Clinical Studies to Circumvent Drug Resistance

规避耐药性的临床研究

• 批准号: 9153612
• 负责人: susan bates
• 金额: $ 15.85万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 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/9153612
• 关键词: ABCB1 gene; ABCG2 gene; Alkanesulfonates; Antineoplastic Agents; Binding; Biological Markers; Blood - brain barrier anatomy; Blood capillaries; Bone Marrow; Brain; Breast cancer metastasis; CCR; CSF3 gene; Cancer Model; Cancer Therapy Evaluation Program; Cell Death; Cells; Chemotherapy-Oncologic Procedure; Cleaved cell; Clinic; Clinical; Clinical Research; Clinical Trials; Collaborations; Cytotoxic Chemotherapy; DNA; DNA Damage; DNA repair protein; Data; Development; Developmental Therapeutics Program; Dose; Dose-Limiting; Drug Efflux; Drug resistance; Endothelium; Enrollment; Epigenetic Process; Etiology; Evaluation; Excision; FDA approved; Future; Genes; Glioblastoma; Growth; Hair bulb structure; Hair follicle structure; Human; Image; Immune; In Vitro; Incidence; Informatics; Institutes; Kinetics; Label; Laboratories; Lead; Learning; Licensing; Link; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Medical center; Metastatic Lesion; Metastatic Neoplasm to the Central Nervous System; Myelosuppression; Neoplasm Metastasis; Neutropenia; Operative Surgical Procedures; P-Glycoprotein; Paclitaxel; Patients; Peptides; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Play; Positron-Emission Tomography; Preclinical Drug Evaluation; Process; Protocols documentation; Renal Cell Carcinoma; Research Personnel; Role; Sampling; Schedule; Severities; Signal Transduction; Site; Staining method; Stains; Tariquidar; Testing; Thrombocytopenia; Toxic effect; Tumor Tissue; Tyrosine Kinase Inhibitor; Universities; University of Pittsburgh Cancer Institute; Variant; Vascular Endothelial Growth Factor Receptor; Work; Xenograft procedure; bevacizumab; capillary; drug development; drug distribution; efflux pump; esterase; immunogenic; inhibitor/antagonist; interest; mTOR Inhibitor; malignant breast neoplasm; man; meetings; multi drug transporter; neoplastic cell; novel; phase 1 study; phase 2 study; phase I trial; phase II trial; pilot trial; pre-clinical; receptor; response; response marker; transcytosis; tumor; tumor growth; uptake

Project Summary I. Drug Resistance Due to Limited Drug Distribution Although our laboratory has shifted from studies of Pgp and ABCG2 in recent years to a focus on epigenetic therapies, we remain convinced that limited drug distribution likely contributes to drug resistance, and that there are likely diverse etiologies of limited drug distribution, one of which may be drug efflux pumps. This straightforward question cannot be answered: does restricted drug distribution play a role in cancer chemotherapy drug resistance? Numerous small trials measuring drug concentrations in tumor tissue, or pharmacodynamic imaging studies of labeled drug, suggest a wide range of drug distribution in cancer. We too observed variable uptake of a drug surrogate, sestamibi, in lung cancer. Nowhere is the issue of drug distribution more relevant than in the brain, where drug uptake is limited by the need to cross the blood brain barrier (BBB). Crossing the BBB requires an active process and evasion of the multidrug transporters ABCG2 and ABCB1, among other regulators of brain capillary endothelium. GRN1005 in CNS Metastases from Breast Cancer We have participated in a clinical trial of GRN1005, a novel drug conjugate that consists of three molecules of paclitaxel linked to a peptide that binds the LRP receptor. The conjugate was developed to cross the Blood Brain Barrier via transcytosis after binding the LRP receptor. Active drug is thought to be released in tumor cells when intracellular esterases cleave GRN1005 and release the free paclitaxel (107). Additionally, this conjugate is thought to evade the multidrug efflux transporters. GRN1005 (now ANG1005) was licensed by Geron Pharmaceuticals to conduct registration studies in glioblastoma and breast cancer after a positive signal in Phase I testing. We originally planned to participate in both a multi-institutional trial in breast cancer and to conduct a pilot trial that would include surgical resection of breast or lung cancer that had metastasized to the brain, to study the access of GNR1005 to metastatic lesions. Soon after the study opened, Geron announced that GRN1005 had failed to meet its first interim efficacy analysis - 0 responses among the first 30 patients accrued at 550 mg/m2 (whereas 4 of 13 patients (31%) had objective responses at 650 mg/m2). The trial was abruptly closed without further accrual; the multi-site PIs learned of this decision after the fact. However, review of data after the closure decision revealed that data were missing in 10 patients, and that the excessive toxicity that had led to the dose reduction to 550 mg/m2 included neutropenia in the absence of GCSF support. Geron returned the license for the drug to its original developer, Angiochem. Given our interest in this field, and our observation of activity of the agent in several NCI patients, we argued for and were allowed to keep open the NCI sub-study including FLT-PET imaging. We currently have one patient on study for over 8 months with a confirmed major response to GRN1005. II. A Novel Agent for Drug Resistant Cancers While there are multiple FDA-approved agents for renal cell cancer (RCC), all have a limited efficacy duration. To develop novel agents that would overcome or circumvent drug resistance without directly targeting drug efflux mechanisms, we collaborated with the NCI drug screen to identify com-pounds with particular activity in RCC in vitro and in xenografts (108,109). Although DNA appears to be the target for these compounds, they are unique as assessed by informatics evaluation. A lead compound, DMS612, was selected for Phase I, first in human studies carried out at the NCI (we serve as coordinating center), University of Pittsburgh, and Hershey Medical Center. We have tested 2 schedules - a day 1, 8, and 15 schedule that had cumulative thrombocytopenia as dose limiting toxicity, but minimal other toxicity. Two responses were observed; we are now studying a second schedule - day 1,2 administration every 21 days. Christophe Redon in the laboratory of William Bonner performed gamma-H2AX staining, documenting DNA damage in peripheral blood mononuclear cells and hair follicle cells, showing a dose response curve. DNA damage was more obvious in plucked hair bulbs than in PBMCs, appearing earlier and in greater numbers. While in PBMCs the signal at 3 mg/m2 was about 25% of that at 9 mg/m2 after 24 h, in the hair bulbs, it was 65%. In addition, damage was apparent earlier in the hair bulbs. Interestingly, DNA damage, as reflected by expression of gamma-H2AX, appeared to correlate with myelosuppression incidence and severity, supporting a hypothesis that DNA damage is biologically relevant to the mechanisms of action. Going Forward with DMS612 We plan to study DMS612 in the Phase II setting, first in RCC, using the day 1, 2 schedule. We will examine gamma-H2AX staining in hair follicles, PBMCs, and in tumor tissue where accessible. We recognize developing a novel agent in RCC will be challenging, since four VEGFR tyrosine kinase inhibitors, two mTOR inhibitors, and bevacizumab are approved by the FDA. We would argue that those agents have mechanistic overlap, and that agents with new mechanisms of action are needed since no existing therapy is curative. Further, the new immune checkpoint inhibitors may renew interest in "immunogenic cell death inducers" such as cytotoxic therapy (110). CTEP will support the trial in their Phase II centers and investigators have agreed to participate. Additional positive data could lead to studies in other tumor types. A potential selective biomarker was identified by Yves Pommier, who found that variants of a gene encoding a DNA repair protein, ATAD5, predicted cell sensitivity to DMS612. We have gathered samples from patients enrolled on the DMS612 Phase I study to perform ATAD5 sequencing. III. In collaboration with Dr. Tito Fojo, we have continued our efforts to characterize tumor growth kinetics and to evaluate whether those growth kinetics can be used to aid drug development. Dr. Wilfred Stein works on this highly productive project that may offer a paradigm shift for how drug effects can be assessed.

项目总结 I. 有限的药物分布导致的耐药性 尽管我们的实验室近年来已从 Pgp 和 ABCG2 的研究转向表观遗传治疗，但我们仍然相信有限的药物分布可能会导致耐药性，并且可能存在耐药性。药物分布受限的多种病因，其中之一可能是药物外排泵。这个简单的问题无法回答：限制药物分布是否在癌症化疗耐药性中发挥作用？许多测量肿瘤组织中药物浓度的小型试验或标记药物的药效成像研究表明，药物在癌症中分布广泛。我们也观察到肺癌中药物替代物塞他米比的摄取存在差异。药物分布问题在大脑中最为重要，因为药物的吸收因需要穿过血脑屏障 (BBB) 而受到限制。穿过 BBB 需要多药物转运蛋白 ABCG2 和 ABCB1 以及脑毛细血管内皮的其他调节因子的主动过程和逃避。 GRN1005 在乳腺癌中枢神经系统转移中的作用 我们参与了 GRN1005 的临床试验，GRN1005 是一种新型药物缀合物，由与 LRP 受体结合的肽连接的三个紫杉醇分子组成。该缀合物被开发为在结合 LRP 受体后通过转胞吞作用穿过血脑屏障。当细胞内酯酶裂解 GRN1005 并释放游离紫杉醇时，活性药物被认为在肿瘤细胞中释放 (107)。此外，这种结合物被认为可以逃避多药外排转运蛋白。 GRN1005（现为 ANG1005）在 I 期测试中出现阳性信号后，获得 Geron Pharmaceuticals 许可进行胶质母细胞瘤和乳腺癌的注册研究。我们最初计划参加一项针对乳腺癌的多机构试验，并进行一项试点试验，其中包括手术切除已转移至大脑的乳腺癌或肺癌，以研究 GNR1005 进入转移性病变的途径。研究开始后不久，Geron 宣布 GRN1005 未能满足其首次中期疗效分析——在 550 mg/m2 剂量下，前 30 名患者中出现 0 例缓解（而 13 名患者中有 4 名 (31%) 在 650 mg/m2 剂量下出现客观缓解）平方米）。试验突然结束，没有进一步计提；多站点 PI 事后才获悉这一决定。然而，关闭决定后对数据的审查显示，10 名患者的数据缺失，并且导致剂量减少至 550 mg/m2 的过度毒性包括在没有 GCSF 支持的情况下出现中性粒细胞减少症。 Geron 将该药物的许可证返还给其原始开发商 Angiochem。鉴于我们对该领域的兴趣，以及我们对该药物在几名 NCI 患者中的活性的观察，我们主张并被允许继续开放 NCI 子研究，包括 FLT-PET 成像。目前，我们有一名患者接受了超过 8 个月的研究，并确认对 GRN1005 有重大反应。二.治疗耐药性癌症的新型药物 虽然 FDA 批准了多种治疗肾细胞癌 (RCC) 的药物，但所有药物的疗效持续时间都有限。为了开发能够克服或规避耐药性而不直接针对药物流出机制的新型药物，我们与 NCI 药物筛选合作，鉴定在体外 RCC 和异种移植物中具有特定活性的化合物 (108,109)。尽管 DNA 似乎是这些化合物的目标，但根据信息学评估评估，它们是独特的。先导化合物 DMS612 被选为 I 期试验，首先是在 NCI（我们作为协调中心）、匹兹堡大学和好时医学中心进行的人体研究。我们测试了 2 个方案 - 第 1 天、第 8 天和第 15 天的方案，其中累积血小板减少作为剂量限制性毒性，但其他毒性最小。观察到两种反应；我们现在正在研究第二个时间表 - 每 21 天第 1,2 天给药一次。 William Bonner 实验室的 Christophe Redon 进行了 γ-H2AX 染色，记录了外周血单核细胞和毛囊细胞中的 DNA 损伤，显示了剂量反应曲线。与 PBMC 相比，拔下的毛球中的 DNA 损伤更明显，出现得更早，数量也更多。 24 小时后，在 PBMC 中，3 mg/m2 的信号约为 9 mg/m2 的信号的 25%，而在毛球中，该信号为 65%。此外，毛球的早期损伤也很明显。有趣的是，正如γ-H2AX表达所反映的，DNA损伤似乎与骨髓抑制的发生率和严重程度相关，这支持了DNA损伤与作用机制在生物学上相关的假设。 DMS612 的进展 我们计划在 II 期研究中研究 DMS612，首先是在 RCC 中，使用第 1、2 天的时间表。我们将检查毛囊、PBMC 和可触及的肿瘤组织中的 γ-H2AX 染色。我们认识到开发一种治疗肾细胞癌的新药将具有挑战性，因为 FDA 批准了四种 VEGFR 酪氨酸激酶抑制剂、两种 mTOR 抑制剂和贝伐珠单抗。我们认为这些药物在机制上有重叠，并且需要具有新作用机制的药物，因为现有的疗法没有治愈性。此外，新的免疫检查点抑制剂可能会重新引起人们对“免疫原性细胞死亡诱导剂”（例如细胞毒性疗法）的兴趣（110）。 CTEP 将支持其 II 期中心的试验，研究人员已同意参与。额外的积极数据可能会导致对其他肿瘤类型的研究。 Yves Pommier 发现了一种潜在的选择性生物标志物，他发现编码 DNA 修复蛋白 ATAD5 的基因变体可以预测细胞对 DMS612 的敏感性。我们收集了参与 DMS612 I 期研究的患者的样本，以进行 ATAD5 测序。三．我们与 Tito Fojo 博士合作，继续努力表征肿瘤生长动力学，并评估这些生长动力学是否可用于辅助药物开发。威尔弗雷德·斯坦博士致力于这个高效的项目，该项目可能会为如何评估药物效果提供范式转变。

项目成果

PARP inhibitors in BRCA1/BRCA2 germline mutation carriers with ovarian and breast cancer.

• DOI: 10.3410/b2-10
• 发表时间: 2010-02-11
• 期刊: F1000 biology reports
• 作者: Annunziata, Christina M;Bates, Susan E
• 通讯作者: Bates, Susan E

Upregulation of ABCG2 by romidepsin via the aryl hydrocarbon receptor pathway.

• DOI: 10.1158/1541-7786.mcr-10-0270
• 发表时间: 2011-04
• 期刊: Molecular cancer research : MCR
• 作者: To KK;Robey R;Zhan Z;Bangiolo L;Bates SE
• 通讯作者: Bates SE

Mechanisms of resistance to PARP inhibitors--three and counting.

• DOI: 10.1158/2159-8290.cd-12-0514
• 发表时间: 2013-01
• 期刊: Cancer discovery
• 影响因子: 28.2
• 作者: Fojo T;Bates S
• 通讯作者: Bates S

Developing precision medicine in a global world.

• DOI: 10.1158/1078-0432.ccr-14-0091
• 发表时间: 2014-03-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Rubin EH;Allen JD;Nowak JA;Bates SE
• 通讯作者: Bates SE

A phase I study of the P-glycoprotein antagonist tariquidar in combination with vinorelbine.

• DOI: 10.1158/1078-0432.ccr-08-0938
• 发表时间: 2009-05-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Abraham J;Edgerly M;Wilson R;Chen C;Rutt A;Bakke S;Robey R;Dwyer A;Goldspiel B;Balis F;Van Tellingen O;Bates SE;Fojo T
• 通讯作者: Fojo T