater number of Scavenger Receptors B1 (SCARB1), receptors that import cholesterol for cells, in ccRCC tumors. This led researchers to knock out these receptors in both in vitro and in vivo mouse studies as well as block SCARB1 with a molecule called Block Lipid Transporter-1. ccRCC cells and tumors could not survive without functioning SCARB1.

“There are multiple reasons why the scientific community will likely focus on SCARB1 and the development of SCARB1 inhibitors in the near future,” Simon said. A Phase 1 clinical trial was started to investigate the potential for ITX-5061, a SCARB1 inhibitor, to be used as a way to treat hepatitis-C, the researchers said, and other research has tied SCARB1 to the disease progression of SARS-CoV-2.

The research team says that while these results are promising, future work will need to confirm the safety and efficacy of using inhibitors like ITX-5061 to impede SCARB1 and ccRCC in people. They also say the increased incidence of ccRCC in both men and women over the last decade has been suspected to be linked to increased rates of obesity and elevated body mass indices (BMIs) in western populations. This study suggests a causative relationship between obesity, BMI, and circulating HDL cholesterol and likelihood of developing ccRCC that can be further investigated.

参考文献 

Romain Riscal et al, Cholesterol auxotrophy as a targetable vulnerability in clear cell renal cell carcinoma, Cancer Discovery (2021). DOI: 10.1158/2159-8290.CD-21-0211

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