Novel Pathways in the Control of Lineage Plasticity in Neuroendocrine Prostate Cancer

控制神经内分泌前列腺癌谱系可塑性的新途径

基本信息

批准号：
10616482
负责人：
Maria Teresa Diaz Meco Conde
金额：
$ 42.4万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10616482
关键词：
Address Adenocarcinoma Adenosine Adopted Anabolism Androgen Receptor Cancer Patient Carbon Cell Proliferation Cells Chromatin Remodeling Factor Clinical Complex DNA Methylation Data EZH2 gene Enzymes Epigenetic Process Generations Histologic Human In Vitro Incidence Laboratories Malignant Neoplasms Malignant neoplasm of prostate Mediating Metabolic Metabolism Metastatic Prostate Cancer Methionine Methyltransferase Molecular Neuroendocrine Prostate Cancer Pathway interactions Phenotype Phosphorylation Phosphotransferases Production Proliferating Protein Kinase C Publishing Receptor Signaling Regulation Resistance Role Scheme Serine Small Cell Carcinoma Supporting Cell Therapeutic Tumor Suppressor Proteins Up-Regulation Variant aggressive therapy cancer cell cancer genome castration resistant prostate cancer design drug resistance development epigenetic regulation histone methylation in vivo inhibitor neoplastic cell neuroendocrine differentiation neuroendocrine phenotype next generation novel novel therapeutics preclinical efficacy programs prostate cancer cell refractory cancer resistance mechanism success targeted treatment therapeutically effective trait tumor

项目摘要

SUMMARY Acquired resistance to targeted therapies in cancer is a rising unmet clinical need. In prostate cancer (PCa), the success of next-generation androgen receptor (AR) pathway inhibitors have been hampered by the development of drug resistance. This acquired resistance involves, in many cases, the reactivation of the AR axis through several different mechanisms. However, it has become apparent that an alternative mechanism of resistance is driven by the reprogramming of prostate cancer cells to undergo lineage plasticity to adopt an AR-independent state and to acquire a neuroendocrine phenotype, that allow them to grow and survive and escape AR-therapy. More potent and sustained AR targeting has driven an increased incidence of neuroendocrine prostate cancer (NEPC), which is an extremely aggressive, highly proliferative and metastatic PCa variant. Therefore, understanding the molecular mechanisms that govern NEPC differentiation is a pressing unmet clinical need. Our preliminary data have identified protein kinase C (PKC)l/i as a novel tumor suppressor in NEPC. Our recently published data demonstrate that the kinase PKCl/i is downregulated in human NEPC patients, and its loss promotes a metabolic reprogramming that sustains increased proliferation, as well as epigenetic changes needed by PCa cells to undergo cancer cell plasticity towards NEPC differentiation. The loss of PKCl/i results in the upregulation of the serine and one-carbon pathway metabolism that leads to increased production of S- adenosine methionine (SAM), which is the methyl donor for DNA and histone methylation. Our new unpublished data demonstrate that PKCl/i, in addition to be critical to produce SAM, also directly regulates DNMT1 and EZH2, key methyltransferases that utilize SAM, and are the ultimate chromatin modifiers. Therefore, our overarching hypothesis is that PKCl/i by regulating not only SAM generation but also the epigenetic modifiers of the PCa genome during NEPC differentiation creates new vulnerabilities that can be exploited therapeutically. Three key questions will be addressed in this proposal: (Aim 1) How does PKCl/i-mediated phosphorylation control EZH2 and DNMT1 functions during NEPC differentiation? (Aim 2) How does DNMT1 and EZH2- dependent epigenetic reprogramming downstream of PKCl/i contribute to the acquisition of the different NEPC traits? (Aim 3) Is PHGDH (the limiting enzyme in serine biosynthesis) inhibition alone or in combination with epigenetic inhibitors an effective therapeutic approach for treating NEPC tumors? The successful completion of this proposal will allow us to advance our understanding of the molecular mechanisms governing lineage plasticity during NEPC differentiation and help in the identification of new vulnerabilities that could lead to novel therapies in this lethal PCa.

概括对癌症靶向治疗的获得性耐药是一个日益增长的未满足的临床需求。在前列腺癌 (PCa) 中，下一代雄激素受体（AR）通路抑制剂的成功受到了开发的阻碍的耐药性。在许多情况下，这种获得性抵抗涉及通过以下方式重新激活 AR 轴：几种不同的机制。然而，很明显，另一种耐药机制是由前列腺癌细胞重新编程驱动，经历谱系可塑性，采用不依赖 AR 的状态并获得神经内分泌表型，使它们能够生长、生存并逃避 AR 治疗。更有效和持续的 AR 靶向导致神经内分泌前列腺癌的发病率增加 (NEPC)，这是一种极具侵袭性、高度增殖性和转移性的 PCa 变体。所以，了解控制 NEPC 分化的分子机制是一个紧迫的未满足的临床需求。我们的初步数据已确定蛋白激酶 C (PKC)l/i 是 NEPC 中的新型肿瘤抑制因子。我们的最近发表的数据表明，激酶 PKCl/i 在人类 NEPC 患者中下调，其损失促进代谢重编程，维持增殖增加以及表观遗传变化 PCa 细胞经历癌细胞向 NEPC 分化的可塑性所需。 PKCl/i 结果丢失丝氨酸和一碳途径代谢的上调，导致 S- 产量增加腺苷甲硫氨酸 (SAM)，它是 DNA 和组蛋白甲基化的甲基供体。我们的新未发表数据表明 PKCl/i 除了对产生 SAM 至关重要之外，还直接调节 DNMT1 和 EZH2 是利用 SAM 的关键甲基转移酶，是最终的染色质修饰剂。因此，我们的总体假设是 PKCl/i 不仅可以调节 SAM 的生成，还可以调节表观遗传修饰因子 NEPC 分化过程中 PCa 基因组的变化产生了可用于治疗的新漏洞。本提案将解决三个关键问题：（目标 1）PKCl/i 介导的磷酸化是如何进行的在NEPC分化过程中控制EZH2和DNMT1功能？（目标 2）DNMT1 和 EZH2 如何- PKCl/i 下游依赖的表观遗传重编程有助于获得不同的 NEPC 特质？（目标 3）PHGDH（丝氨酸生物合成中的限制酶）抑制是单独抑制还是联合抑制表观遗传抑制剂是治疗 NEPC 肿瘤的有效治疗方法吗？顺利完成该提案将使我们能够加深对控制谱系的分子机制的理解 NEPC 分化期间的可塑性，有助于识别可能导致新的漏洞的新漏洞这种致命性 PCa 的治疗方法。