Translational Studies to facilitate Rational Therapeutic Combinations of Letrozole for the Treatment of Glioblastoma

促进来曲唑合理组合治疗胶质母细胞瘤的转化研究

• 批准号: 10662543
• 负责人: PANKAJ B DESAI
• 金额: $ 38.92万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10662543
• 关键词: Acceleration; Adjuvant; Alkylating Agents; Animal Model; Animal Testing Alternatives; Aromatase; Aromatase Inhibitors; Automobile Driving; BRCA2 gene; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Breast Cancer Treatment; CDK4 gene; Categories; Cell Cycle; Cell Line; Cell Proliferation; Cell Survival; Cells; Cerebrum; Clinical; Clinical Data; Clinical Trials; Combined Modality Therapy; DNA; DNA Repair; Data; Development; Disease; Dose; Down-Regulation; Drug Kinetics; Excision; Excretory function; FDA approved; Future; Genotype; Glioblastoma; Glioma; Goals; Growth; Half-Life; Hour; Human; Immunocompetent; Immunocompromised Host; Immunologic Deficiency Syndromes; Implant; In Vitro; Intellectual Property; Letrozole; Licensing; Malignant neoplasm of brain; Malignant neoplasm of central nervous system; Measures; Medical; Messenger RNA; Metabolism; Microdialysis; Modeling; Molecular; Mus; National Institute of Neurological Disorders and Stroke; Nude Rats; Oncogenes; Oncogenic; Operative Surgical Procedures; Patients; Penetration; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase 0/1 Clinical Trial; Phase II Clinical Trials; Phenotype; Plasma; Poly(ADP-ribose) Polymerase Inhibitor; Prognosis; Proliferation Marker; Proteins; Radiation therapy; Rattus; Recurrence; Resistance; SCID Mice; Safety; Sampling; Sprague-Dawley Rats; Survival Rate; Testing; Therapeutic; Therapeutic Agents; Tissues; Tumor Suppression; Tumor Volume; Up-Regulation; Xenograft Model; Xenograft procedure; absorption; blood-brain barrier crossing; blood-brain barrier permeabilization; brain tissue; chemotherapy; cohort; commercialization; drug development; efficacy study; hormone receptor-positive; in vivo; in vivo Model; indexing; malignant breast neoplasm; multidisciplinary; neuro-oncology; new therapeutic target; novel therapeutics; patient prognosis; pharmacokinetics and pharmacodynamics; pre-clinical; programs; response; standard of care; temozolomide; transcriptome sequencing; translational study; tumor

The prognosis for patients with glioblastoma (GBM), one of the most lethal brain tumors, remains dismal. Our recent discoveries provide robust evidence suggesting that letrozole (LTZ), an aromatase inhibitor used in the treatment of breast cancer, has the potential to be a breakthrough therapeutic for the treatment of GBM. Our data include: 1) LTZ treatment of patient-derived GBM cells markedly reduced cell viability and spheroid growth; 2) LTZ potentiated the activity of temozolomide (TMZ), the primary agent used in chemotherapy of GBM in TMZ- resistant cells; 3) Pharmacokinetics/Pharmacodynamics (PK/PD) studies in immunocompetent rats orthotopically implanted with C6 rat glioma revealed that LTZ readily crosses the blood-brain barrier (BBB), markedly reduces tumor volume and extends survival (10 vs. > 60 days in control vs. LTZ); and 4) immunohistochemical analysis of tissues (N > 90 patients) demonstrated that the aromatase expression is strikingly higher (> 5X) in GBM relative to low-grade gliomas. Moreover, in an ongoing phase 0/1 clinical trial in which recurrent GBM patients received LTZ (2.5 -12.5 mg, N = 14 subjects) prior to surgical resection, analyses of the excised tumor revealed that LTZ readily traverses the BBB in humans. RNAseq analysis showed significant downregulation of oncogenes driving cell proliferation markers and upregulation of tumor suppression markers (reduced DNA damage repair capacity) in a LTZ dose-dependent manner. Our long-term goal is to repurpose LTZ as an anti-GBM drug. Given the phenotypic/genotypic complexity of GBM, combination therapy will be a clinical necessity. To support this goal, our objective here is to conduct comprehensive PK/PD studies of LTZ and combination agents in patient-derived orthotopic xenograft (PDOX) immunodeficient (athymic nude) rats. Typically, such studies are performed utilizing athymic/SCID mice. However, the elimination half-life of LTZ in mice is short (~ 2.5 hours), whereas LTZ PK in rats are closer to that in humans requiring the use of athymic nude rats. Thus, we propose to conduct a quantitative milestone-based study employing primary and recurrent patient-derived GBM. We will rigorously test combination agents for LTZ, strongly suggested collectively by our RNAseq and other data and rationally advance 2-3 combinations for phase II clinical trials. Specific Aims: 1: Rank-order combination partners for LTZ based on synergistic effects against GBM lines in vitro 2: Determine in vivo BBB permeability of combination agents ± LTZ. 3: Establish PDOX athymic nude rat models for in vivo PK/PD studies, 4: Evaluate PK/PD of LTZ ± combination agent employing the PDOX models. The R61 phase milestones include synergistic inhibition of cell viability (Combination Index, CI< 1) and BBB permeability (plasma to brain partitioning) (Aims 1 and 2). Concurrently, an athymic nude rat models will be established/validated in Aim 3. Using these models in the R33 phase (Aim 4), dose-response relationship will be derived to advance 2-3 LTZ combinations to phase II clinical trials. A multidisciplinary team of collaborators will participate in this important next step to repurpose LTZ for GBM treatment, an urgent unmet medical need.

胶质母细胞瘤（GBM）是最致命的脑肿瘤之一，其预后仍然令人沮丧。我们的 最近的发现提供了强有力的证据表明来曲唑（LTZ）是一种芳香酶抑制剂，用于 乳腺癌的治疗，有可能成为治疗 GBM 的突破性疗法。我们的 数据包括：1) LTZ 治疗患者来源的 GBM 细胞显着降低细胞活力和球体生长； 2) LTZ 增强替莫唑胺 (TMZ) 的活性，替莫唑胺 (TMZ) 是用于 GBM 化疗的主要药物 TMZ- 耐药细胞； 3) 免疫活性大鼠的药代动力学/药效学（PK/PD）研究 原位植入 C6 大鼠神经胶质瘤显示 LTZ 很容易穿过血脑屏障 (BBB)， 显着减小肿瘤体积并延长生存期（对照与 LTZ 相比，生存期为 10 天，> 60 天）；和 4) 组织免疫组织化学分析（N > 90 名患者）表明芳香酶表达 相对于低级别神经胶质瘤，GBM 显着升高（> 5 倍）。此外，在一项正在进行的 0/1 期临床试验中 分析了哪些复发性 GBM 患者在手术切除前接受了 LTZ（2.5 -12.5 mg，N = 14 名受试者） 切除肿瘤的结果显示，LTZ 很容易穿过人类的血脑屏障。 RNAseq分析显示 显着下调驱动细胞增殖标志物的癌基因和上调肿瘤抑制 标记物（DNA损伤修复能力降低）以LTZ剂量依赖性方式。我们的长期目标是 将 LTZ 重新用作抗 GBM 药物。鉴于 GBM 表型/基因型的复杂性，联合治疗 将成为临床必需品。为了支持这一目标，我们的目标是进行全面的 PK/PD 研究 LTZ 和联合药物在患者来源的原位异种移植物 (PDOX) 免疫缺陷（无胸腺裸）中的作用 老鼠。通常，此类研究是利用无胸腺/SCID 小鼠进行的。然而，消除半衰期 小鼠中的 LTZ 较短（约 2.5 小时），而大鼠中的 LTZ PK 更接近人类，需要使用 无胸腺裸鼠。因此，我们建议进行一项基于里程碑的定量研究，采用主要和 复发性患者源性 GBM。我们将严格测试 LTZ 组合制剂，强烈建议 根据我们的RNAseq和其他数据，合理推进2-3个组合进行II期临床试验。 具体目标：1：LTZ 的排名顺序组合伙伴基于对 GBM 系的协同效应 体外2：确定组合药物±LTZ的体内BBB通透性。 3：建立PDOX无胸腺裸鼠 用于体内 PK/PD 研究的模型，4：使用 PDOX 模型评估 LTZ ± 组合药物的 PK/PD。 R61 阶段里程碑包括细胞活力的协同抑制（组合指数，CI < 1）和 BBB 渗透性（血浆到大脑的分配）（目标 1 和 2）。同时，将建立无胸腺裸鼠模型。 在目标 3 中建立/验证。在 R33 阶段（目标 4）使用这些模型，剂量反应关系将 推导2-3个LTZ组合进入II期临床试验。多学科合作团队 将参与这一重要的下一步，将 LTZ 重新用于 GBM 治疗，这是一项紧迫的未满足的医疗需求。