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首页> 外文学位 >Androgen receptor and DNA damage response crosstalk: Mechanisms and impact on cancer progression.
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Androgen receptor and DNA damage response crosstalk: Mechanisms and impact on cancer progression.

机译：雄激素受体和DNA损伤反应串扰：机制及其对癌症进展的影响。

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摘要

Prostate cancer (PCa) is the most frequently diagnosed non-cutaneous malignancy and the second leading cause of cancer-related death amongst men living in the United States. While localized disease can be effectively treated/managed through radical prostatectomy and/or radiation therapy, treatment of disseminated PCa represents a significant clinical challenge. As studies have determined that PCa development and progression is driven by androgen receptor (a ligand dependent nuclear receptor) activity at all stages of disease, targeted inhibition of this pathway, usually through systemic hormonal therapy or direct AR antagonism, is the first-line and most effective therapeutic option for treatment of advanced and metastatic disease. While these treatments are initially effective, tumors resistant to AR-directed therapies ultimately arise through a variety of mechanisms, with no durable treatment options available at this stage. Thus, significant efforts have been directed at characterizing the collective networks that impinge upon the AR signaling axis and drive therapeutic resistance and subsequent progression to advanced stages of disease. Work herein will describe mechanisms of cross talk between AR and the DNA damage response (DDR) that promote therapeutic resistance and advanced tumor phenotypes in PCa and characterize a transcriptional regulatory role for the DDR factor DNA-dependent protein kinase catalytic subunit (DNA-PKcs) that drives PCa progression and metastatic development. Collectively, these studies utilized models encompassing in vitro (cell lines), in vivo (subcutaneous xenografts and metastatic development), and ex vivo (primary human tumor explants) systems. Techniques encompassing biochemistry, pharmacology, molecular biology, genetics, histology, and pathology were utilized to investigate hypotheses. Based on the data collected, it will be concluded that crosstalk between AR and the DDR results in a positive feedback circuit contributing to proliferation and therapeutic resistance, and that one AR-regulated DDR factor, DNA-PKcs, is a key transcriptional modulator of gene networks that drive disease progression and metastatic formation and a clinical predictor of development of metastases and poor outcome. Combined, these findings identify novel therapeutic options for treatment of advanced PCa.
机译：前列腺癌（PCa）是在美国居住的男性中最常被诊断出的非皮肤恶性肿瘤，并且是与癌症相关的死亡的第二大主要原因。尽管可以通过根治性前列腺切除术和/或放射疗法有效地治疗/控制局限性疾病，但弥散型PCa的治疗仍是一项重大的临床挑战。研究表明，在疾病的各个阶段，PCa的发展和进程是由雄激素受体（一种依赖配体的核受体）活性驱动的，因此，通常通过全身激素治疗或直接的AR拮抗作用来靶向抑制该途径是一线和治疗晚期和转移性疾病的最有效的治疗选择。虽然这些治疗起初是有效的，但最终通过多种机制出现了对AR定向疗法产生抗药性的肿瘤，目前尚无持久的治疗选择。因此，已经做出了巨大的努力以表征撞击在AR信号传导轴上并驱动治疗抗性和随后发展为疾病晚期的集体网络。本文的工作将描述AR与DNA损伤反应（DDR）之间的串扰机制，该机制可促进PCa中的治疗抗性和晚期肿瘤表型，并表征DDR因子DNA依赖性蛋白激酶催化亚基（DNA-PKcs）的转录调控作用驱动PCa进展和转移性发展。总的来说，这些研究利用的模型涵盖了体外（细胞系），体内（皮下异种移植和转移性发育）和离体（原发性人类肿瘤外植体）系统。利用包括生物化学，药理学，分子生物学，遗传学，组织学和病理学在内的技术研究假设。根据收集的数据，可以得出结论，AR和DDR之间的串扰会导致正反馈电路，从而促进增殖和治疗抗性，并且一个AR调控的DDR因子DNA-PKcs是基因的关键转录调节因子。驱动疾病进展和转移形成的网络，以及转移和不良预后的临床预测指标。结合起来，这些发现确定了用于治疗晚期PCa的新颖治疗选择。

著录项

  • 作者

    Goodwin, Jonathan F.;

  • 作者单位

    Thomas Jefferson University.;

  • 授予单位 Thomas Jefferson University.;
  • 学科 Oncology.;Pharmacology.;Biochemistry.
  • 学位 Ph.D.
  • 年度 2015
  • 页码 308 p.
  • 总页数 308
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 财务管理、经济核算;
  • 关键词

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