MICA: Phase IIb randomised clinical trial repurposing ATRA as a stromal targeting agent in a novel drug combination for pancreatic cancer (STAR-PAC2).

胰腺癌（PDAC：胰腺导管腺癌）是一种致命的疾病。目前，手术切除受影响的胰腺提供了最好的治愈机会。然而，这在不到十分之一的患者中是可能的。研究和临床试验表明，这种疾病需要新的治疗策略。目前，没有化疗或放疗治疗可用于不符合前期手术条件的患者，这将缩小肿瘤;因此，能够随后手术切除胰腺癌。根据我们在Ib期临床试验（STARPAC）中治疗患者的初步观察以及我们的实验室研究，该提案是一项概念验证临床试验，可使无法接受初次手术的患者受益。我们建议结合联合收割机最先进的化疗（吉西他滨和nab-Paclitazone）靶向癌细胞，并研究全反式维甲酸（ATRA）靶向间质的再利用。胰腺癌的特征在于特别致密的瘢痕组织（称为结缔组织增生），这阻碍了化疗药物的成功递送。一种特殊的细胞类型，胰腺星状细胞（或PSC），是这种促纤维增生基质的关键。事实上，我们已经通过实验证明，PSC使癌细胞存活更长时间，扩散更快。癌细胞从休眠状态激活PSC。反过来，这些激活的PSC通过向癌细胞和免疫细胞发送许多不同的信号来设计促癌反应。我们已经证明，我们可以改变这种PSC行为回到休眠或静止状态。静止期PSC（正常胰腺）储存视黄醇或维生素A，在激活状态（胰腺癌）中丢失。胰腺癌患者缺乏维生素A。因此，他们不能恢复到正常的PSC的行为，没有药物来改变他们的behavior. We的实验室实验表明，我们可以有效地目标和测量内的变化，间质后靶向PSC，使用ATRA。此外，我们证明，使用ATRA也可以靶向其他细胞（免疫细胞和血管），从而损害肿瘤行为。ATRA的作用是加强，以减少肿瘤的大小与国家的最先进的化疗（吉西他滨和nab-Paclitazone）相结合。如果我们能够大幅缩小肿瘤的大小，我们就可以在更多的胰腺癌患者中进行手术切除肿瘤，而不是目前的可能性。我们已经在正在进行的Ib期临床试验中证明，联合收割机这些药物对胰腺癌患者是安全的，不会增加毒性。这项拨款提案是将令人鼓舞的实验室和临床结果转化为常规临床实践的下一步努力。现在，我们将评估这种药物组合在延长胰腺癌患者生存期和缩小肿瘤方面的疗效。除此之外，我们的目标将是开发一种有效的治疗方法，在手术前给予患者，以增加手术切除胰腺癌的机会。因此，这种将实验室实验转化为临床试验的提议利用了癌症和基质区室两者的“共靶向”，并且涉及基于临床观察和合理的生物学实验来重新利用现有的药剂。

Pancreatic cancer (PDAC: pancreatic ductal adenocarcinoma) is a lethal disease. Currently, surgical removal of the affected pancreas offers the best chance for cure. However, this is possible in less than one-tenth of patients. Research and clinical trials indicate that this disease requires new treatment strategies. At present, there are no chemotherapy or radiotherapy treatments available for patients not eligible for upfront surgery which will shrink the tumour; thus, enabling subsequent surgical removal of the pancreatic cancer. Based on our preliminary observations from treating patients in Phase Ib clinical trial (STARPAC) as well as our laboratory research, this proposal is a proof-of-concept clinical trial to benefit those patients who cannot undergo initial surgery. We propose to combine state-of-the-art chemotherapy (gemcitabine and nab-Paclitaxel) to target cancer cells and investigate repurposing of All Trans Retinoic Acid (ATRA) to target the stroma.Stroma is the scar tissue surrounding the cancer cells. Pancreatic cancer is characterised by a particularly dense scar tissue (termed desmoplasia) which hampers successful delivery of chemotherapy drugs. A particular cell type, the Pancreatic stellate cells (or PSC), is critical for this desmoplastic stroma. In fact, we have shown experimentally that PSC enable cancer cells to survive longer and spread faster. Cancer cells activate PSC from their dormant state. These activated PSC, in turn, engineer a pro-cancer response by sending many different signals to cancer cells and immune cells. We have demonstrated that we can change this PSC behaviour back to the dormant or quiescent state. Quiescent PSC (normal pancreas) store retinol or vitamin A which is lost in activated state (pancreatic cancer). Pancreatic cancer patients are deficient in Vitamin A. Thus they cannot revert to the normal PSC behaviour without medications to alter their behaviour.Our laboratory experiments show that we can both target effectively and measure changes within, the stroma following targeting of PSC, using ATRA. Moreover we demonstrate that other cells (immune cells and blood vessels) also can also be targeted, to the detriment of tumour behaviour, using ATRA. ATRA's effect is potentiated to reduce tumour size in combination with state-of-the-art chemotherapy (gemcitabine and nab-Paclitaxel). If we can substantially reduce tumour size, we can enable surgical removal of the tumour in more patients with pancreatic cancer then what is possible currently.We already have demonstrated in the on-going Phase Ib clinical trial that it is safe to combine these agents without increasing toxicity when given to patients with pancreatic cancer. This grant proposal is the next step in efforts to translate the encouraging laboratory and clinical results to a routine clinical practice. Now we will estimate the efficacy of this drug combination to prolong survival and shrink tumours of pancreatic cancer patients. Beyond this proposal, our goal will then be to develop an effective treatment to be given to patients before surgery, to increase the chances of surgical removal of cancer of the pancreas. Thus, this translational proposal of laboratory experiments into a clinical trial exploits the 'co-targeting' of both cancer and stromal compartments and involves repurposing existing agents based on clinical observations and sound biological experiments.