MICA: Early phase clinical trial repurposing ATRA as stromal targeting agent in a novel drug combination for pancreatic cancer (STAR-PAC)

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，这在不到五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。事实上，目前并没有任何化疗或放射治疗方法可以缩小肿瘤，使不符合手术资格的病人可以接受手术切除胰腺癌。基于我们治疗患者的观察和我们的实验室研究，这项建议是一项概念验证临床试验，旨在使那些不能提前接受手术的患者受益。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，并重新利用所有反式维甲酸(ATRA)来靶向间质。间质是癌细胞周围的疤痕组织。胰腺癌的特点是疤痕组织特别致密，从而阻碍了化疗药物的成功输送。一种特殊的细胞类型：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，我们的研究表明，PSC使癌细胞存活得更长，扩散得更快。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一种亲癌策略。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，我们已经证明，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。如果我们能够大幅缩小肿瘤的大小，我们可以使更多的胰腺癌患者能够接受手术切除肿瘤，这项拨款建议是将这些令人鼓舞的实验室结果转化为常规临床实践的第一步。在这项提案中，我们希望确定是否可以在不增加胰腺癌患者毒性的情况下将这些药物联合使用。我们将循序渐进地增加药物剂量，以证明这种组合可以在没有额外副作用的情况下使用。如果我们能证明这是可行的，那么我们还需要确定这种药物在血流和胰腺癌中是否达到了预期的效果。最后，我们需要能够衡量这种影响。因此，在这一早期临床试验中，我们将研究如何在不增加副作用的情况下以适当的剂量提供治疗，并监测治疗的有益和有害影响。未来，除了目前的建议外，我们将对不能预先接受手术的胰腺癌患者进行这种联合治疗与其他最先进或已有的治疗方法的比较。我们的目标将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，将实验室实验的建议转化为临床试验的提议利用了癌症和间质隔室的“共同靶向”。

Pancreatic cancer (PDAC: pancreatic ductal adenocarcinoma) is a lethal disease. At present, surgical removal of the affected pancreas offers the best chance for cure. However, this is possible in less than a fifth of patients. Research and clinical trials have suggested that this disease required new treatment strategies. At present, in fact, there are no chemotherapy or radiotherapy treatments available which will shrink the tumour to enable surgical removal of pancreatic cancer in the patients not eligible for surgery upfront. Based on our observations from treating patients as well as our laboratory research, this proposal is a proof-of-concept clinical trial to benefit those patients who cannot undergo surgery up front. We propsoe to combine state-of-the-art chemotherapy (gemcitabine and nab-Paclitaxel) to target cancer cells and repurposing All Trans Retinoic Acid (ATRA) to target the stroma.Stroma is the scar tissue surrounding the cancer cells. Pancreatic cancer is charactereised by a particularly dense scar tissue such that it hampers successful delivery of chemotherapy drugs. A particular cell type: Pancreatic stellate cells ( or PSC) are critical for this desmoplastic stroma. In fact, our research has shown 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 strategy by sending many different signals to cancer cells and immune cells. We have demonstrated that we can change this PSC behaviour back to 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 have shown 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 tumour in more patients with pancreatic cancer then what is possibly currently.This grant proposal is the first step to translate these encouraging laboratory results to a routine clinical practice. In this proposal we want to determine whether we can combine these drugs without increasing toxicity when given to patients with pancreatic cancer. We will increase the dose of drugs in a step wise manner to demonstrate that this combination can be administered without additional side-effects. If we can demonstrate this is feasible, then we also need to determine if this drug is reaching the required levels in blood stream as well as in pancreatic cancer to have the desired effect. Finally we need to be able to measure this effect. Hence in this early phase clinical trial, we will investigate that we can deliver treatment at appropriate dose without increasing side-effects as well as monitor the beneficial and harmful effects of the treatment. In future, that is outside this current proposal, we will carry out comparison of this combination treatment with other state-of-the-art or established treatments for patients with pancreatic cancer who cannot undergo surgery upfront. Our goal will then be to develop an effective treatment given to patients before surgery, to increase the chances of surgical removal of cancer of the pancreas. Thus, translation proposal of of laboratory experiments into a clinical trial exploits the 'co-targeting' of both cancer and stromal compartments.