转：[靶向治疗] 抗癌新药-OTS964

刚刚看到一位病友提到一种新的抗癌新药OTS964问世，寻找了一些相关信息，与大家分享：

来自芝加哥大学等处的研究人员研发出了一种新型抗癌药，命名为 OTS964，这种药物 被证明能消除抑制在小鼠体内的侵袭性人肺癌组织。研究人员指出，其作用机理在于OTS964能抑制 一种蛋白的活性，这种蛋白在包括肺癌和乳腺癌在内的多种癌症中过量表达，在健康成人组织中却 鲜有表达。 这一研究成果公布在Science Translational Medicine杂志上，领导这一研究的是来自芝加哥大学医学教 授Yusuke Nakamura博士，这位原属于东京大学人类基因组中心的日本顶尖遗传学家曾领导了日本一 些最大的科研项目，同时他也是一位成功的生物技术企业家，创立了OncoTherapy Science公司。由于 Nakamura博士的努力，日本在国际HapMap项目中大约完成了四分之一的工作。

Nakamura教授说，“十年前，我们就发现了这种药物的分子靶标，但却花费了近十年的时间才找到抑 制它的有效方法。我们最初筛选出了 300,000 个化合物，然后合成了其中的1,000 多个，再从中找到 了一些在人体中发挥作用的化合物。最后我们定位在最有效的一个，我认为现在我们终于找到了非 常有前景的东西。”

OTS964可以口服，可以注射入人体，其一大特点就是毒性低，采用注射的方式比口服的毒性还可以 降低一些（因为前者包在一种脂质体中），Science Translational Medicine杂志详细介绍了这两种方法，结果表明这两种方法均能完全消除抑制的肿瘤。

从原理上说，OTS964 的靶标是 TOPK （T¬lymphokine¬activated killer cell¬originated protein kinase），这是一种多种人类癌症都会表达的蛋白，其作用被认为是促进肿瘤生长。高表达TOPK与 乳腺癌和肺癌患者的预后不良有关。 OTS964的前生是OTS514，后者也能有效杀死癌细胞，但是却会干扰新生血红细胞和白细胞的生成， 而且还会增加血小板的数量。后来研究人员将药物封存在脂质体中后，就发现这种副作用消失了， 这一方法“完全避免了造血毒性”，作者写道。 之后研究人员分别检测了 OTS964单独使用和在脂质体中使用的效果，他们将高侵袭性人类肺癌LU¬ 99移植入小鼠体内，令其生长到150 立方毫米，大约为一粒葡萄干的大小，然后通过静脉注射给六只 小鼠进行药物治疗，一周两次，为期三周。 结果研究人员发现肿瘤迅速地收缩了，并且在治疗中止后也持续收缩，这六只小鼠中有五只肿瘤完 全消失，其中三只肿瘤在开始治疗后的第25天就完全消失了，两只小鼠肿瘤在29天内消失，小鼠检 测证明没有出现毒副作用。

此外，研究人员也证明了这种药物在大剂量口服方面的有效性。六只带有LU¬99肺癌的小鼠，两周内 每日服用100 毫克/公斤的OTS964药物，同样在肿瘤持续收缩了，直至完全消失，不过所有的小鼠在 治疗后都出现了低白血细胞计数现象，但它们在两周内也恢复了正常。 TOPK 可作为多种类型癌症的药物靶标。这项研究涉及的主要是肺癌，但这一基因在乳腺癌，脑癌， 肝癌，膀胱癌等实体肿瘤，以及某些类型的白血病中出现了增加。目前研究人员正在与肿瘤学家共 同努力，希望能在2015年开展I期临床试验。

英文原版新闻：
Highly Effective New Anti-Cancer Drug Shows Few Side Effects in Mice
As injections or pills, drug inhibits an enzyme that is active in many cancer types
Released: 17-Oct-2014 4:00 PM EDT
Embargo expired: 22-Oct-2014 2:00 PM EDT
Source Newsroom: University of Chicago Medical Center

Newswise — A new drug, known as OTS964, can eradicate aggressive human lung cancers transplanted into mice, according to a report in Science Translational Medicine. The drug, given as a pill or by injection, inhibits the action of a protein that is overproduced by several tumor types, including lung and breast, but is rarely expressed in healthy adult tissues. Without this protein, cancer cells fail to complete the cell-division process and die.

When taken by mouth, the drug was well tolerated with limited toxicity. An intravenous form, delivered within a liposome, was just as effective with fewer side effects. Both approaches—described in the October 22, 2014 issue of STM—led to complete regression of transplanted tumors.

“We identified the molecular target for this drug ten years ago, but it took us nearly a decade to find an effective way to inhibit it,” said study author Yusuke Nakamura, MD, PhD, professor of medicine at the University of Chicago and deputy director of the University’s Center for Personalized Therapeutics. “We initially screened 300,000 compounds and then synthesized more than 1,000 of them, and found a few that were likely to work in humans. We focused on the most effective. We think we now have something very promising.”

OTS964 targets TOPK (T – lymphokine-activated killer cell – originated protein kinase), a protein that is produced by a wide range of human cancers and is believed to promote tumor growth. High TOPK expression correlates with poor prognosis in patients with breast and lung cancer.

Initial studies of the drug, and a precursor called OTS514, found they were effective in killing cancer cells. But they could disrupt the production of new red and white blood cells, causing hematopoietic toxicity such as mild anemia and increasing the risk of infection. At the same time, the drugs increased the production of platelets, which help in blood clotting.

When the researchers encapsulated the drugs in liposomes—microscopic bubbles similar to a cell membrane, commonly used to transport drugs within the body—the drug no longer caused this decrease in red and white blood cells. This approach “completely eliminated the hematopoietic toxicity,” the researchers wrote.

They tested OTS964 alone and in liposomes in mice with a highly aggressive human lung tumor known as LU-99. They allowed the tumors to grow to 150 cubic millimeters—about the size of a raisin—and then administered the drug intravenously to six mice, twice a week for three weeks. The tumors shrank rapidly and continued to shrink even after treatment stopped. In five of the six mice, the tumors completely disappeared—three within 25 days of the first treatment and two within 29 days. Mice that received the liposome-coated drug had no detectable toxicity.

The drug also proved effective when taken in larger doses by mouth. Six mice with LU-99 lung tumors were fed 100 milligrams per kilogram of OTS964 every day for two weeks. Again, continuous tumor shrinkage was observed after the final dose of the drug. In all six mice the tumors completely regressed. All of the mice had low white-blood-cell counts after treatment, but they recovered within two weeks.
Although this was a small study, the outcome was dramatic. Seeing these results was a “quite exciting moment,” said Nakamura, who stepped down from his role as Director in the Japanese Government's Office of Medical Innovation to join the faculty at the University of Chicago in April 2012. “It is rare to see complete regression of tumors in a mouse model,” he said. “Many drugs can repress the growth, but it is uncommon to see them eradicated. This has rarely been reported.”

Similar studies of the drug’s effects on tumor cells growing outside the body enabled the researchers to videotape the process as the cancer cells died. TOPK appears to play a central role late in cytokinesis, the final stage in cell division. Dividing cancer cells would begin to separate into two new cells, but were unable to fully disconnect, retaining an intercellular bridge.

“Without TOPK the cells can’t seem to divide; they can’t make the break,” Nakamura said. “They can’t complete the process. Instead they remain tethered by a tiny bridge. When that finally breaks apart, they can’t close the membrane. Everything within the cells spills out, they suffer and then die.”

TOPK may provide a good drug target for several types of cancer. This study involved primarily lung cancers, but the gene is frequently upregulated in breast, brain, liver, bladder and other solid tumors as well as certain types of leukemia. The researchers are working with oncologists at the University to begin a phase-1 clinical trial as soon as the fall of 2015.

Funding for the study was provided by the New Energy and Industrial Technology Development Organization (NEDO) of Japan and OncoTherapy Science Inc. (OTS) of Kawasaki, Kanagawa, Japan, which produces OTS964. OTS was founded in 2001 to develop anti-cancer medicines based on research targeting oncogenes and proteins by Nakamura.

Additional authors include Jae-Hyun Park and Houda Alachkar of the University of Chicago; and Yo Matsuo, Takashi Miyamoto, Shinji Yamamoto and Shoji Hisada of OncoTherapy Science Inc. Nakamura and Park are advisors to OTS and Nakamura is a stockholder.
芝加哥大学, Nakamura, 东京大学, 科研项目, 乳腺癌

964 有人试了 副作用比较大

Jerry7214 发表于 2015-10-19 15:42
964 有人试了 副作用比较大

是不是合格的964都是个问题！比如分子式对不对？

入脑吗？