Acute Leukemia in the Elderly: Development of Novel, Targeted Therapeutics

老年人急性白血病：新型靶向治疗药物的开发

• 批准号: 7963875
• 负责人: Dan Longo
• 金额: $ 33.59万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7963875
• 关键词: 2-tyrosine; Accelerated Phase; Acute; Acute Myelocytic Leukemia; Acute leukemia; Adult; Adult Acute Lymphocytic Leukemia; Affect; Aftercare; Age; Base Excision Repairs; Blast Cell; Blast Phase; Bortezomib; Cancer Therapy Evaluation Program; Cell Cycle Checkpoint; Cell Line; Cells; Clinic; Clinical Treatment; Clinical Trials; DNA; DNA Double Strand Break; Data; Development; Dose; Double Strand Break Repair; Drug Kinetics; Elderly; Experimental Designs; Frequencies; Future; Genetic; Goals; Guanine; Hour; Human; Immunoassay; In Vitro; Induction of Apoptosis; Inhibition of Cell Proliferation; Kinetics; Laboratories; Lesion; Lymphoid; Maximum Tolerated Dose; Measurement; Measures; Mismatch Repair; Monitor; Myelogenous; Nature; Neoadjuvant Therapy; Nonhomologous DNA End Joining; Pan Genus; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Physiologic pulse; Play; Poly Adenosine Diphosphate Ribose; Poly(ADP-ribose) Polymerases; Proteasome Inhibitor; Protein Tyrosine Kinase; Proteins; Refractory; Relapse; Research; Research Personnel; Resistance; Role; Safety; Schedule; Testing; Therapeutic; Time; Toxic effect; Transferase; Translations; Treatment Protocols; Tyrosine Kinase Inhibitor; Visit; Work; aggressive therapy; alpha-Thalassemia; base; chemotherapeutic agent; clinical application; homologous recombination; in vivo; inhibitor/antagonist; interest; killings; leukemia; meetings; new therapeutic target; novel therapeutic intervention; older patient; outcome forecast; prognostic; repaired; response; temozolomide; therapy resistant; translational study

Despite therapeutic advances, treatment of adult ALL results in long term survival of only 30-40% of patients, with a significantly worse prognosis for patients over the age of 60. There are 2 sub-projects, one of which will be entering clinical trial in the near future. 1. The PARP Inhibitor ABT-888 Potentiates the Anti-Leukemic Activity of Temozolomide in Human Acute Leukemia Cells with Limited DSB Repair Capacity. Purpose: Adults with poor prognosis acute leukemias have few therapeutic options due to genetic lesions rendering leukemic blasts resistant to therapy, and the toxic nature of aggressive therapies in heavily pretreated and/or elderly patients. The goal of this study was to determine the potential in vitro efficacy of a regimen combining inhibition of base excision repair (BER) using the poly(ADP-ribose) polymerase (PARP) inhibitor ABT-888 with temozolomide (TMZ) against human leukemia cell lines and primary cells as a prelude to a potential phase I/II clinical trial of this regimen. Experimental Design: Leukemia cells were cultured in the presence of ABT-888 or TMZ alone or in combination at concentrations and times that approximate what is clinically achievable, and inhibition of cell proliferation, induction of apoptosis, and cell cycle checkpoint activation were monitored. The kinetics of induction of DNA double strand breaks (DSB) and their repair was monitored by immunohistochemical determination of -H2AX and Rad51 focus formation. Results: Culture in TMZ or ABT-888 as single agents have limited anti-leukemic activity, however the combination demonstrated enhanced anti-leukemic activity on approximately half of the cell lines and primary isolates tested. Efficacy of the combination was not dependent on the level of endogenous PARP activity, nor on the lineage (lymphoid versus myeloid) of the leukemic blasts. Both sensitive and resistant cells demonstrated a similar S/G2 arrest with rapid activation of Chk1 and Chk2, however, in the continued presence of inhibition of BER, only resistant cells could repair DNA DSB, indicating that other repair pathways, probably homologous recombination (HR), play a critical role in determining the cells fate after treatment with this regimen. Conclusion: The combination of TMZ and ABT-888, when used in vitro in a pulse manner similar to the clinical application of these drugs, leads to enhance killing of leukemia cells, and that efficacy it determined by the capacity of the leukemic blasts to repair DSB. Based on this laboratory work, a clinical trial has been approved by CTEP and will be distributed to co-investigators this week. In this trial adults with relapsed or refractory AML or ALL; Ph+ ALL if failed 2 tyrosine kinase inhibitors; CML in accelerated phase or blast crisis having failed two tyrosine kinase inhibiors; AML arising in the setting of antecedent MDS, MPD, or secondary leukemia; de novo AML or AML in patients older than 60 with poor prognostic features or who are unwilling to receive standard induction therapy. Patients will be treated with temozolomide (TMZ) 150 mg/m2 for 7d with 10 mg PO BID of ABT-888. If this is tolerated, TMZ will be increased to 200 mg/m2 d1-7 with 10 mg BID ABT-888. If tolerated the dose of ABT-888 will be escalated up to 80 mg/m2 or MTD, whichever comes first by standard phase I dose escalation criteria. Translational studies will include measurement of MGMT protein levels, PAR levels pre and post treatment using an NCI-validated immunoassay, analysis of gamma-H2AX foci as measure of DS DNA breaks, and determination of mismatch repair status in patients with low MGMT levels. Endpoints are: Primary Objectives 1.To define the maximum tolerated dose (MTD) and Recommended Phase II Dose (RP2D) of ABT-888 administered in combination with temozolomide in patients with acute leukemias. 2.To evaluate the feasibility, safety, and toxicity of administering ABT-888 in combination with temozolomide in patients with acute leukemias. Secondary Objectives 1. To document responses in acute leukemias. 2.To observe the pharmacokinetics of both ABT-888 and temozolomide when administered alone and in combination. 3.To study the pharmacodynamics: a) to determine the levels of poly(ADP-ribose) (PAR) before and after administration of ABT-888 and temozolomide in patient leukemia blasts; b) to analyze methyl-guanine methyl-transferase (MGMT) protein levels in primary leukemia blasts; c) to quantify the induction of γ-H2AX and RAD51 foci in patient leukemia blasts after treatment; d) to determine whether PARP inhibitor ABT-888 affects non-homologous end-joining (NHEJ) repair activity in vivo and whether ABT-888 reduces the frequency of NHEJ repair errors. 2. The second project involved study with a pan-Akt inhibitor from Abbott labs called A443654. We have accumulated extensive data with cell lines and primary cells demonstrating the activity of this agent alone and in combination with proteasome inhibitors and inhibitors of Bcl-2/Bcl-XL. The latter studies are especially interesting and demonstrate synergistic induction of apoptosis withing a few hours of treatment, suggesting that drug availability in vivo may not be limiting. We are visiting CTEP next week, and will discuss what studies are needed to move these concepts into the clinic.

尽管有治疗性的进展，但对成年人的治疗都导致长期存活仅为30-40％，而60岁以上的患者的预后明显较差。有2个次项目，其中一项将在不久的将来参加临床试验。 1。PARP抑制剂ABT-888增强了替莫唑胺在人类急性白血病细胞中的抗白血病活性，DSB修复能力有限。目的：预后不良的成年人急性白血病几乎没有治疗选择，因为遗传病变使白血病爆炸具有抗疗法的抗性爆炸，并且在经过预处理和/或老年患者中具有侵略性疗法的毒性性质。这项研究的目的是确定一种使用聚（ADP-核糖）聚合酶（PARP）抑制剂ABT-888与替莫唑酚（TMZ）对人白血病细胞系对人类白血病细胞系和原代细胞作为潜在的II/II II临床临床临床试验的pRELUDE的抑制剂（pARP）聚合酶（PARP）聚合酶（PARP）聚合酶（PARP）抑制剂ABT-888的潜在体外功效。 实验设计：单独存在ABT-888或TMZ的存在或在浓度和时间组合中培养白血病细胞，以近似于临床上可实现的内容，并抑制细胞增殖，凋亡诱导和细胞周期检查点激活。 DNA双链断裂（DSB）的诱导动力学及其修复的动力学通过免疫组织化学测定-H2AX和RAD51焦点形成。 结果：TMZ或ABT-888作为单个药物的培养具有有限的抗白血病活性，但是该组合表现出对大约一半的细胞系和测试的原代分离株的抗白血病活性增强。该组合的功效不取决于内源性PARP活性的水平，也不取决于白血病爆炸的谱系（淋巴和髓样）。敏感和抗性细胞都表现出相似的S/G2停滞，而CHK1和CHK2的快速激活，但是，在继续抑制BER的情况下，只有抗性细胞可以修复DNA DSB，这表明其他维修途径（可能是同源重组（HR））在确定该治疗后的细胞效果方面起着关键作用。 结论：当在体外以类似于这些药物的临床应用的脉冲方式使用时，TMZ和ABT-888的组合会导致白血病细胞的杀伤，以及由白血病爆炸能力来修复DSB的能力确定的功效。 基于这项实验室工作，CTEP已批准了一项临床试验，并将在本周分发给共同投资者。在这个试验中，成年人患有复发或难治性AML或全部； pH+如果失败了2个酪氨酸激酶抑制剂； CML在加速相或爆炸危机中失败了两个酪氨酸激酶抑制剂； AML在先前的MDS，MPD或继发性白血病的情况下出现；从Ne军AML或AML的60岁以上患者的预后特征或不愿接受标准诱导疗法的患者。患者将用替莫唑胺（TMZ）150 mg/m2进行7D治疗，并使用10 mg PO BID为ABT-888。如果可以耐受这一点，则使用10 mg BID ABT-888，TMZ将增​​加到200 mg/m2 D1-7。如果耐受的ABT-888剂量将升级为80 mg/m2或MTD，以标准I期剂量升级标准首先采用的剂量。翻译研究将包括测量MGMT蛋白水平，使用NCI验证的免疫测定时的PAR水平和治疗后的PAR水平，分析γ-H2AX FOCI作为DS DNA断裂的量度以及确定低MGMT水平患者的不匹配修复状态。端点是： 主要目标 1.在急性白血病患者中，定义ABT-888的最大耐受剂量（MTD）和建议的II期剂量（RP2D）。 2.评估急性白血病患者中施用ABT-888与替莫唑胺结合使用的可行性，安全性和毒性。 次要目标 1。记录急性白血病的反应。 2.当单独和组合使用时，观察ABT-888和替莫唑胺的药代动力学。 3.研究药效学：a）确定在患者白血病爆炸中施用ABT-888和替莫唑胺之前和之后的聚（ADP-核糖）（PAR）的水平； b）分析原发性白血病爆炸中甲基瓜氨酸甲基转移酶（MGMT）蛋白水平； c）在治疗后量化患者白血病爆炸中γ-H2AX和RAD51灶的诱导； d）确定PARP抑制剂ABT-888是否会影响体内的非同源最终连接（NHEJ）修复活性，以及​​ABT-888是否会降低NHEJ修复误差的频率。 2。第二个项目涉及对Abbott Labs的Pan-Akt抑制剂的研究，称为A443654。我们已经用细胞系和原代细胞积累了广泛的数据，证明了该药物的活性，并与Bcl-2/bcl-XL的蛋白酶体抑制剂和抑制剂结合使用。后一项研究特别有趣，并通过几个小时的治疗来证明凋亡的协同诱导诱导，这表明体内药物的可利用性可能不会受到限制。我们下周将访问CTEP，并将讨论将这些概念转移到诊所的需要的研究。