由于AACR（美国癌症研究协会）年会迅速接近，许多行业和学术科学家正忙着为他们希望的谈判和海报做准备，这将是癌症治疗中的下一个新的波浪或下一个“新的和改进”的临床前模型yaboapp体育官网。然而，虽然这些可能是长镜头，但它是改进的科学驱动，让我们向前迈进。因为，患者和临床医生，我们迫切地寻找新的疗法，即使赔率是针对我们的。履行未满足的医疗需求的愿望完全如何发现一种新药。新的肿瘤药物只有5％的成功率，一旦将I阶段临床试验到FDA批准。这是21个主要疾病适应症中的最低成功率。1
因为，患者和临床医生，我们迫切地寻找新的疗法，即使赔率是针对我们的。履行未满足的医疗需求的愿望完全如何发现一种新药。
这种成功率差的率从患者到Benchtop科学家留下了每个人，质疑模型的有效性和所产生的数据。这在癌症研究中没有什么新鲜事;我们都试图治疗一种有能力愚弄其宿主并适应生存的疾病。说最少的是非常具有挑战性的。
它已经很好地发布，临床节数据和临床结果之间存在根本的断开。yaboapp体育官网十九次尝试将新的肿瘤治疗带到诊所将失败。这约为其他治疗区域的一半;如心血管和炎症。肿瘤学的成功率非常低，导致药物公司和FDA在让新疗法到绝望的患者人口时更宽松。不幸的是，这导致了临床环境中迅速失败的药物。在〜10年的跨度中，9,985名新药进入I阶段临床试验，单独肿瘤患者31.2％（3,163）。1,2The high failure rate leads to industry criticism that the traditional preclinical animal models are, at best, limited in their power of predictability and, at worst, grossly inaccurate. This may be the easy scapegoat. Improving and evolving the current preclinical animal models is essential to understanding their potential and, equally as important, their limitations. Traditional preclinical (xenograft and syngeneic) models have worked in the past and continue to be highly valuable tools. However, the interpretation of the data that is produced by all of these models and how it is used to predict clinical response may be where the biggest discrepancy lies.
在努力更密切地模仿人类疾病时，许多人和鼠肿瘤细胞系已进一步验证为原位植入物。植入原产地组织中的人或鼠肿瘤细胞可导致病理分布，其概括了人类疾病，并且与传统的皮下模型相比，可以增加转移性受累的速率。3.与所有型号一样，具有原位植入物存在局限性;主要监测疾病进展可以限于不理想的生存终点。最佳情况是通过使用临床上可翻译的成像技术（MRI或CT）或光学成像（BLI或FMT）来利用原位植入物。使用成像技术（临床翻译或光学）的能力允许在与临床中进行相同的动物在同一个动物中评估实体肿瘤或血液癌。以这种方式跟踪疾病负担和反应有可能成为将新药物的临床前活性（反应）转化为临床成功的非常强大的工具。yaboapp体育官网
如果我们可以集体将酒吧汇集到更严格的临床前标准，以评估新型癌症治疗，我们可能会降低诊所的失败率。yaboapp体育官网下游在审查临床前数据时，它将提高临床医生和患者的信心。yaboapp体育官网
近年来，在利用患者衍生的异种移植物（PDXS）中具有显着的增强。在对细胞毒性和靶向疗法的回顾性分析中，PDX模型在临床相关剂量水平时清楚地预测（〜90％精确）的临床结果。3.这是癌症研究领域的显着改善，但这些模型也有局限性。获得新鲜的人类组织是挑战性和成功植入的机会，即使在严重的免疫普及的小鼠中也是大约30％。3.如果植入成功，请将这些PDX线保持为低通道模型，以供将来使用更多并发症。从组织获取到运行疗效研究的基础上获取和维护模型的物流可能是最重要的障碍，可以是广泛的频繁使用和接受这些PDX模型的障碍。
Clinically, the most commonly utilized endpoints to evaluate the effectiveness of a therapy are an industry standardized set of terms and definitions (RECIST criteria). Paramount to this list is the responsiveness of the disease to treatment; complete response (CR), partial response (PR), and overall increase in survival. CRs are defined as complete regressions of the primary tumor mass. PRs are defined as a partial reduction in the primary tumor by at ~30%. Therapies are considered successful if they are able to induce either CRs or PRs which can lead to a positive impact on survival. However, in the preclinical setting the commonly used endpoints are tumor growth inhibition and tumor growth delay; both are defined as a slowing of disease progression. Unfortunately, tumor growth inhibition does not directly correlate to an overall increase in survival. This is a critical difference; the evaluation of preclinical efficacy data within the research community is less rigorous and held to a different set of standards than its clinical counterparts. The lower standards allow for more drugs to get through to clinical trials which results in a greater number of clinical failures. This idea of aligning our preclinical and clinical standards is not novel. In an editorial published in the Journal of the National Cancer Institute, the authors called for a consensus among drug developers that unequivocally define what successful preclinical endpoints are.4.如果我们可以集体将酒吧汇集到更严格的临床前标准，以评估新型癌症治疗，我们可能会降低诊所的失败率。yaboapp体育官网下游在审查临床前数据时，它将提高临床医生和患者的信心。yaboapp体育官网
现在我们都知道改变是困难的和期待anything to happen overnight is naïve, but small changes in perceptions and practices now could have significant impact later. The preclinical models that we have all invested years and years in developing are effective if we use them correctly. This starts with concise protocol design and ends with consistent data evaluations. In clinical trials new drugs will be facing patients with established disease. The research community can use this assumption to design more rigorous preclinical experiments. In the clinic, tumors are well established within the origin tissue with a vascular bed in place to ensure survival at the time treatment is initiated. We can mimic this environment preclinically with either subcutaneous or orthotopic implants by just allowing the tumor to grow and become more established. The time that it takes for tumors to become established is highly dependent on the tumor line and the implant location. Subcutaneous tumors can be monitored easily with standard calipers to ensure progressive growth. Orthotopic models are a bit trickier to ensure that the tumor is actively growing unless you have the ability to image the tumors over time. This relatively straightforward step would save time and money that is wasted on false positive results generated from studies designed to treat tumors that are not at all or only barely established. At the time of final data analysis scientist and drug developers need to also alter how they define an active new drug. Using the clinical standards as a guideline for activity would decrease the number of new drugs being pushed into the clinic that inevitably fail. This starts with a shift away from tumor growth inhibition endpoints to the clinically translatable endpoints CRs, PRs, and overall all increase in survival.
这不是小要求;试图说服整个科学家和药物开发商的领域，更加努力地看待他们的临床前疗效数据，并将其持有更强大的标准将显然影响感知的成功率。yaboapp体育官网但是，如果迫切需要努力，迫切将这些新药迫使这些新药，而不是将它们推入诊所，其实际成功的机会将增加。yaboapp体育官网所有这些都在长期以来会节省时间，金钱和潜在的生活。
1Thomas TW，Burns J，Audette J，Corrol A，Dow-Hygelund C，Hay M.临床发展成功率2006-2015。生物产业分析2016年6月。
2KAMB A.我们的CALER模型有什么问题？自然评论2005年2月;卷。4。
3.Ruggeri BA，孟加尔露营，米科尼茨基S.动物模型：癌症前临床动物模型及其在药物发现中的应用和效用。生物化学药理学2014;卷。87,150-161。
4.Berttotti A，Trusolino L.从长凳到床边：翻译肿瘤的剂量临床前实践需要一些重建？yaboapp体育官网JNCI 2013;卷。105，问题19。
