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)是一种致命性疾病。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，没有任何化疗或放射治疗方法可供不符合条件的患者进行前期手术，以缩小肿瘤，从而使随后的手术切除胰腺癌成为可能。基于我们在治疗患者在Ib期临床试验(STARPAC)中的初步观察以及我们的实验室研究，这项建议是一项概念验证临床试验，旨在使那些无法接受初始手术的患者受益。我们建议结合最先进的化疗(吉西他滨和NAB-紫杉醇)来靶向癌细胞，并研究所有反式维甲酸(ATRA)的重新用途以靶向间质。间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输送。一种特殊的细胞类型，即胰腺星状细胞(或PSC)，对这种促结缔组织间质至关重要。事实上，我们已经在实验中证明，PSC能够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。这些激活的PSC反过来通过向癌细胞和免疫细胞发送许多不同的信号来设计亲癌反应。我们已经证明，我们可以将这种PSC行为改回休眠或静止状态。静止的PSC(正常胰腺)储存视黄醇或维生素A，在激活状态下丢失(胰腺癌)。胰腺癌患者缺乏维生素A，因此如果没有药物改变他们的行为，他们无法恢复正常的PSC行为。我们的实验室实验表明，我们可以有效地靶向并测量靶向PSC后间质内的变化，使用ATRA。此外，我们还证明，使用全反式维甲酸也可以靶向其他细胞(免疫细胞和血管)，从而损害肿瘤的行为。ATRA的作用与最先进的化疗(吉西他滨和NAB-紫杉醇)相结合，可以增强缩小肿瘤大小的作用。如果我们可以大幅缩小肿瘤的大小，我们可以在更多的胰腺癌患者中进行手术切除肿瘤，而不是目前可能的情况。我们已经在正在进行的Ib期临床试验中证明，联合使用这些药物是安全的，并且不会增加胰腺癌患者的毒性。这项赠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和缩小肿瘤方面的疗效。除了这项建议外，我们的目标是开发一种有效的治疗方法，在手术前为患者提供治疗，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隔室的“共同靶向”，并涉及基于临床观察和合理的生物学实验重新使用现有药物。

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.