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，外科手术去除受影响的胰腺提供了最好的治愈机会。但是，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。目前，实际上，没有化学疗法或放射治疗可用，可以收缩肿瘤，以便在不符合预期手术的患者中可以手术去除胰腺癌。根据我们对患者和实验室研究的观察结果，该提案是一项概念验证临床试验，可使那些无法接受手术的患者受益。我们将最先进的化学疗法（吉西他滨和NAB-甲氟列赛）结合起来靶向癌细胞，并重新利用所有反式视网膜酸（ATRA）以靶向基质。质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，使得它阻碍了化疗药物的成功递送。特定的细胞类型：胰腺星状细胞（或PSC）对于这种去塑性基质至关重要。实际上，我们的研究表明，PSC使癌细胞的生存更长并扩散得更快。癌细胞从休眠状态激活PSC。这些激活的PSC反过来又通过向癌细胞和免疫细胞发送了许多不同的信号来设计一种亲癌的策略。我们已经证明，我们可以将此PSC行为更改为休眠状态或静止状态。静止的PSC（正常胰腺）储存视黄醇或维生素A，其在活化状态（胰腺癌）中丢失。胰腺癌患者的维生素A缺乏。因此，如果没有药物改变其行为，他们就无法恢复正常的PSC行为。我们的实验室实验表明，我们可以有效地靶向靶向和测量靶向PSC后的基质，使用ATRA，使用ATRA。此外，我们已经证明，使用ATRA，其他细胞（免疫细胞和血管）也可以损害肿瘤行为。 ATRA的作用增强以减少肿瘤大小与最先进的化学疗法（吉西他滨和Nab-Paclitaxel）结合使用。如果我们可以实质上减少肿瘤的大小，我们可以在更多的胰腺癌患者中进行手术切除肿瘤，那么目前可能是什么。这项赠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。在此提案中，我们要确定在患有胰腺癌患者时是否可以将这些药物结合起来而无需增加毒性。我们将以明智的方式增加药物的剂量，以证明可以在没有额外副作用的情况下进行这种组合。如果我们可以证明这是可行的，那么我们还需要确定该药物是否达到血液中所需的水平以及胰腺癌的所需水平，以具有所需的作用。最后，我们需要能够衡量这种效果。因此，在这项早期临床试验中，我们将调查我们可以在不增加副作用的情况下以适当的剂量进行治疗，并监测治疗的有益和有害影响。将来，这是当前提案之外的，我们将对无法预先进行手术的胰腺癌患者进行这种联合治疗的比较。然后，我们的目标是在手术前开发对患者的有效治疗方法，以增加胰腺癌手术的机会。因此，将实验室实验的翻译建议转化为临床试验，利用了癌症和基质室的“共同靶向”。

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