Investigating the molecular mechanism that mediates the addiction of inflammatory breast cancer cells to HDAC6 function

总结 炎症性乳腺癌（IBC，约占所有乳腺癌的5%）是乳腺癌中最致命的形式 其5年生存率低于非IBC患者的一半。此外，其死亡率 在过去的20年里持续增长。尽管如此，人们对IBC的了解仍然很少， 全身性疾病的管理完全依赖于化疗。值得注意的是，我们发现 IBC细胞主要依赖组蛋白去乙酰化酶6（HDAC 6）的功能，而非IBC细胞主要是独立的。 重要的是，我们已经证明了主要的HDAC 6抑制剂（Rocilinostat/ACY 1215，Acetylon Inc）， 它目前正在其他肿瘤的临床试验中进行测试，在IBC细胞中具有抗癌活性， 临床前模型。我们的研究结果为IBC患者开发新的靶向治疗提供了机会。 假设和目的：我们假设HDAC 6调控的关键生物学过程是至关重要的， 维持IBC细胞的稳态。在这个建议中，我们的目标是描述参与的机制， IBC细胞对HDAC 6功能的成瘾，以便能够将我们的发现转化为临床。 具体目标1。揭示HDAC 6调节IBC细胞稳态的分子机制。 HDAC 6是一种IIB类组蛋白脱乙酰酶，在细胞对HDAC 6积累的反应中具有关键功能。 错误折叠的蛋白质和受损的线粒体，由于其在形成侵略体，线粒体侵略体和 自噬我们将研究在IBC细胞中观察到的致死性是由于典型功能的丧失还是不同的功能。 - 目的1.a）评估HDAC 6在有毒生物产品代谢中的功能。 - 目的1.b）评估HDAC 6在基础自噬中的功能。 目的1.b）研究新的推定HDAC 6底物。 具体目标2。用于IBC治疗的HDAC 6抑制的组合疗法的设计和评价。 在上皮癌中通常需要组合不同抗癌剂的全身治疗以实现 最大的治疗效益。在这里，我们假设组合疗法将规避耐药性， 基于HDAC 6抑制的单一疗法。我们将进行基于候选人和无偏见的研究， 优化含有HDAC 6抑制剂的方案的抗癌活性。 - 目的2.a）使用化疗加HDAC 6抑制的基于候选物的疗法。 - 目标2.b）无偏系统生物学研究，以确定与 对HDAC 6抑制的反应。 意义该提案代表了将我们的发现转化为靶向治疗所需的临床前研究。 治疗IBC患者。我们的建议的重要性在于，它可能导致死亡率下降， 最致命的乳腺癌，也是特征较少的一组乳腺癌。

SUMMARY Inflammatory breast cancer (IBC, ~5% of all breast cancers) is the most lethal form of breast cancer presenting a 5-year survival rate that is less than the half of the non-IBC patients. Furthermore, its mortality has continued to increase during the last 20 years. Despite these facts, IBC remains poorly understood and systemic disease management relies exclusively on chemotherapy. Remarkably, we have found that survival of IBC cells depend on histone deacetylase 6 (HDAC6) function while non-IBC cells are mainly independent. Importantly, we have demonstrated that the leading HDAC6 inhibitor (Rocilinostat/ACY1215, Acetylon Inc), which is currently being tested in clinical trials for other tumors presents anticancer activity in IBC cells in preclinical models. Our findings represent an opportunity to develop novel targeted therapies for IBC patients. Hypothesis and Objective: We hypothesize that key biological processes regulated by HDAC6 are essential to maintain the homeostasis of IBC cells. In this proposal our goal is to characterize the mechanisms involved in the addiction of IBC cells to HDAC6 function in order to be able to transition our finding to the clinic. Specific Aim1. Uncover the molecular mechanisms by which HDAC6 regulate the homeostasis of IBC cells. HDAC6 is a class-IIB histone deacetylase with a critical function on the cell's response to accumulation of misfolded proteins and damaged mitochondria due to its role in formation of aggresome, mito-aggresome and autophagy. We will study if the lethality seen in IBC cells is due to loss of canonical functions or a different one. -Aim 1.a) Evaluate the function of HDAC6 in the metabolism of toxic bioproducts. -Aim 1.b) Evaluate the function of HDAC6 in basal autophagy. -Aim 1.b) Investigate novel putative HDAC6 substrates. Specific Aim2. Design and evaluation of combination therapy with HDAC6 inhibition for IBC treatment. Systemic therapy combining different anticancer agents is generally needed in epithelial cancer to achieve maximum therapeutic benefit. Here, we hypothesize that combinatorial therapy will circumvent resistance to monotherapy based on HDAC6 inhibition. We will perform both candidate based and unbiased studies to optimize the anticancer activity of regimens containing HDAC6 inhibitors. -Aim 2.a) Candidate based therapy using chemotherapy plus HDAC6 inhibition. -Aim 2.b) Unbiased system biology studies for the identification of Master Regulators (MR) associated with the response to HDAC6 inhibition. Significance. This proposal represents the preclinical studies necessary to translate our findings into targeted therapy for IBC patients. The importance of our proposal is that it could lead to a decrease in mortality from the most lethal and one the less characterized group of breast cancers.