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）是一种致命的疾病。目前，手术切除受影响的胰腺是治愈的最佳机会。然而，只有不到五分之一的患者可以做到这一点。研究和临床试验表明，这种疾病需要新的治疗策略。事实上，目前还没有可用的化疗或放疗方法来缩小肿瘤，以便对不适合预先手术的患者进行胰腺癌手术切除。根据我们对治疗患者的观察以及实验室研究，该提案是一项概念验证临床试验，旨在使那些无法预先接受手术的患者受益。我们建议结合最先进的化疗（吉西他滨和白蛋白结合紫杉醇）来靶向癌细胞，并重新利用全反式视黄酸（ATRA）来靶向基质。基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，从而阻碍化疗药物的成功输送。特定的细胞类型：胰腺星状细胞（或 PSC）对于促纤维增生基质至关重要。事实上，我们的研究表明 PSC 使癌细胞能够存活更长时间并扩散得更快。癌细胞将 PSC 从休眠状态激活。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促癌策略。我们已经证明，我们可以将这种 PSC 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，但在激活状态（胰腺癌）中会丢失。胰腺癌患者缺乏维生素 A。因此，如果不使用药物来改变其行为，他们就无法恢复正常的 PSC 行为。我们的实验室实验表明，使用 ATRA，我们可以有效地靶向 PSC 后的间质并测量其内部的变化。此外，我们已经证明，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。与最先进的化疗（吉西他滨和白蛋白结合型紫杉醇）联合使用，ATRA 的效果可增强，可缩小肿瘤大小。如果我们能够大幅减小肿瘤的大小，我们就可以对更多的胰腺癌患者进行手术切除肿瘤，而目前的情况是可能的。这项拨款提案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。在本提案中，我们希望确定是否可以将这些药物联合使用，而不会增加胰腺癌患者的毒性。我们将逐步增加药物剂量，以证明这种组合可以在没有额外副作用的情况下给药。如果我们能够证明这是可行的，那么我们还需要确定这种药物是否达到了血流以及胰腺癌中所需的水平，以达到预期的效果。最后我们需要能够衡量这种影响。因此，在这个早期临床试验中，我们将研究是否可以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，在当前提案之外，我们将针对无法预先接受手术的胰腺癌患者，将这种联合治疗与其他最先进或既定的治疗方法进行比较。我们的目标是在手术前为患者开发一种有效的治疗方法，以增加手术切除胰腺癌的机会。因此，将实验室实验转化为临床试验的建议利用了癌症和基质区室的“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.