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

MICA：将 ATRA 重新用作胰腺癌新型药物组合 (STAR-PAC) 中的基质靶向剂的早期临床试验

• 批准号: MR/M015610/1
• 负责人: Hemant Kocher
• 金额: $ 74.41万
• 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: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM015610%2F1
• 关键词: MICA; Early; phase; clinical; trial

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.

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，目前还没有化疗或放疗可以缩小肿瘤，使不符合手术条件的患者能够手术切除胰腺癌。根据我们对治疗患者的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，旨在使那些无法提前接受手术的患者受益。我们建议结合联合收割机最先进的化疗（吉西他滨和nab-紫杉醇）靶向癌细胞和再利用全反式维甲酸（ATRA）靶向间质。胰腺癌的特征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，扩散更快。癌细胞从休眠状态激活PSC。反过来，这些激活的PSC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，我们可以改变这种PSC行为回到休眠或静止状态。静止期PSC（正常胰腺）储存视黄醇或维生素A，在激活状态（胰腺癌）中丢失。胰腺癌患者缺乏维生素A。因此，他们不能恢复到正常的PSC的行为，没有药物来改变他们的behavior. We的实验室实验表明，我们可以有效地目标和测量内的变化，间质后靶向PSC，使用ATRA。此外，我们已经表明，其他细胞（免疫细胞和血管）也可以使用ATRA靶向，从而损害肿瘤行为。ATRA的作用是加强，以减少肿瘤的大小与国家的最先进的化疗（吉西他滨和nab-Paclitazone）相结合。如果我们能够大幅缩小肿瘤的大小，我们就可以在更多的胰腺癌患者中手术切除肿瘤，而不是目前可能的情况。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。在这个建议中，我们想确定我们是否可以联合收割机这些药物，而不增加毒性时，给予胰腺癌患者。我们将逐步增加药物的剂量，以证明这种组合可以在没有额外副作用的情况下给药。如果我们能证明这是可行的，那么我们还需要确定这种药物是否在血流中达到所需的水平，以及在胰腺癌中达到所需的效果。最后，我们需要能够衡量这种影响。因此，在这项早期临床试验中，我们将研究我们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。在未来，也就是在目前的提议之外，我们将对这种联合治疗与其他最先进的或已建立的治疗方法进行比较，这些治疗方法适用于无法提前接受手术的胰腺癌患者。我们的目标将是开发一种有效的治疗方法，在手术前给予患者，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两者的“共靶向”。

项目成果

Phase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer.

• DOI: 10.1038/s41467-020-18636-w
• 发表时间: 2020-09-24
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Kocher HM;Basu B;Froeling FEM;Sarker D;Slater S;Carlin D;deSouza NM;De Paepe KN;Goulart MR;Hughes C;Imrali A;Roberts R;Pawula M;Houghton R;Lawrence C;Yogeswaran Y;Mousa K;Coetzee C;Sasieni P;Prendergast A;Propper DJ
• 通讯作者: Propper DJ

Additional file 2: of A new pragmatic design for dose escalation in phase 1 clinical trials using an adaptive continual reassessment method

附加文件 2：使用适应性持续重新评估方法在 1 期临床试验中进行剂量递增的新实用设计

• DOI: 10.6084/m9.figshare.8330966
• 发表时间: 2019
• 作者: North B