Understanding the mechanisms of treatment resistance in colorectal cancer using organoid models

在英国，结直肠癌每年影响超过45000人，只有大约50-60%的肠癌患者在确诊后存活5年。提高肠癌患者存活率的方法之一是在进行任何手术之前进行化疗和/或放疗以缩小癌症。这就是所谓的“新辅助疗法”，已经被大量用于癌症影响到肠道最后一部分（后通道）的患者。直到最近，一项名为FOXTROT的研究才发现，它可能对肠道其他部位（结肠）的癌症患者也有效。尽管取得了这些进展，但这种治疗方法只能使大约10-20%的患者的肿瘤大幅缩小。我们想要改善这一点，因为在出现大量萎缩的患者中他们比没有任何萎缩的患者做得好得多。我已经进行了一项关于后通道癌症的研究显示了两种可能的方法我们可以通过给予两种不同的，非常新的，药物治疗来增加收缩除了标准治疗。我们通过制造被称为类器官的“迷你化身”发现了这一点，类器官是在实验室里从病人的癌症样本中培养出来的癌症。在实验室中，这些细胞对治疗的反应与患者接受癌症治疗时的反应完全相同。我想通过培养更多结肠癌模型来扩展我所做的研究，然后用它们来模拟新辅助治疗，然后用基因测序来分析它们。这将使我们了解是什么使他们对治疗产生抗药性，然后确定新的治疗方法（由肿瘤学专家选择），可能使他们更敏感。然后我们可以用这些新药重新治疗耐药模型，看看它们是否有效。通过这项研究，我们希望进一步提高术前治疗对患者的益处，提高肠癌患者的存活率，并通过为患者选择正确的治疗方法来减少患者身上出现的一些毒性。

Colorectal (bowel) cancer affects more than 45,000 people in the UK each year, and only about 50-60% of people treated for bowel cancer survive 5 years after being diagnosed. One of the ways to improve the survival of patients with bowel cancer is by giving chemo and/or radiotherapy to shrink the cancer down before any surgery is carried out. This is known as "neoadjuvant therapy" and has been used a lot for patients with cancer affecting the last bit of the bowel (the back passage). It has only recently been found in a research study called FOXTROT that it may be effective in patients with cancer in other parts of the bowel (the colon) as well. Despite these advances, this type of treatment only leads to substantial shrinkage of the cancer in approximately 10-20% of patients. We would like to improve this, as in patients where a lot of shrinkage occurs they do much better than patients who do not get any shrinkage. I have carried out research in cancer of the back passage that shows two potential ways we could increase the shrinkage by giving two different, very new, drug therapies in addition to the standard treatment. We have found this by making "mini-avatars" called organoids, which are cancers grown in the laboratory from a specimen of the patient's cancer. These undergo exactly the same response to treatment in the laboratory as the patient would experience when their cancer is treated. I would like to expand the research I have done by growing more models of colon cancer, and then using them to simulate neoadjuvant treatment and then analyse them using genetic sequencing. This will allow us to understand what makes them resistant to treatment, and then identify new treatments (chosen by expert oncologists) that may make them more sensitive. We can then re-treat the resistant models with these new drugs to see if they work.Through this, we hope to further increase the benefit of treatment given before surgery to patients, increasing survival from bowel cancer and reducing some of the toxicity seen in patients by picking the correct treatment for them.