Identifying new approaches to the treatment of endocrine resistant breast cancer

确定治疗内分泌耐药性乳腺癌的新方法

• 批准号: MR/P018521/1
• 负责人: Kirsty Balachandran
• 金额: $ 43.62万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP018521%2F1
• 关键词: Identifying; new; approaches; treatment; endocrine

Breast cancer is the most common cancer that affects women. Up to 80% of patients with breast cancer have tumour cells that contain a protein, known as the estrogen receptor alpha (ER). ER mediates the effects of the hormone, estrogen and is instrumental to the growth and proliferation of breast cancer cells. When cancer affects the breast alone, it is often readily treatable. Unfortunately, when breast cancer cells spread (metastasise) to other parts of the body, the disease becomes incurable. It is believed that higher levels of ER in certain breast cancers may contribute to the risk of spread and the cancer consequently becoming incurable.Currently, most tumours that contain ER are treated with hormone treatments that reduce the levels of estrogen in the body and thereby block the actions of ER. This is often initially successful at controlling the cancer but in the case of cancer that has spread, eventually the drug stops being effective; resistance develops. At present, there are very few other treatment options available for patients when this happens - usually a different type of hormone treatment is used. This may also be effective initially but with each new anti-hormone drug used, the duration of efficacy becomes shorter and shorter. Many mechanisms for the development of resistance to these hormone treatments have been proposed. In the last 18 months, important new studies have discovered that in about 40% of patients who have breast cancer that has spread and become resistant to hormone treatment, mutations in the ER gene are present and it is believed that these mutations overcome the need of ER to be activated by estrogen and thus these cancers grow despite the estrogen reducing therapies. There is an urgent need to determine the mechanisms of action of these mutant ER proteins in the laboratory, so as to identify treatment options for patients with ER mutations. To do this, the laboratory has created metastatic breast cancer cells that have been genetically modified to gain the ER mutations. These cells recapitulate resistance to hormone treatments and so represent a very useful means of determining how the mutant proteins work and for rapid evaluation of new treatments to overcome hormone treatment resistance. In the presence of estrogen, ER can also bind with specific proteins (transcription factors) that regulate the expression of other genes. Some of these other genes regulate proteins that are responsible for the detection of hormones, bile acids and other substances (nuclear receptors) whilst others are essential to many cellular functions including metabolism and signalling (kinases). We have found that levels of some of these proteins are increased in the breast cancer cells with ER mutations. We propose that drugs that target one or more of these proteins could provide the means to treat breast cancer with ER mutations.We aim to carry out studies with the cell lines making the mutant ER proteins, to determine if any of the over-represented proteins are important for growth of these cancer cells and to test if blocking their action with specific drugs can be used to kill cells with ER mutations. Drugs that target many of these up-regulated proteins are already available and used in other clinical settings so may easily be repurposed if found to be effective. If our findings suggest that these drugs are efficacious in breast cancer cells, we would develop a clinical trial in the future to confirm these findings in patients with breast cancer. The work will be conducted by Dr Kirsty Balachandran, a specialist registrar in medical oncology who is dedicated to improving the care patients with breast cancer receive by investigating potential new treatment strategies in the laboratory and developing these to expand therapies available in clinical practice.

乳腺癌是影响女性的最常见癌症。多达80%的乳腺癌患者的肿瘤细胞含有一种被称为雌激素受体α(ER)的蛋白质。ER介导激素和雌激素的作用，并有助于乳腺癌细胞的生长和增殖。当癌症只影响到乳房时，它通常是很容易治愈的。不幸的是，当乳腺癌细胞扩散(转移)到身体的其他部位时，这种疾病就变得无法治愈。据认为，在某些乳腺癌中，较高水平的ER可能会增加扩散的风险，从而导致癌症变得无法治愈。目前，大多数含有ER的肿瘤都是通过激素治疗来降低体内的雌激素水平，从而阻止ER的作用。这通常在最初控制癌症方面是成功的，但在癌症已经扩散的情况下，最终药物不再有效；产生抗药性。目前，当这种情况发生时，患者几乎没有其他治疗选择-通常使用不同类型的激素治疗。这在最初可能也是有效的，但随着每使用一种新的抗激素药物，有效时间变得越来越短。对这些激素治疗产生抗药性的机制有很多种。在过去的18个月里，重要的新研究发现，在大约40%已经扩散并对激素治疗产生抗药性的乳腺癌患者中，存在ER基因突变，人们认为这些突变克服了雌激素激活ER的需要，因此尽管进行了雌激素减少治疗，这些癌症仍在生长。迫切需要在实验室中确定这些突变的ER蛋白的作用机制，以便确定ER突变患者的治疗方案。为了做到这一点，实验室创造了转移性乳腺癌细胞，这些细胞已经经过基因改造，获得了ER突变。这些细胞概括了对激素治疗的耐药性，因此是确定突变蛋白如何工作和快速评估克服激素治疗耐药性的新治疗方法的非常有用的手段。在雌激素存在的情况下，ER还可以与调节其他基因表达的特定蛋白质(转录因子)结合。这些其他基因中的一些调节负责检测激素、胆汁酸和其他物质(核受体)的蛋白质，而另一些基因则对许多细胞功能至关重要，包括新陈代谢和信号传递(激酶)。我们发现，在ER突变的乳腺癌细胞中，其中一些蛋白质的水平会增加。我们建议针对这些蛋白质中的一种或多种的药物可以提供治疗带有ER突变的乳腺癌的手段。我们的目标是对产生突变的ER蛋白的细胞系进行研究，确定是否有任何过度表达的蛋白质对这些癌细胞的生长是重要的，并测试是否可以用特定的药物阻断它们的作用来杀死具有ER突变的细胞。针对这些上调蛋白中的许多的药物已经可以获得，并在其他临床环境中使用，因此如果发现有效，可能很容易改变用途。如果我们的发现表明这些药物对乳腺癌细胞有效，我们将在未来开发一项临床试验，以证实这些发现在乳腺癌患者中的应用。这项工作将由科斯蒂·巴拉钱德兰博士进行，他是一名医学肿瘤学专业注册员，致力于通过在实验室研究潜在的新治疗策略并开发这些策略来扩大临床实践中可用的疗法，以改善乳腺癌患者得到的护理。

项目成果

The Impact of Age on Assessment and Treatment of Breast Cancer in Older People: You Are Only as Old as Your Oncologist Thinks You Are .

年龄对老年人乳腺癌评估和治疗的影响：您的年龄取决于肿瘤科医生认为您的年龄。

• DOI: 10.1016/j.clon.2022.02.017
• 发表时间: 2022
• 期刊: Clinical oncology (Royal College of Radiologists (Great Britain))
• 作者: Balachandran K

Genome engineering for estrogen receptor mutations reveals differential responses to anti-estrogens and new prognostic gene signatures for breast cancer.

• DOI: 10.1038/s41388-022-02483-8
• 发表时间: 2022-10
• 期刊: Oncogene
• 影响因子: 8
• 作者: Harrod A;Lai CF;Goldsbrough I;Simmons GM;Oppermans N;Santos DB;Győrffy B;Allsopp RC;Toghill BJ;Balachandran K;Lawson M;Morrow CJ;Surakala M;Carnevalli LS;Zhang P;Guttery DS;Shaw JA;Coombes RC;Buluwela L;Ali S
• 通讯作者: Ali S