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（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疗机会。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条件的前期手术，以缩小肿瘤；因此，使后续手术切除胰腺癌成为可能。根据我们对Ib期临床试验（STARPAC）患者的初步观察以及我们的实验室研究，该建议是一项概念验证临床试验，可使那些无法接受初始手术的患者受益。我们建议联合最先进的化疗（吉西他滨和nab-紫杉醇）靶向癌细胞，并研究全反式维甲酸（ATRA）靶向基质的重新利用。基质是癌细胞周围的疤痕组织。胰腺癌的特征是特别致密的疤痕组织（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），对这种结缔组织增生基质至关重要。事实上，我们已经通过实验证明，PSC使癌细胞存活时间更长，扩散速度更快。癌细胞从休眠状态激活PSC。这些被激活的PSC依次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，我们可以将PSC的行为改变回休眠或静止状态。静止的PSC（正常胰腺）储存视黄醇或维生素A，在激活状态下（胰腺癌）会丢失。胰腺癌患者缺乏维生素a，因此，如果没有药物来改变他们的行为，他们就不能恢复正常的PSC行为。我们的实验室实验表明，我们可以使用ATRA有效地靶向并测量PSC靶向后基质内的变化。此外，我们证明其他细胞（免疫细胞和血管）也可以被靶向，使用ATRA损害肿瘤行为。与最先进的化疗（吉西他滨和nab-紫杉醇）联合使用时，ATRA的效果被增强，可以减小肿瘤大小。如果我们能大大缩小肿瘤的大小，我们就能让更多的胰腺癌患者接受手术切除肿瘤。我们已经在正在进行的Ib期临床试验中证明，当给予胰腺癌患者时，联合使用这些药物是安全的，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功效。除了这个建议，我们的目标是开发一种在手术前给病人的有效治疗方法，以增加手术切除胰腺癌的机会。因此，这项将实验室实验转化为临床试验的建议利用了癌症和间质室的“共同靶向”，并涉及根据临床观察和可靠的生物学实验重新利用现有药物。

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.