多种药物并用将癌症变成可控疾病

【美国《每日科学》网站7月11日报道】题：多种药物并用将癌症变成可控疾病

    哈佛大学研究癌症抗药性的专家说，几十年后，“很多很多癌症可能是可以控制住的”。

    进化动力学项目主任、数学和生物学教授马丁·诺瓦克说：“很多人将不必因罹患癌症而死亡，在与癌症的战斗中，这项研究可能提供一种新策略。100年前，很多人死于细菌感染。如今，我们有了治疗细菌感染的办法———感染者不必因此而死亡。我认为，对于癌症，我们正在接近类似的时期。”

诺瓦克的研究表明，攻克癌症的关键是改变临床医生的抗癌方式。


    近些年来，医生和研究人员越来越多地采用“靶向疗法”———利用干扰其生长和扩散能力的药物来抗癌———而非传统的化疗，不过这种疗法远不完善。多数靶向疗法只管几个月的时间，之后癌症就有了抗药能力。

   诺瓦克说，简言之，在患者身上数以十亿计的癌细胞中，对靶向疗法的药物具有抗药能力的所占比例极小———约为百万分之一。治疗一开始，非抗药细胞被消灭。然而，为数不多的抗药细胞很快让癌重生，导致治疗失败。

    诺瓦克研究小组的成员、数学博士后伊万娜·博齐克说：“我们的研究证明，由于从一开始抗药性就存在，所以用单一药物治疗不会奏效。”

    诺瓦克说，答案很简单：不要在靶向疗法中只用一种药物，治疗癌症至少要用两种药物。

    癌症的治疗必须因人而异，而且必须以癌的基因构成为依据。诺瓦克说，或许更重要的是，同时使用的两种药物一定不能交叉使用：只要出现一个变异，就会让癌变得对两种药物都具有抗药性，这就会像用单一药物治疗那样失败。

    诺瓦克估计，要解决治疗中可能出现的所有变异，可能需要数百种药。他说，近期的问题是要开发出那些药品来。

    诺瓦克说：“我认为，这将是今后10年及以后癌症治疗研究的主要途径。随着越来越多的药物开发出来用于靶向疗法，我认为我们将会看到癌症治疗的革命。”

是考慮輪換藥物還是聯合用藥？

癌症的治疗必须因人而异，而且必须以癌的基因构成为依据。诺瓦克说，或许更重要的是，同时使用的两种药物一定不能交叉使用：只要出现一个变异，就会让癌变得对两种药物都具有抗药性，这就会像用单一药物治疗那样失败。


比如用a药杀到剩下抗药的细胞，剩下的会继续发展，成为抗a药的肿瘤。用b药时就会杀到剩下能同时抗ab药的肿瘤。。。。。。。。。。。是这样理解么

药物开发的进度，不能满足我们的需要啊。

“只要出现一个变异，就会让癌变得对两种药物都具有抗药性，这就会像用单一药物治疗那样失败。”——如果这样，联合用药就很不合算，一但抗药，联合的药都一起被废，能有多少药这样成双成对地被废？
多种药联合大包围，理论上似乎可得到很强的威力，但忽略了联合的各药的剂量和副作用的总和，联合的各药如果都小剂量，合起来可能都不着边际；如果各药的剂量都达到治疗的剂量，那么副作用的叠加会非常可怕。
这文章给我的结论是：尽可能多种的药和频繁的轮流使用仍是最好的方法。

把原文贴上来，懂英文的更好理解一些。
Transforming Cancer Into a Manageable Illness With Multi-Drug Approach
ScienceDaily (July 11, 2012) — A Harvard researcher studying the evolution of drug resistance in cancer says that, in a few decades, "many, many cancers could be manageable."
"Many people are dying needlessly of cancer, and this research may offer a new strategy in that battle," said Martin Nowak, a professor of mathematics and of biology and director of the Program for Evolutionary Dynamics. "One hundred years ago, many people died of bacterial infections. Now, we have treatment for such infections -- those people don't have to die. I believe we are approaching a similar point with cancer."

Nowak is one of several co-authors of a paper, published in Nature on June 28, that details how resistance to targeted drug therapy emerges in colorectal cancers and describes a multidrug approach to treatment that could make many cancers manageable, if not curable.

The key, Nowak's research suggests, is to change the way clinicians battle the disease.

Physicians and researchers in recent years have increasingly turned to "targeted therapies" -- drugs that combat cancer by interrupting its ability to grow and spread -- rather than traditional chemotherapy, but such treatment is far from perfect. Most targeted therapies are effective for only a few months before the cancer evolves resistance to the drugs.

The culprit in the colon cancer treatment examined in the Nature paper is the KRAS gene, which is responsible for producing a protein to regulate cell division. When activated, the gene helps cancer cells develop resistance to targeted-therapy drugs, effectively making the treatment useless.

To better understand what role the KRAS gene plays in drug resistance, a team of researchers led by Bert Vogelstein, the Clayton Professor of Oncology and Pathology at the Johns Hopkins Kimmel Cancer Center, launched a study that began by testing patients to determine if the KRAS gene was activated in their tumors. Patients without an activated KRAS gene underwent a normal round of targeted therapy treatment, and the initial results -- as expected -- were successful. Tests performed after the treatment broke down, however, showed a surprising result: The KRAS gene had been activated.

As part of the research, Vogelstein's team analyzed a handful of mutations that can lead to the activation of the KRAS gene. To help interpret those results, they turned to Nowak's team, including mathematicians Benjamin Allen, a postdoctoral fellow in mathematical biology, and Ivana Bozic, a postdoctoral fellow in mathematics.

Analyzing the clinical results, Allen and Bozic were able to mathematically describe the exponential growth of the cancer and determine whether the mutation that led to drug resistance was pre-existing, or whether it occurred after treatment began. Their model was able to predict, with surprising accuracy, the window of time from when the drug is first administered to when resistance arises and the drug begins to fail.

"By looking at their results mathematically, we were able to determine conclusively that the resistance was already there, so the therapy was doomed from the start," Allen said. "That had been an unresolved question before this study. Clinicians were finding that these kinds of therapies typically don't work for longer than six months, and our finding provides an explanation for why that failure occurs."

Put simply, Nowak said, the findings suggest that, of the billions of cancer cells that exist in a patient, only a tiny percentage -- about one in a million -- are resistant to drugs used in targeted therapy. When treatment starts, the nonresistant cells are wiped out. The few resistant cells, however, quickly repopulate the cancer, causing the treatment to fail.

"Whether you have resistance prior to the start of treatment was one of the large, outstanding questions associated with this type of treatment," Bozic said. "Our study offers a quantitative understanding of how resistance evolves, and shows that, because resistance is there at the start, the single-drug therapy won't work."

The answer, Nowak said, is simple: Rather than the one drug used in targeted therapy, treatments must involve at least two drugs.

Nowak isn't new to such strategies. In 1995 he participated in a study, also published in Nature, that focused on the rapid evolution of drug resistance in HIV. The result of that study, he said, was the development of the drug "cocktail" many HIV-positive patients use to help manage the disease.

Such a plan, however, isn't without challenges.

The treatment must be tailored to the patient, and must be based on the genetic makeup of the patient's cancer. Perhaps even more importantly, Nowak said, the two drugs used simultaneously must not overlap: If a single mutation allows the cancer to become resistant to both drugs, the treatment will fail just as the single-drug therapy does.

Nowak estimated that hundreds of drugs might be needed to address all the possible treatment variations. The challenge in the near term, he said, is to develop those drugs.

"This will be the main avenue for research into cancer treatment, I think, for the next decade and beyond," Nowak said. "As more and more drugs are developed for targeted therapy, I think we will see a revolution in the treatment of cancer."

支持憨哥的说法。

憨豆精神 发表于 2012-7-21 15:36

                               
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“只要出现一个变异，就会让癌变得对两种药物都具有抗药性，这就会像用单一药物治疗那样失败。”——如果这 ...

是的，我贴这篇报道的意图就在这。

“或许更重要的是，同时使用的两种药物一定不能交叉使用：只要出现一个变异，就会让癌变得对两种药物都具有抗药性，这就会像用单一药物治疗那样失败。 ”

原文：Perhaps even more importantly, Nowak said, the two drugs used simultaneously must not overlap: If a single mutation allows the cancer to become resistant to both drugs, the treatment will fail just as the single-drug therapy does.
这句话照原文“硬译”应该是：
  也许更重要的是，诺瓦克说，两种同时使用的药物不能重叠，因为如果一个单一的突变使得癌症对二种药抗药，治疗将失败。就像单一药物治疗失败一样。
  就是说二种（多种）药物要先后用（序贯），而不能同时用（联用）。大哥的理解完全正确！

但是，原文里他把这种建议与他在1995年提出的HIV病毒cocktail疗法相提并论，有些不能理解，众所周知HIV鸡尾酒疗法就是多药联合。
  

《  生物物理所研究发现肿瘤血管生成新机制
                同时提出肿瘤治疗联合给药策略 》


6月20日，BLOOD杂志在线发表了中国科学院生物物理研究所阎锡蕴课题组在肿瘤血管生成方面的最新研究成果。这是该课题组继发现CD146是肿瘤血管新靶标之后的又一重大突破。

此项研究揭示了肿瘤血管内皮标志分子CD146作为细胞表面受体促进血管生成的最新分子机制，是CD146作为肿瘤血管生成标志分子的最直接证据。这一发现最重要的意义是其提供了一种更加有效的治疗肿瘤的新策略，即靶向CD146作为VEGFR-2共受体这一角色进行抗体联合治疗。

血管内皮细胞生长VEGF是肿瘤血管生成过程中最重要的调控因子，因此，靶向VEGF治疗已经成为靶向肿瘤血管治疗的热点，其中最有效的抗体药物是贝伐单抗(Bevacizumab)，即抗VEGF的单克隆抗体，它通过阻断VEGF与其受体VEGFR-2的结合，阻断VEGF引起的内皮细胞活化和血管生成，从而抑制肿瘤生长。自2004年作为第一个有效抑制肿瘤血管生成的抗体药物被美国FDA批准上市后，贝伐单抗已经被批准应用于治疗结直肠癌、乳腺癌、非小细胞肺癌、肾癌等癌症，年产值约为60亿美元。

阎锡蕴课题组研究发现，CD146是血管内皮细胞生长因子受体VEGFR-2的共受体，调节VEGF诱导的VEGFR-2的活化及下游信号的传递，进而促进肿瘤血管生成。基于CD146是VEGFR-2共受体这一分子机制，研究人员利用抗CD146单克隆抗体AA98及抗VEGF单克隆抗体Bevacizumab，建立了靶向血管生成的抗体联合治疗模型，该联合策略的有效性在接种人胰腺癌细胞和人黑素瘤细胞的裸鼠荷瘤模型中得到验证，即与单一抗体给药相比，AA98及Bevacizumab联合给药具有协同效应，其抑瘤率是Bevacizumab单独给药组1.5倍。

上述研究成果不仅揭示了CD146作为内皮细胞受体促进肿瘤血管生成的新机制，同时也为临床靶向血管新生治疗肿瘤提供了新思路和新策略，这种联合治疗策略的高效性为更多癌症患者带来了曙光。

抗药性到底是原来的癌细胞就部分有，还是用了药之后才产生有抗药性的癌细胞？