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

MICA：IIb 期随机临床试验，将 ATRA 重新用作胰腺癌新型药物组合 (STAR-PAC2) 中的基质靶向剂。

• 批准号: MR/S036601/1
• 负责人: Hemant Kocher
• 金额: $ 196.17万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS036601%2F1
• 关键词: MICA; Phase; IIb; randomised; clinical

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.

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，只有不到十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。目前，对于不适合进行前期手术缩小肿瘤的患者，尚无可用的化疗或放疗治疗方法；因此，可以进行随后的胰腺癌手术切除。根据我们对 Ib 期临床试验 (STARPAC) 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，旨在使那些无法接受初次手术的患者受益。我们建议结合最先进的化疗（吉西他滨和白蛋白结合型紫杉醇）来靶向癌细胞，并研究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），对于这种促纤维增生基质至关重要。事实上，我们已经通过实验证明 PSC 可以使癌细胞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反应。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 后的间质并测量间质内的变化。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。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，那么我们就可以通过手术切除更多的胰腺癌患者的肿瘤，而目前是不可能的。我们已经在正在进行的 Ib 期临床试验中证明，将这些药物联合起来是安全的，不会增加胰腺癌患者的毒性。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对延长胰腺癌患者的生存期和缩小肿瘤的功效。除了这项提议之外，我们的目标是开发一种在手术前给予患者的有效治疗方法，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建议利用了癌症和基质区室的“共同靶向”，并涉及根据临床观察和合理的生物实验重新利用现有药物。