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

在英国，每年有超过45000人罹患结直肠癌，而接受治疗的结肠癌患者中，只有大约50%-60%的人在确诊后能存活5年。提高肠癌患者存活率的方法之一是在手术前进行化疗和/或放射治疗，以缩小癌症范围。这种疗法被称为“新辅助疗法”，已被广泛应用于癌症患者的肠道末梢(后肠道)。直到最近，在一项名为狐步舞的研究中才发现，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，但这种类型的治疗仅在大约10%-20%的患者中导致癌症显著缩小。我们希望改善这一点，因为在发生大量收缩的患者中，他们的表现比没有任何收缩的患者要好得多。我对后路癌症进行了研究，显示了两种可能的方法，我们可以通过在标准治疗之外给予两种不同的、非常新的药物疗法来增加萎缩。我们通过制造被称为有机化身的“迷你化身”发现了这一点，有机化身是在实验室里从患者的癌症标本中培育出来的癌症。这些患者在实验室接受治疗时的反应与患者接受癌症治疗时的反应完全相同。我想通过种植更多的结肠癌模型来扩展我所做的研究，然后使用它们来模拟新辅助治疗，然后使用基因测序对它们进行分析。这将使我们能够了解是什么使他们对治疗产生抵抗力，然后确定可能使他们更敏感的新治疗方法(由专家肿瘤学家选择)。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。通过这一点，我们希望进一步增加患者在手术前接受治疗的好处，增加肠癌的存活率，并通过为患者选择正确的治疗方法来减少患者的一些毒性。

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.