A Novel Strategy for Defining and Targeting Cancer Addiction to Anti-Apoptotic BC

描述(由申请人提供)：由于癌细胞的大量表型异常，有人假设癌细胞需要阻断凋亡才能存活。癌细胞可能利用的维持生存的一个潜在机制是表达bcl2家族的抗凋亡蛋白。我们已经开发了一种新的方法，称为BH3图谱，它可以检测对抗凋亡蛋白的依赖。它特别有用，因为它可以用来研究新分离的原发癌症组织，而不需要进一步的体外培养。我们将使用这项技术和其他更标准的技术来研究几个系统中的细胞凋亡调控。首先，我们将研究慢性淋巴细胞白血病(CLL)细胞是否依赖bcl2生存。我们还将检查CLL细胞是否对新的bcl2拮抗剂ABT-737治疗敏感。我们将进一步确定支撑这种敏感性的分子事件。接下来，我们将研究对bcl2拮抗剂的获得性耐药性。我们已经确定了一组对ABT-737治疗敏感的造血癌细胞株。由于获得性耐药是一种重要的临床现象，我们将研究细胞对ABT-737产生耐药的分子机制。确定这些机制将是设计克服耐药性的治疗方法的关键。我们提出了一系列基于机制的联合疗法，以测试它们在细胞系和CLL细胞中克服耐药性和促进对ABT-737的反应的能力。最后，我们到目前为止的研究表明，与非恶性的正常细胞相比，癌细胞更有可能依赖于抗凋亡蛋白。我们将通过使用BH3图谱系统地评估正常血细胞的抗凋亡需求来检验这一假说。我们的目标是提供对可能具有重要临床意义的二分法的分子理解，因为它暗示了正常细胞和癌细胞之间有趣的治疗窗口。这些研究旨在确定癌细胞维持自身生存的具体方式，这些方式可能只被癌细胞使用，而不是正常、健康的细胞。了解这一点将使我们能够识别能够杀死癌细胞而不是正常细胞的靶点。这样的策略有望改善癌症的治疗，使治疗对癌细胞更具选择性，从而降低对正常、健康组织的毒性。

DESCRIPTION (provided by applicant): It has been hypothesized that cancer cells require a block in apoptosis for survival, due to their numerous phenotype irregularities. One potential mechanism cancer cells might exploit to maintain survival is the expression of antiapoptotic proteins of the BCL-2 family. We have developed a novel method, called BH3 profiling, that detects dependence on antiapoptotic proteins. It is particularly useful as it can be used to study freshly isolated primary cancer tissues without need for further culture ex vivo. We will use this and other more standard techniques to study regulation of apoptosis in several systems. First, we will investigate whether chronic lymphocytic leukemia (CLL) cells are dependent on BCL-2 for survival. We will also examine whether CLL cells are sensitive to treatment with a novel BCL-2 antagonist, ABT-737. We will furthermore determine the molecular events underpinning this sensitivity. Next, we will investigate acquired resistance to BCL-2 antagonism. We have identified a panel of hematopoietic cancer cell lines that are sensitive to ABT-737 treatment. Since acquired resistance to therapy is an important clinical phenomenon, we will study the molecular mechanisms by which cells might become resistant to ABT-737. Identification of these mechanisms will be critical to designing therapies to overcome resistance. We propose a series of mechanism-based combination therapies to be tested for their ability to overcome resistance and facilitate response to ABT-737 in cell lines and CLL cells. Finally, our studies to date suggest that cancer cells are far more likely to be dependent on anti-apoptotic proteins than non-malignant, normal cells. We will test this hypothesis by systematically evaluating the anti-apoptotic requirements of normal blood cells using BH3 profiling. Our goal is to provide a molecular understanding of what may be a dichotomy of vital clinical significance, as it suggests an intriguing therapeutic window between normal and cancer cells. These studies are directed at determining the specific ways cancer cells keep themselves alive, ways that may be used only by cancer cells, but not by normal, healthy cells. Understanding this would allow us to identify targets that would kill cancer cells, but not normal cells. Such a strategy has the promise to improve treatment of cancer by making treatment more selective for cancer cells, and therefore less toxic to normal, healthy tissues.