Project 3: Targeting Stress-induced MK2 as Novel Strategy in Pancreatic Cancer

项目摘要 我们提出了一项1期临床试验，以测试一种新的治疗策略的安全性和初步疗效， 旨在增强胰腺癌标准化疗的疗效。迄今为止， 化疗仍然是胰腺癌的主要治疗方法。FOLFIRINOX是一种组合药物， 治疗胰腺癌的最佳跟踪记录的化疗方案， 手术;然而，即使有最好的治疗，大多数患者仍然会死于这种疾病 在确诊后的一到两年内。这部分是由于胰腺癌细胞对肿瘤细胞产生了耐药性。 化疗药物另一个生存率差和免疫治疗临床经验不成功的原因 是因为胰腺癌周围密集的非癌细胞不仅阻止了化疗 药物到达癌细胞，但也使抗肿瘤免疫细胞丧失能力。这些挑战支持 需要进一步研究克服联合化疗的耐药性和提高疗效 免疫疗法的最新进展。 使用无偏蛋白质阵列分析，我们发现胰腺癌细胞显著上调MK2， 当暴露于FOLFIRINOX化疗时，酶及其伴侣分子Hsp 27。MK2和Hsp 27 当胰腺癌细胞的DNA被化疗击中时，保护它们免于细胞死亡。当MK2被封锁时 通过ATI-450，胰腺癌细胞变得更容易受到化疗诱导的死亡的影响。中 在侵袭性胰腺癌小鼠模型（KPC小鼠）中，ATI-450加FOLFIRINOX的组合有效地 据我们所知，这一观察结果尚未报道。ATI-450 导致癌症周围的免疫细胞转化为更容易受到癌症影响的类型。 免疫疗法，为免疫治疗方案的发展铺平了道路，我们将在这方面建立 提议重要的是，ATI-450现在已经在中重度类风湿患者的临床试验中 关节炎，是非常好的耐受性，除了罕见的，轻度头晕和头痛，这减少了我们的 与FOLFIRINOX联合使用时增加毒性的问题。 在本提案中，我们将进行I期临床试验，以确定ATI-450与 FOLFIRINOX治疗不能手术的胰腺癌患者（目的1）。我们将确定一个安全的，可耐受的剂量 ATI-450联合FOLFIRINOX，并获得关于该联合治疗是否更有效的早期指示。 比单独使用FOFIRINOX更有效。我们计划在接受ATI治疗的患者中采集肿瘤和血液样本- 在本试验中使用ATI-450和FOLFIRINOX，并对其进行分析，以确认添加ATI-450对 克服了对FOLFIRINOX的耐药性，并改变了癌症周围的免疫细胞，就像它在 动物模型（目标2）。最后，我们发现MK2激活抗癌免疫。通过分析患者 用MK2抑制剂处理的样品并产生新的最先进的遗传小鼠模型，我们将研究 MK2靶向免疫治疗胰腺癌的研究 3）。

PROJECT SUMMARY We propose a phase 1 clinical trial to test the safety and preliminary efficacy of a new therapeutic strategy that aims at augmenting the efficacy of standard chemotherapy in pancreatic cancer. To date, combination chemotherapies remain the mainstay treatment of pancreatic cancer. FOLFIRINOX is a combination chemotherapy regimen with the best track record for treatment of pancreatic cancer that cannot be treated with surgery; however, even with the best treatment, the majority of the patients will still succumb to the disease within one to two years of diagnosis. This is in part due to pancreatic cancer cells developing resistance to the chemotherapy drugs. Another reason for poor survival and unsuccessful clinical experience of immunotherapy is because of the dense non-cancer cells that surround the pancreatic cancer not only prevent the chemotherapy drugs from reaching the cancer cells, but also incapacitate anti-tumor immune cells. These challenges support the need for further research into overcoming resistance to combination chemotherapy and improving the effect of immunotherapy in pancreatic cancer. Using an unbiased protein array analysis, we found that pancreas cancer cells dramatically upregulate MK2 enzyme and its partnering molecule Hsp27, when exposed to FOLFIRINOX chemotherapy. Both MK2 and Hsp27 protect pancreas cancer cells from cell death when their DNA is hit by chemotherapy. When MK2 was blocked by ATI-450, pancreatic cancer cells became much more vulnerable to chemotherapy-induced death. In an aggressive pancreas cancer mouse model (KPC mice), the combination of ATI-450 plus FOLFIRINOX potently ablated the cancer, an observation that to our best knowledge, has not been reported. Furthermore, ATI-450 causes immune cells surrounding the cancer to be converted to the types that were more susceptible to immunotherapy, paving the way for development of an immunotherapy regimen, which we will establish in this proposal. Importantly ATI-450 is now already in clinical trial for patients with moderate to severe rheumatoid arthritis and is very well-tolerated except for infrequent, mild dizziness and headaches, which lessens our concerns of added toxicities when combined with FOLFIRINOX. In this proposal, we will conduct a phase I clinical trial to establish the safety of combining ATI-450 with FOLFIRINOX in patients with inoperable pancreatic cancer (Aim 1). We will determine a safe, tolerable dose of ATI-450 in combination with FOLFIRINOX and get an early indication on whether this combination is more effective than FOFIRINOX alone. We plan to obtain tumor and blood samples in patients who are receiving ATI- 450 and FOLFIRINOX on this trial and analyze those to confirm that the addition of ATI-450 was useful to overcome the resistance to FOLFIRINOX, and changed the immune cells surrounding the cancer, as it did in animal models (Aim 2). Lastly, we made discovery that MK2 activates anti-cancer immunity. By analyzing patient samples treated with MK2 inhibitor and generating new state-of-the art genetic mouse models, we will investigate the mechanism and develop a novel MK2 inhibitor-based immunotherapy strategy for pancreatic cancer (Aim 3).