An MD Anderson drug developed to starve cancer is tested on an aggressive leukemia

几十年来，联合化疗一直是治疗急性髓性白血病（AML）的主要治疗方法 - 在血液和骨髓的侵袭性癌症。

“的年轻患者大约有40％长期生存，并为65岁以上，存活率下降到10％，”说Marina Konopleva, M.D., Ph.D., professor of白血病。“There’s been no drug approved for the last 40 years for AML, and outcomes haven’t significantly improved with targeted therapies.”

Researchers atMD Anderson’s Institute for Applied Cancer Science(IACS) are hoping to put an end to that drought with a drug they developed to starve these malignant blood cells to death.

The initial Phase I clinical trial of the drug known as IACS-10759 opened for patients in October, a milestone for IACS, which acts as a biotech company embedded in a cancer center. The institute connects MD Anderson faculty with drug discovery and development expertise.

Konopleva and Naval Daver, M.D., assistant professor of Leukemia, lead the AML trial, which is funded by a $3.5 million investment from the Leukemia and Lymphoma Society under its Therapy Acceleration Program, part of an intensive campaign the society launched against AML in late 2016.

把癌症的致命饮食

Based on an approach discovered by the institute, IACS-10759 is designed to target a metabolic vulnerability of AML cells.

大部分细胞依赖于两个代谢过程中生存。细胞器线粒体称为通过所谓的氧化磷酸化（OXPHOS）过程中使用氧气存储在糖，脂肪酸和蛋白质转化为能量的能量转换。细胞也通过被称为糖酵解效率较低的过程葡萄糖转化为能量在不存在氧气。IACS-10759抑制OXPHOS，从而代谢的两个臂癌细胞提供能量和构建块中的一个。

Konopleva说，她的团队的研究表明，白血病细胞188bet体育网址高度依赖于这些线粒体驱动的流程。

“氧化磷酸化是他们如何生存，但没有人有临床可行的抑制剂，”她说。

Enter IACS, where scientists, applying their drug development expertise and capacity for rapidly testing and understanding the mechanism of possible drugs in preclinical models, developed IACS-10759.

“正常细胞可以通过调高糖酵解避开OXPHOS抑制作用，但我们已经确定了一些癌症一样AML不能做足够的生存，”约瑟夫Marszalek，博士，翻译生物学的负责人说，中心联合临床试验。

Create, test, refine, test again

它采取了超过25人的团队成功地把IACS-10759进入临床试验。艾米利亚迪弗朗西斯博士，IACS药物化学的副主任，带领一个小组，虽然避免了脱靶工艺品的小分子药物对肿瘤细胞有效地击中目标的影响。

Marszalek’s group puts those drugs to the test in cell lines and mouse models. What they discover about the drug’s efficacy and side effects is fed back to Di Francesco’s group, which fine-tunes the drug.

This intensive, reiterative process allowed them to analyze a series of molecules over 18 months before zeroing in on IACS-10759 for development.

“We needed to refine the drug for the clinic and build in all the properties to make it more effective in patients,” Di Francesco says.

了解更多关于IACS和IACS-10759的MD安德森的年度报告。