Defining PARP Inhibitor Response and Resistance in Prostate Cancer

定义前列腺癌中的 PARP 抑制剂反应和耐药性

• 批准号: 10440522
• 负责人: Alan Lombard
• 金额: $ 16.65万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10440522
• 关键词: Address; Apoptosis; Biochemical; CDC2 gene; Cancer Patient; Cell Cycle; Cell Cycle Checkpoint; Cell Death; Cell Line; Cell Maintenance; Cell Survival; Cells; Cessation of life; Clinical Oncology; Clinical Treatment; Critical Illness; DNA Damage; DNA Repair; Data; Defect; Development; Disease; Disease model; Drug resistance; Drug usage; Educational workshop; Environment; Exhibits; FDA approved; Faculty; Fostering; G2/M Arrest; G2/M Checkpoint Pathway; Gene Mutation; Genomics; Goals; Grant; IGFBP3 gene; Knowledge; LNCaP; Lead; Link; M cell; Maintenance; Malignant neoplasm of prostate; Mediating; Mentored Research Scientist Development Award; Mentors; Methods; Modeling; Monitor; PARP inhibition; Patients; Pharmaceutical Preparations; Phase; Phenotype; Positioning Attribute; Principal Investigator; Prostate Cancer therapy; Proteomics; RNA Interference; Research Personnel; Resistance; Resistance development; Resources; Role; Signal Transduction; Single Strand Break Repair; Stress; TP53 gene; Techniques; Testing; Therapeutic; Training; Training Activity; Up-Regulation; Work; Writing; advanced prostate cancer; castration resistant prostate cancer; cell repository; clinical translation; clinically relevant; cytotoxicity; experience; experimental study; gene repair; homologous recombination; improved; in vivo; inhibitor; interest; neoplastic cell; novel; novel therapeutics; overexpression; patient subsets; potential biomarker; pre-clinical; prostate cancer cell; prostate cancer cell line; prostate cancer model; repository; response; senescence; success; transcriptomics; treatment response; treatment strategy; tumor; tumor progression; vector

PROJECT SUMMARY/ABSTRACT The objective of this K01 award is to promote the development of Dr. Alan Lombard into an independent prostate cancer researcher. The proposed project will expand understanding of PARP inhibition for the treatment of prostate cancer and position Dr. Lombard, the principal investigator, to launch an independent line of study. Furthermore, intense mentoring and focused training goals are described to facilitate Dr. Lombard's transition from mentee to independent investigator. Advanced prostate cancer remains an incurable disease. PARP inhibitors (PARPi), such as rucaparib and olaparib, are an exciting new therapy recently approved for the treatment of a subset of patients. It is thought that PARPi's function by causing DNA damage and exacerbating homologous recombination deficiency to elicit synthetic lethality. While PARP inhibition promises to significantly improve the management of prostate cancer patients, questions remain regarding their use including 1) how do PARP inhibitor sensitive prostate tumor cells respond to treatment and 2) what mechanisms will ultimately give rise to PARP inhibitor resistance. To address these questions, two olaparib resistant prostate cancer models were developed, LN-OlapR and 2B-OlapR, using the PARPi sensitive LNCaP and C4-2B cell lines, respectively. OlapR models exhibit robust resistance to olaparib and cross-resistance to other clinically relevant PARPi's. Preliminary data suggests that PARPi sensitive cells respond to treatment not only through cell death but also through G2/M arrested, p21 dependent senescence, which may provide a repository of surviving cells that evade PARPi cytotoxicity and give rise to resistance. PARPi induced senescence leads to activation of the senescence associated secretory phenotype (SASP) which promotes maintenance of senescence and cellular viability. Interestingly, OlapR cells 1) do not increase p21 expression, 2) do not G2/M arrest, and 3) blunt senescence in response to PARP inhibition, suggesting that resistance is predicated upon cell cycle checkpoint override, which data suggests can be targeted through inhibition of CDK1. The observations lead to the hypothesis that PARPi induced p21 dependent senescence is overcome in resistance through cell cycle checkpoint override. In Aim 1, studies will determine whether senescence is a general response to PARPi's and mechanistically define the importance of p21 in this phenotype. In Aim 2, characterization of the PARPi induced SASP will be undertaken, with emphasis on understanding the role of IGFBP3, a known SASP factor. Lastly, Aim 3 will further develop the strategy of targeting CDK1 for the treatment of PARPi resistant prostate cancer and seek to understand how resistant cells override the G2/M checkpoint. The environment at UC Davis is replete with all the resources, expertise, and faculty needed to foster the development of Dr. Lombard and completion of proposed studies. Dr. Lombard will undergo a number of training activities, including workshops in proteomics, genomics, disease modeling, and grant writing, and will be mentored by an expert team to guide him to independence.

项目总结/摘要 这个K 01奖的目的是促进艾伦·隆巴德博士发展成为一个独立的 前列腺癌研究者拟议的项目将扩大对PARP抑制的理解， 治疗前列腺癌，并定位Lombard博士，主要研究者，推出一个独立的系列 学习。此外，强烈的指导和重点培训目标的描述，以促进博士。 从学员到独立调查员的转变。晚期前列腺癌仍然是一种不治之症。 PARP抑制剂（PARPi），如rucaparib和olaparib，是一种令人兴奋的新疗法，最近被批准用于 对一部分病人的治疗人们认为PARPi的作用是引起DNA损伤， 加剧同源重组缺陷以引发合成致死性。虽然PARP抑制承诺 为了显著改善前列腺癌患者的管理，关于它们的使用仍然存在问题。 包括1）PARP抑制剂敏感的前列腺肿瘤细胞如何对治疗作出反应，以及2） 机制将最终引起PARP抑制剂抗性。为了解决这些问题，两个olaparib 使用PARPi敏感的LNCaP，开发了抗性前列腺癌模型，LN-OlapR和2B-OlapR， 和C4-2B细胞系。OlapR模型显示出对奥拉帕尼的稳健耐药性和对 其他临床相关PARPi。初步数据表明，PARPi敏感细胞对治疗的反应不 不仅通过细胞死亡，而且通过G2/M阻滞，p21依赖性衰老，这可能提供了一个新的途径。 存活细胞的储存库，其逃避PARPi细胞毒性并产生抗性。PARPi诱导 衰老导致衰老相关分泌表型（SASP）的激活， 维持衰老和细胞活力。有趣的是，OlapR细胞1）不增加p21表达， 2)不G2/M期阻滞，和3）钝衰老响应PARP抑制，表明抗性是 预测细胞周期检查点覆盖，数据表明可以通过抑制 CDK1.这些观察结果导致了PARPi诱导的p21依赖性衰老的假设， 通过细胞周期检查点覆盖克服抗性。在目标1中，研究将确定 衰老是对PARPi的一般反应，并机械地定义了p21在这一过程中的重要性。 表型在目标2中，将对PARPi诱导的SASP进行表征，重点是 了解IGFBP 3的作用，这是一种已知的SASP因子。最后，目标3将进一步发展 靶向CDK 1用于治疗PARPi抗性前列腺癌，并寻求了解如何抵抗 细胞覆盖G2/M检查点。加州大学戴维斯分校的环境充满了所有的资源，专业知识， 和教师需要促进隆巴德博士的发展和完成拟议的研究。博士 Lombard将参加一些培训活动，包括蛋白质组学，基因组学，疾病 建模，并授予写作，并将由一个专家团队指导，以指导他独立。