Non-Canonical Phosphatidylinositol Kinases in Triple Negative Breast Cancer

项目摘要 三阴性乳腺癌（TNBC）占所有乳腺癌的15-20%。患有TNBC的女性 与其他亚型相比，经历死亡的可能性要高出一倍。TNBC的预后不良可归因于 缺乏有效的靶向治疗。虽然TP 53突变在TNBC中经常发现，但很难在TNBC中发现。 针对p53缺乏症使用药物。我们已经确定了一个非经典磷脂酰肌醇激酶家族， 磷脂酰肌醇-5-磷酸4-激酶（PI 5 P4 Ks）及其在具有TP 53的癌症生长中的关键作用 畸变此外，我们发现了PI 5 P4 Ks在自噬中的作用，并首次表明， 这些酶定位于溶酶体，表明PI 5 P4 Ks可能对溶酶体功能很重要， 以及揭示了p53突变型癌症中PI 5 P4 K抑制的抗癌机制。使用临床前 在新型基因工程小鼠乳腺肿瘤模型、人乳腺癌细胞系和患者中的研究 乳腺肿瘤样本，我们建议调查这些“药物”功能的生化基础。 内切酶我们还将验证它们作为药物干预人类癌症的靶点，特别是对于 靶向治疗尚未成功的TNBC。我们的首要假设是PI 5 P4 Ks的作用 作为代谢应激的传感器，允许细胞调节溶酶体事件，包括自噬， 维持细胞内环境稳定。此外，我们认为与p53突变相关的代谢重新连接， 产生了对PI 5 P4 K的新的依赖性，用于TNBC细胞生长和存活。 在目标1中，我们将确定合成脆弱性的机制，通过该机制，PI 5 P4 Ks成为 当p53缺陷时肿瘤细胞生长。为此，我们将描述突变型p53，无论是功能丧失， 和功能的获得，有助于合成的致命性，以及解剖的代谢后果， 在p53突变TNBC细胞中的PI 5 P4 K损失。 在目标2中，我们将使用我们的基因工程技术测试靶向TNBC中的PI 5 P4 K的治疗效果。 工程化小鼠乳腺肿瘤模型和患者乳腺肿瘤样品。 该项目的最终目标和总体影响是将PI 5 P4 Ks表征为肿瘤的新易感性 与TP 53突变，以确定这些TNBC患者的治疗干预的机会， 突变，目前缺乏靶向治疗。

PROJECT SUMMARY Triple negative breast cancer (TNBC) accounts for 15–20% of all breast cancers. Women with TNBC are three times more likely to experience death compared to other subtypes. The poor prognosis of TNBC can be attributed to the lack of effective targeted therapy. Although TP53 mutations are frequently found in TNBC, it is difficult to target p53-deficiency with drugs. We have identified a family of non-canonical phosphatidylinositol kinases, the phosphatidylinositol-5-phosphate 4-kinases (PI5P4Ks) and their crucial role in the growth of cancers with TP53 aberrations. Furthermore, we discovered a role for the PI5P4Ks in autophagy, and for the first time, showed that these enzymes localize to lysosomes, suggesting that the PI5P4Ks may be important for lysosome function, as well as shedding light on the anti-cancer mechanism of PI5P4K inhibition in p53 mutant cancers. Using preclinical studies in novel genetically engineered mouse breast tumor models, human breast cancer cell lines, and patient breast tumor samples we propose to investigate the biochemical basis for the function of these ‘druggable’ enzymes. We will also validate them as targets for pharmaceutical intervention in human cancers, especially for TNBC where targeted therapies have not been successful. Our overarching hypothesis is that the PI5P4Ks act as sensors of metabolic stress that allow cells to modulate lysosomal events, including autophagy, in order to maintain cellular homeostasis. Further, we posit that the metabolic rewiring associated with p53 mutations, create a novel dependency on the PI5P4Ks for TNBC cell growth and survival. In Aim 1 we will determine the mechanism of synthetic vulnerability by which the PI5P4Ks become essential for tumor cell growth when p53 is defective. To this end we will characterize how mutant p53, both loss of function and gain of function, contributes to the synthetic lethality as well as dissect the metabolic consequences of PI5P4K loss in p53 mutant TNBC cells. In Aim 2 we will test the therapeutic effectiveness of targeting the PI5P4Ks in TNBC using our genetically engineered mouse breast tumor models and patient breast tumor samples. The ultimate goal and the overall impact of this project are to characterize PI5P4Ks as a novel liability for tumors with TP53 mutations in order to define opportunities for therapeutic intervention for TNBC patients with these mutations, which currently lack targeted therapy.