Dynamics of multi-modal anti-angiogenic, anti-vascular, and cytotoxic therapies: Potential for significant clinical impact

物理学和数学在医学上的应用是跨学科研究中发展最快的领域之一。数学建模可以提供一个定量的框架来详细讨论复杂生物系统的所有组成部分之间的相互作用，以及测试各种治疗干预措施。以实验和临床数据为基础的新型计算技术和数学模型的结合，为生物医学研究提供了一个强大的新工具。确定影响肿瘤治疗反应的主要因素一直是临床肿瘤学感兴趣和相关的问题。虽然放射治疗和化疗等传统的细胞毒性治疗在癌症控制方面取得了重大进展，但在许多肿瘤部位仍有显著的改进空间。新的分子靶向治疗，如肿瘤血管生成的抑制剂(从预先存在的血管形成血管)，具有补充传统治疗的潜力。目前只有最少的临床前或临床证据可以作为决定如何最佳地结合抗血管生成和细胞毒治疗的基础。我们的工作假设是，基于现有的和新的肿瘤血管、间质和细胞间相互作用的生物物理模型，以及对这些相互作用对向癌细胞输送营养的影响的数学建模，可以指导现有细胞毒治疗的抗血管生成治疗的基本原理排序。该项目将围绕数学模型开发和改进的动态过程，使用来自动物组织学和成像研究的数据，以及来自子宫颈癌和其他肿瘤患者正在进行的临床研究的患者数据。

The application of physics and mathematics to medicine is one of the most rapidly growing areas of interdisciplinary research. Mathematical modeling can provide a quantitative framework to discuss, in detail, the interaction between all components of complex biological systems, as well as to test various therapeutic interventions. The combination of novel computational techniques and mathematical models, grounded in experimental and clinical data, thus provides a powerful new tool in biomedical research. The identification of major factors that influence treatment response in cancerous tumors has been a problem of long-standing interest and relevance to clinical oncology. While conventional cytotoxic treatments like radiotherapy and chemotherapy have contributed to major advancement in cancer control, there remains significant room for further improvement in many tumor sites. Novel molecularly-targeted treatments, like inhibitors of tumor angiogenesis (the formation of blood vessels from pre-existing vessels), have the potential to complement conventional treatments. There is currently minimal pre-clinical or clinical evidence on which to base decisions about how to optimally combine anti-angiogenic and cytotoxic therapies. Our working hypothesis is that mathematical modeling based on existing and novel biophysical models of the interactions between the vascular, interstitial and cellular compartments of a tumor, and the impact on these interactions on nutrient delivery to cancer cells, can guide the rationale sequencing of anti-angiogenic therapies with existing cytotoxic treatments. The project will revolve around a dynamic process of mathematical model development and refinement, using data derived from histologic and imaging studies in animals, and patient data from ongoing clinical studies in patients with cervix cancer and other tumors.