UNFOLDED PROTEIN RESPONSE IN DRUG SENSITIVITY AND RESISTANCE

由于血液供应不足，肿瘤细胞存在于破坏的微环境中，侵袭 正常的蛋白质折叠，并能激活未折叠的蛋白质反应(DPR)。除了对以下方面做出贡献 肿瘤的生长和存活，来自细胞培养研究的数据表明，药物激活 UPR还可以改变细胞对化疗药物的敏感性，使它们在某些情况下更加敏感 病例和其他情况下更具抗药性。在前一个资金周期中，我们表明普遍定期审议的激活既是 充分必要地降低对拓扑异构酶II的敏感性，并发现这是一种 福利激活的结果。我们建议在接下来的周期中进行基因分析，以确定责任 目标(S)，并在异种移植研究中确定UPR对药物敏感性的影响程度。相反， UPR的激活增加了细胞对顺铂的敏感性，顺铂对DNA和蛋白质都有损害。作为一名 许多抗癌药物具有相似的特征，我们建议探索这些药物之间的相互作用 并确定存在协同作用的机制或相互作用。考虑到广泛的 UPR对细胞过程的影响，这一途径很可能会与其他 化疗药物。事实上，我们的初步数据表明，普遍定期审议的激活降低了 细胞对拓扑异构酶I毒物拓扑替康的敏感性。最后，正在使用抗血管生成药物。 抑制肿瘤血管生成，这可能有助于肿瘤中UPR的激活。然而，最近 数据表明，它们还可以促进血管重塑，这一点尚不清楚。 UPR激活。由于UPR导致促血管生成的转录和加工增加 有必要了解抗血管生成药物对UPR的影响，并确定是否 UPR在对这些药物的耐药性中发挥作用。在这个提案中，我们描述了确定 普遍定期审议增加对某些药物的敏感性而降低对其他药物的敏感性的机制， 探索与其他化疗药物的可能相互作用，并确定UPR的影响 在动物模型中对药物敏感性的激活。此外，我们将延长对普遍定期审议的初步审查 在肿瘤样本中激活到其他UPR靶点和多种类型的肿瘤，以确定其范围 我们的发现对儿童癌症的意义。

Due to inadequate blood supply, tumor cells exist in a compromised microenvironment that impinges on normal protein folding and can activate the unfolded protein response (DPR). In addition to contributing to tumor growth and survival, data from cell culture studies demonstrate that pharmacological activation of the UPR can also alter the sensitivity of cells to chemotherapeutic agents, making them more sensitive in some cases and more resistant in others. In the previous cycle of funding, we showed that UPR activation is both necessary and sufficient to reduce the sensitivity to topoisomerase II targeted therapy and found that this is a result of PERK activation. We propose genetic analyses in the coming cycle to identify the responsible target(s) and determine to what extent the UPR affects drug sensitivity in xenograft studies. Conversely, UPR activation increases the sensitivity of cells to cisplatin, which damages both DMA and proteins. As a number of anti-cancer agents have similar characteristics, we propose to explore interactions between these agents and the UPR and to determine the mechanism or interaction where synergies exist. Given the broad affects of the UPR on cellular processes, it is likely that this pathway will interact with other chemotherapeutic agents. Indeed, our preliminary data demonstrate that activation of the UPR reduces the sensitivity of cells to the topoisomerase I poison, topotecan. Finally, anti-angiogenic agents are being used to inhibit tumor vascularization, which should contribute to UPR activation in the tumor. However, recent data demonstrate that they can also promoter vascular remodeling, making it unclear how this will affect UPR activation. Since the UPR leads to both increased transcription and processing of pro-angiogenic factors, it is essential to understand the affect of anti-angiogenic agents on the UPR and to determine if the UPR plays a role in resistance to these agents. In this proposal, we describe experiments to determine the mechanisms by which the UPR increases sensitivity to some agents while decreasing sensitivity to others, explore possible interactions with additional chemotherapeutic agents, and determine the affect of UPR activation on drug sensitivity in animal models. In addition, we will extend our initial examination of UPR activation in tumor samples to other UPR targets and multiple types of tumors to establish the scope of the significance of our findings to pediatric cancers.