Exploiting The Heterogeneous Composition Of Tumor Tissue And The Altered Metabolism Of Tumor Cells For Cancer Therapy Design

题目：利用肿瘤组织的异质性组成和肿瘤细胞代谢的改变来设计癌症治疗方案成人多细胞生物（如人类）的细胞数量受到非常严格的控制，在正常情况下；在新细胞产生和细胞死亡之间存在某种平衡。粗略地说，当细胞数量控制系统出现一些故障，导致细胞分裂过度或细胞死亡减少时，癌症就会发生。使癌症治疗如此困难的是，这种故障可能以许多不同的方式发生在许多不同的位置，因此需要不同的量身定制的治疗。此外，癌症组织通常是异质的，因为它是不同功能障碍细胞的混合物。因此，针对一种功能失调的细胞进行治疗可能导致其他类型的功能失调细胞占主导地位，表现为在癌症治疗中通常观察到的获得性耐药现象。因此，为了获得更好的治疗效果，需要确定优势细胞亚群，以便针对其进行治疗。该项目的第一个目标是通过实验证明这种方法的可行性，这种方法使用的是不同种类的癌细胞系。该项目的第二个目标是利用癌细胞的代谢改变来设计针对癌细胞的不同疗法。更具体地说，该项目旨在通过癌细胞系实验验证将抗糖尿病（代谢靶向）药物二甲双胍作为癌症联合鸡尾酒疗法的一部分的益处。由于这两个目标都是为了改善癌症治疗，这个项目的潜在社会效益可能是巨大的。此外，该项目将在德克萨斯农工大学新成立的生物信息学和基因组系统工程中心（CBGSE）进行，在那里广泛传播研究成果，向研究生传授真正跨学科的实践教育，并有利于少数民族和少数民族机构，这是重中之重。癌症是与细胞周期控制丧失相关的大量疾病的总称，这些疾病导致细胞增殖失控和/或细胞凋亡减少（程序性细胞死亡）。这种细胞周期控制的丧失通常是由于细胞信号通路的不同功能障碍造成的。由于癌症组织通常是异质的，因此首先确定优势亚群，然后相应地定制靶向治疗是合适的，有望获得更好的治疗效果。该项目的第一个目标是利用分层贝叶斯方法开发的这种方法，并使用含有已知突变的混合癌细胞系进行实验验证。为了介绍第二个目标，我们注意到，传统的癌症治疗方法是通过使用治疗药物、放射等诱导癌细胞死亡。大多数这些治疗对正常细胞是有毒的，并且有明显的副作用。另一方面，癌细胞会对葡萄糖上瘾，而正常的成年细胞则不会。这就提出了一个自然的问题，即是否可以通过靶向葡萄糖的供应来实现对癌细胞的优先杀伤。事实上，流行病学研究表明，常用的抗糖尿病药物二甲双胍在预防或减缓乳腺癌和某些其他癌症的发病方面具有有益作用。受此启发，该项目的第二个目标是实验研究二甲双胍作为联合治疗设计的一部分在癌症治疗中的作用。由于大多数化疗药物都有毒副作用，而二甲双胍没有，因此将后者作为癌症联合治疗的一部分，肯定有可能提高癌症患者的生活质量。

Title: Exploiting the heterogeneous composition of tumor tissue and the altered metabolism of tumor cells for cancer therapy designThe number of cells in an adult multicellular organism such as a human being is under very tight control and, under normal circumstances; there is some kind of a balance between new cell production and cell death. Roughly speaking, cancer results when there is excessive cell division or reduced cell death due to some malfunctioning in the cell number control system. What makes cancer therapy so difficult is that this malfunctioning can happen in many different ways and at many different locations and would, therefore, require different tailored treatments. Furthermore, cancer tissue is usually heterogeneous in the sense that it is a mixture of cells with different malfunctions. As a result, directing treatment at one type of malfunctioning cells may lead to the dominant emergence of other types of malfunctioning cells, manifesting itself in the phenomenon of acquired drug resistance usually observed in cancer therapy. Thus, to achieve better therapeutic outcome, the dominant cell subpopulation needs to be identified so that the therapy can be targeted towards it. The first goal of this project is to experimentally demonstrate the feasibility of such an approach using a heterogeneous mixture of cancer cell lines. The second goal of this project is to exploit metabolic alteration in cancer cells to design therapies that differentially target cancer cells. More specifically, the project seeks to experimentally validate via cancer cell lines the benefits of including the anti-diabetic (metabolism targeting) drug Metformin as part of a combination cocktail therapy for cancer. Since both the goals are directed towards improving cancer treatment, the potential societal benefits of this project could be enormous. In addition, the project will be carried out at the newly formed Center for Bioinformatics and Genomic Systems Engineering (CBGSE) at Texas A & M University, where widespread dissemination of the research results, imparting truly interdisciplinary hands-on education to graduate students, and beneficially targeting minorities and minority institutions, are top priorities.Cancer is an umbrella term for a large number of diseases that are associated with loss of cell-cycle control, leading to uncontrolled cell proliferation and/or reduced apoptosis (programmed cell death). This loss of cell-cycle control usually results from different malfunction(s) in the cellular signaling pathways. Since cancer tissue is usually heterogeneous, it is appropriate to first identify the dominant subpopulation and then accordingly tailor the targeted treatment, hopefully achieving a better therapeutic outcome. The first goal of this project is to utilize such an approach, developed using hierarchical Bayesian methods, and experimentally validate it using a mixture of cancer cell lines, harboring known mutations. To introduce the second goal, we note that the traditional approach to cancer therapy is to induce cancer cell death by using therapeutic drugs, radiation, etc. Most of these treatments are toxic to normal cells and carry significant side effects. On the other hand, cancer cells are known to be addicted to glucose while normal adult cells are not. This brings up the natural question as to whether the preferential killing of cancer cells could be achieved by targeting the supply of glucose. Indeed, epidemiological studies have shown that the commonly used anti-diabetic drug Metformin has beneficial effects in preventing or slowing the onset of breast and certain other cancers. Motivated by this, the second goal of this project is to experimentally study the role of Metformin in cancer therapy when used as part of a combination therapy design. Since most chemotherapeutic drugs have toxic side effects while Metformin does not, including the latter as part of a combination therapy for cancer certainly has the potential to enhance the quality of life for cancer patients.