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

项目总结 我们建议进行一期临床试验，以测试一种新的治疗策略的安全性和初步疗效 旨在提高胰腺癌标准化疗的疗效。到目前为止，组合 化疗仍然是胰腺癌的主要治疗方法。FOLFIRINOX是一种组合 治疗无法治疗的胰腺癌记录最好的化疗方案 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。 在确诊后一到两年内。这在一定程度上是由于胰腺癌细胞对 化疗药物。免疫治疗存活率低和临床经验不成功的另一个原因 是因为胰腺癌周围致密的非癌细胞不仅阻止了化疗 药物不仅不能到达癌细胞，还会使抗肿瘤免疫细胞丧失能力。这些挑战支持 克服联合化疗耐药和提高疗效的需要进一步研究 在胰腺癌的免疫治疗方面。 使用无偏倚的蛋白质阵列分析，我们发现胰腺癌细胞显著上调MK2 酶及其伴侣分子Hsp27，当暴露于FOLFIRINOX化疗时。MK2和Hsp27 当细胞的DNA受到化疗的打击时，保护胰腺癌细胞免受细胞死亡。当MK2被阻止时 到了ATI-450，胰腺癌细胞变得更容易受到化疗导致的死亡的影响。在一个 ATI-450联合FOLFIRINOX有效联合建立侵袭性胰腺癌小鼠模型(KPC小鼠) 切除了癌症，据我们所知，这一观察结果还没有报道。此外，ATI-450 使癌症周围的免疫细胞转化为更容易感染的类型 免疫疗法，为免疫疗法的发展铺平了道路，我们将在本 求婚。重要的是，ATI-450现在已经在为中到重度类风湿患者进行临床试验 关节炎和耐受性很好，除了罕见的轻微头晕和头痛，这会减少我们的 担心与FOLFIRINOX联合使用时的额外毒性。 在这项提案中，我们将进行I期临床试验，以确定ATI-450与ATI-450联合应用的安全性 FOLFIRINOX用于不能手术的胰腺癌患者(目标1)。我们将确定一个安全的，可耐受的剂量 ATI-450与FOLFIRINOX联合使用，并获得早期迹象，说明这种联合是否 比单用FOFIRINOX有效。我们计划获取接受ATI的患者的肿瘤和血液样本。 450和FOLFIRINOX，并对其进行分析，以确认添加ATI-450对 克服对FOLFIRINOX的耐药性，改变癌症周围的免疫细胞，就像在 动物模型(目标2)。最后，我们发现MK2具有激活抗癌免疫的作用。通过分析患者 用MK2抑制剂处理的样本和产生新的最先进的遗传小鼠模型，我们将研究 基于MK2抑制剂的胰腺癌免疫治疗新策略及其机制研究(AIM) 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).