Non-genetic heterogeneity in response to anti-mitotic chemotherapeutics

“抗有丝分裂药”是一类最初从自然来源分离出来的药物，在癌症化疗中经常使用。这一类别的名称源于这样一个事实，即它们都阻止有丝分裂，即细胞分裂的过程，进而导致细胞死亡。一个主要的例子是紫杉醇(紫杉醇)，最初是从太平洋红豆杉中分离出来的，被广泛用于治疗乳腺癌和卵巢癌。这些传统的化疗药物与现代疗法结合使用时，会给患者带来更大的好处；例如，同时使用抗有丝分裂药物和赫赛汀(曲妥珠单抗)已迅速成为侵袭性乳腺癌手术切除后的首选治疗方法。这种组合似乎在杀死手术后留下的微转移瘤方面非常有效，否则会导致癌症复发。因此，在可预见的未来，抗有丝分裂药物仍将是重要的化疗药物，但这些药物还远远不是完美的。一个问题是，它们有一种相当独特的副作用，即周围神经病变，可能导致手指和脚趾失去知觉。如果一个人的目标是“战胜”他们的癌症，希望有更多的优质年份，这就构成了一个非常现实的两难境地；当这种副作用出现时，肿瘤团队的即时反应是减少剂量，但这会降低治疗的效果吗？有时，患者甚至会专门选择不使用抗有丝分裂药来避免这种副作用。因此，寻找具有相似益处但副作用减少的新药是一项有价值的事业。事实上，学术界、生物技术和制药业的广泛研发努力，耗资约100亿美元，已经产生了一系列广泛的第二代抗有丝分裂药物，例如EG5马达蛋白的抑制剂和Aurora/PLK激酶抑制剂。与原始的、自然产生的抗有丝分裂药物不同，这些新药已经被合成来抑制有丝分裂特异性蛋白，从而在不损害未分裂的神经细胞的情况下杀死分裂细胞。这些药物中的许多都很好；它们以极大的效力和特异性抑制它们设计的蛋白质，而且许多药物在给患者使用时耐受性很好。重要的是，与传统抗有丝分裂药物相关的外周神经病似乎不会发生。然而，到目前为止，这些新药的抗癌效果一直令人失望。原因尚不清楚，但重要的是要注意，这些第二代药物尚未在与传统抗有丝分裂药物最有效的临床环境类似的临床环境中进行测试。这是因为在当前护理标准已经非常好的环境中测试新药是困难的。然而，这些优秀的新药确实存在被抛弃的危险。当然，这将是一个真正的耻辱，因为人类的广泛努力和研究资金导致了这些药物的产生。此外，这可能意味着我们没有意识到一个机会，在治疗乳腺癌时，周围神经病变不再是一个并发症。导致这种情况的因素之一是，我们实际上不知道抗有丝分裂药物是如何杀死细胞的。我的实验室最近发现，暴露在抗有丝分裂药物下的癌细胞可以在有丝分裂中死亡，也可以从有丝分裂中“溜出来”存活下来。从那时起，我们发现了一种控制这种差异的基因：当我们抑制它时，平衡就会朝着有利于滑动的方向移动。这项提议的总体目标是跟进这一发现，目的是看看我们是否可以扭转平衡，也就是有利于死亡。这可能会为组合策略开辟新的机会，使癌细胞不仅对传统的抗有丝分裂药物敏感，而且对第二代药物敏感。

The "anti-mitotics" are a class of drugs originally isolated from natural sources that are used frequently during cancer chemotherapy. The name of this class derives from the fact that they all block mitosis, the process of cell division, in turn leading to cell death. A leading example is paclitaxel (Taxol) originally isolated from the pacific yew tree and widely used to treat breast and ovarian cancer.These traditional chemotherapy drugs give even greater patient benefit when used in combination with modern therapies; for example, simultaneous use of anti-mitotics with Herceptin (trastuzumab) has very quickly become the preferred treatment following surgical removal of an invasive breast cancer. This combination appears to be very effective at killing the micrometastases left behind following surgery that would otherwise lead to reappearance of the cancer. Consequently, the anti-mitotics will continue to be important chemotherapy drugs for the foreseeable future.These drugs are however far from perfect. One problem is that they have a rather unique side affect, peripheral neuropathy, which can lead to loss of sensation in the fingers and toes. If an individual aims to "beat' their cancer, with the hope of many more good-quality years, this poses a very real dilemma; when this side affect appears, the immediate reaction of the oncology team is reduce the dose, but will that reduce the effectiveness of the treatment? Sometimes, patients even opt out of anti-mitotics specifically to avoid this side effect. Therefore, finding new drugs that offer similar benefit but with reduced side affects is a worthwhile cause. Indeed, extensive R&D efforts within academia, biotech and the pharmaceutical industry, efforts approximating $10 billion, has resulted in an extensive array of 2nd generation anti-mitotic drugs, for example, inhibitors of the Eg5 motor protein and Aurora/Plk kinase inhibitors.Unlike the original, naturally occurring anti-mitotics, these new drugs have been synthesized to inhibit mitosis-specific proteins so that they kill divding cells without harming non-dividing nerve cells. Many of these drugs are excellent; they inhibit the proteins they were designed to with great potency and specificity, and many are well tolerated when administered to patients. And importantly, the peripheral neuropathies associated with traditional anti-mitotic drugs do not seem to occur. However, the anti-cancer effects of these new drugs has thus far been rather disappointing.The reasons for this are unclear but it is important to note that these 2nd generation drugs have not yet been tested in clinical settings similar to those where the traditional anti-mitotics are known to be most effective. This is because it is difficult to test new drugs in settings where the current standard of care is already very good. Nevertheless, there is a very real danger that these excellent new drugs will be cast aside. This will of course be a real shame in terms of the extensive human endeavour and research funding that resulted in these drugs being created. Moreover, it may mean that we fail to realise an opportunity whereby peripheral neuropathies are no longer a complication when treating breast cancer.One of the factors contributing to this state of affairs is that we actually don't know how anti-mitotic drugs kill cells. My lab recently discovered that cancer cells exposed to anti-mitotics can either undergo death in mitosis or they can "slip" out of mitosis and survive. Since then we have identified a gene that controls this difference: when we inhibit it, the balance is shifted in favour of slippage. The overall goal of this proposal is to follow up this discovery with the intention of seeing if we can tip the balance the other way, i.e. in favour of death. This may then open up new opportunities for combination strategies that sensitise cancer cells not only to traditional anti-mitotics, but also to the 2nd generation drugs.