Development of 8-chloro-adenosine therapy

8-氯腺苷疗法的开发

基本信息

批准号：
7715216
负责人：
VARSHA GANDHI
金额：
$ 6.93万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7715216
关键词：
8-chloroadenosine Adenosine Adenosine Kinase Affect Antineoplastic Agents Apical Apoptosis Applications Grants Award Biochemical Biological Markers Biology Cancer Center Cell Death Cell Line Cells Chronic Lymphocytic Leukemia Clinic Clinical Clinical Drug Development Clinical Protocols Clinical Trials Clinical Trials Design Clofarabine Collaborations Combined Modality Therapy Complement Cyclin D1 Cyclins Cyclophosphamide Cytarabine DNA DNA Repair DNA Replication Inhibition DNA biosynthesis Data Deoxycytidine Kinase Development Diphosphates Disease Management Disease Resistance Disease remission Doctor of Medicine Dose Drug Kinetics Enzymes Evaluation Family Figs - dietary Funding Goals Heat-Shock Proteins 90 Hematologic Neoplasms In Vitro Indolent Investigation Investigational Drugs Knowledge Laboratories Life Lymphoma Malignant Neoplasms Mantle Cell Lymphoma Messenger RNA Metabolic Metabolism MicroRNAs Mitochondrial Proton-Translocating ATPases Molecular Molecular Models Nelarabine Neoplasms New Agents Oxidative Phosphorylation Pathway interactions Patient Selection Patients Pattern Pharmaceutical Preparations Pharmacodynamics Phase Phosphotransferases Play Poly(A) Tail Polynucleotide Adenylyltransferase Process Protocols documentation Publishing RNA RNA chemical synthesis Rapid Access to Intervention Development Reproduction spores Research Ethics Committees Research Personnel Ribose Role Sampling Schedule Societies Supporting Cell Testing Therapeutic Transcript Transgenic Mice Translating Translational Research Translations United States Food and Drug Administration University of Texas M D Anderson Cancer Center analog base calin cancer cell chemotherapeutic agent clinically relevant conventional therapy cytotoxic design disease characteristic expectation fludarabine gemcitabine genome-wide improved inhibitor/antagonist leukemia leukemia/lymphoma molecular modeling mouse model neoplastic cell novel nucleoside analog overexpression peer prognostic programs resistance mechanism response small molecule sugar translational study tripolyphosphate tumorigenesis

项目摘要

Nucleoside analogues have a played pivotal role in the treatment of hematological malignancies. While the first analogue was used more than 50 years ago, during the last five years, four new congeners were FDA approved for therapy. A common feature among these clinically used analogues is that they are all DNA directed; analogues that are exclusively affecting RNA have not been brought to the clinic. 8- chloroadenosine (8-CI-Ado) is a novel and unique nucleoside analogue that is first in its class to be tested in the clinic. First, in contrast to other clinically used analogues, this agent has a nbose sugar. Second, 8-CI- Ado is phosphorylated by adenosine kinase which is present in high specific activity in cancer cells as opposed to deoxycytidine kinase which activates currently used analogues. Third, the triphosphate of 8-CI- Ado, 8-CI-ATP is incorporated into RNA without any effect on DNA synthesis. Fourth, 8-CI-ATP is also incorporated into poly(A) tail of transcripts resulting in inhibition of polyadenylafion and mRNA synthesis. As a consequence of the actions on mRNA synthesis, there is a depletion of short-lived transcnpts. Fifth, biochemical studies and molecular modeling data have suggested that 8-CI-ADP is a substrate and 8-CI- ATP is an inhibitor for mitochondrial ATP synthase, the apical enzyme of the oxidative phosphorylation pathway which results in a depletion of cellular bioenergy. Collectively these features make this analogue a first in its class. Based on this background, we hypothesize that 8-Cl-Ado will elicit novel pharmacodynamic responses to non-growing or indolent malignant cells. The uniqueness of 8-CI-Ado was recognized by peers in this field as we obtained two RAID awards from NCI, an IND from the FDA, and GMP material to conduct our phase I clinical investigation in patients with CLL. To achieve our overall goal and to test our hypothesis, we plan to pursue the following three aims. First, using well-defined biomarkers, evaluate pharmacokinetics and pharmacodynamics of 8-CI-Ado during phase l/ll clinical trial in patients with CLL. Second, formulate in vitro rationales for clinical translation of mechanism-based combinations of 8-Cl-Ado with small molecule inhibitors. Third, determine metabolism, actions, and cytotoxic endpoints in lymphoma cell lines that will be translated to a clinical trial in lymphoma. RELEVANCE (See instmctions): This Project will test a new agent 8-chloro-adenosine, in chronic lymphocytic leukemia (CLL) and lymphoma. This is a first in its kind of agent to move to clinic. Additionally, different strategies will be investigated regarding best combination approaches for this agent. Hence these investigations are aimed at improving the cure rate of CLL and lymphoma.

核苷类似物在血液恶性肿瘤的治疗中发挥着关键作用。虽然第一个类似物已于 50 多年前使用，在过去五年中，FDA 批准了四种新的同类物批准用于治疗。这些临床使用的类似物的一个共同特点是它们都是DNA 指导；专门影响 RNA 的类似物尚未进入临床。 8- 氯腺苷 (8-CI-Ado) 是一种新颖且独特的核苷类似物，是同类中第一个经过测试的核苷类似物。诊所。首先，与临床上使用的其他类似物相比，该药物含有nbose糖。二、8-CI- Ado 被腺苷激酶磷酸化，腺苷激酶在癌细胞中具有高比活性，如下所示：与激活当前使用的类似物的脱氧胞苷激酶相反。三、8-CI-三磷酸 Ado，8-CI-ATP 掺入 RNA 中，对 DNA 合成没有任何影响。第四，8-CI-ATP也是掺入转录本的 Poly(A) 尾部，导致聚腺苷酸和 mRNA 合成的抑制。作为由于对 mRNA 合成的影响，短期转录因子会被耗尽。第五，生化研究和分子模型数据表明 8-CI-ADP 是底物，8-CI- ATP 是线粒体 ATP 合酶（氧化磷酸化的顶端酶）的抑制剂导致细胞生物能量耗尽的途径。总的来说，这些功能使该模拟成为同类第一。基于这一背景，我们假设 8-Cl-Ado 将引发新的药效学对非生长或惰性恶性细胞的反应。 8-CI-Ado的独特性得到同行认可在这一领域，我们获得了 NCI 的两项 RAID 奖项、FDA 的 IND 以及 GMP 材料来进行我们对 CLL 患者进行的 I 期临床研究。为了实现我们的总体目标并检验我们的假设，我们计划实现以下三个目标。首先，使用明确的生物标志物评估药代动力学以及 8-CI-Ado 在 CLL 患者的 l/ll 期临床试验中的药效学。其次，制定在 8-Cl-Ado 与小分子基于机制的组合临床转化的体外原理抑制剂。第三，确定淋巴瘤细胞系的代谢、作用和细胞毒性终点，转化为淋巴瘤的临床试验。相关性（参见说明）：该项目将测试一种新药 8-氯腺苷，用于治疗慢性淋巴细胞白血病 (CLL) 和淋巴瘤。这是同类药物中首次进入临床。此外，还将采取不同的策略研究了该药物的最佳组合方法。因此，这些调查的目的是提高CLL和淋巴瘤的治愈率。