Non-genetic heterogeneity in response to anti-mitotic chemotherapeutics

“抗有丝分裂剂”是一类最初从天然来源中分离出来的药物，在癌症化疗期间经常使用。该类的名称来源于它们都阻止有丝分裂，细胞分裂的过程，从而导致细胞死亡。紫杉醇（Taxol）是一种从太平洋紫杉中提取的药物，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，患者获益更大。例如，在手术切除浸润性乳腺癌后，同时使用抗有丝分裂药物和赫赛汀（曲妥珠单抗）已迅速成为首选治疗方法。这种组合似乎非常有效地杀死手术后留下的微转移，否则会导致癌症的复发。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，但这些药物还远未达到完美。一个问题是，它们有一个相当独特的副作用，周围神经病变，这可能导致手指和脚趾的感觉丧失。如果一个人的目标是“战胜”癌症，并希望度过更多美好的岁月，这就会带来一个非常真实的困境;当出现这种副作用时，肿瘤学团队的立即反应是减少剂量，但这会降低治疗的有效性吗？有时，患者甚至选择不使用抗有丝分裂药，以避免这种副作用。因此，寻找新的药物，提供类似的好处，但减少副作用是一个值得的事业。事实上，在学术界、生物技术和制药行业内的广泛研发努力（努力接近100亿美元）已经产生了大量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。这些新的药物已经被合成来抑制有丝分裂特异性蛋白质，从而它们杀死分裂细胞而不伤害非分裂的神经细胞。这些药物中的许多都是优秀的;它们以极大的效力和特异性抑制它们被设计用于的蛋白质，并且许多药物在给予患者时耐受性良好。重要的是，与传统的抗有丝分裂药物相关的周围神经病变似乎不会发生。然而，这些新药的抗癌效果迄今为止相当令人失望。原因尚不清楚，但重要的是要注意，这些第二代药物尚未在临床环境中进行测试，类似于传统的抗有丝分裂药物已知是最有效的。这是因为很难在目前的护理标准已经非常好的环境中测试新药。然而，这些优秀的新药有被抛弃的真实的危险。这当然将是一个真实的耻辱，就广泛的人类努力和研究资金而言，导致这些药物被创造出来。此外，这可能意味着我们没有意识到周围神经病变不再是治疗乳腺癌的并发症的机会，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如何杀死细胞。我的实验室最近发现，暴露于抗有丝分裂剂的癌细胞可以在有丝分裂中死亡，也可以从有丝分裂中“溜走”并存活下来。从那时起，我们已经确定了一个控制这种差异的基因：当我们抑制它时，平衡就会转向有利于滑动。这项建议的总体目标是跟进这一发现，看看我们是否可以将天平向另一个方向倾斜，即有利于死亡。这可能会为联合策略开辟新的机会，这些策略不仅使癌细胞对传统的抗有丝分裂药物敏感，而且还对第二代药物敏感。

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.