Clinical Development of First-in-Class Therapy for Metastatic Breast Cancer

转移性乳腺癌一流疗法的临床开发

• 批准号: 10631223
• 负责人: Zdravka O Medarova
• 金额: $ 87.07万
• 依托单位: TRANSCODE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10631223
• 关键词: Amination; Animals; Behavior; Biological Assay; Biopsy; Biopsy Specimen; Blood; Blood specimen; Brain; Breast Cancer Model; Breast Cancer Patient; Cancer Patient; Cells; Clinical; Clinical Research; Clinical Trials; Detection; Dextrans; Disease; Disseminated Malignant Neoplasm; Distant Metastasis; Dose; Drug Delivery Systems; Drug Kinetics; Human; Institutional Review Boards; Investigational Drugs; Investigational New Drug Application; Life; Lung; Magnetic Resonance Imaging; Malignant Neoplasms; Measures; Metastatic breast cancer; Methods; MicroRNAs; Mus; Neoplasm Metastasis; Operative Surgical Procedures; Organ; Pathology; Patient Selection; Patients; Phase; Phase I Clinical Trials; Positron-Emission Tomography; Primary Neoplasm; Prognosis; Protocols documentation; Quantitative Reverse Transcriptase PCR; RNA; Radiation therapy; Radiology Specialty; Recurrence; Reproducibility; Rodent; Sampling; Serum; Site; Specificity; Specimen; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Tissue Sample; Tissues; Toxicology; Work; bone; cancer type; chemotherapy; clinical development; clinical risk; cost; drug development; experimental study; imaging study; intravenous injection; iron oxide nanoparticle; lymph nodes; malignant breast neoplasm; mouse model; nanotherapeutic; neoplastic cell; novel therapeutic intervention; pharmacokinetics and pharmacodynamics; pharmacologic; phase 2 study; preclinical study; sensor; systemic toxicity; therapeutic development; therapeutic target; uptake

We have developed a new therapeutic approach that relies on specific eradication of metastatic tumor cells through pharmacological inhibition of miRNA-10b. miR-10b is a master regulator of the viability of metastatic tumor cells and has been thoroughly validated as a promising therapeutic target in over 100 clinical studies across 18 metastatic cancer types. The approach relies on a therapeutic agent that specifically inhibits microRNA-10b in metastatic cells. The therapeutic (termed MN-anti- miR10b) consists of ultrasmall dextran-coated iron oxide nanoparticles (MN), conjugated to antagomirs targeting miRNA-10b. In our preclinical studies, we found that the therapeutic is taken up avidly by metastatic tumor cells in the lymph nodes, lungs, bone, and brain, following intravenous injection. We demonstrated that the miR-10b inhibitory therapeutic could elicit durable regression of lymph node and distant metastases in mouse models of breast cancer with no evidence of systemic toxicity. Specifically, just four to six weekly treatments with MN-anti-miR10b in combination with low dose chemotherapy led to complete regression of detectable metastases. Following elimination of metastases, therapy was discontinued. No recurrence was observed for the natural life of the animals. In this application, we propose to perform key translational experiments including IND- enabling and IND-supported imaging studies that would assess the uptake of MN-anti-miR10b by radiologically confirmed metastatic lesions in breast cancer patients, as a final step before entry into phase I clinical trials.

我们已经开发了一种新的治疗方法，依赖于特异性根除转移性 肿瘤细胞通过药理学抑制miRNA-10 b。miR-10 b是一个主要的调节因子， 转移性肿瘤细胞的活力，并已被彻底验证为有前途的治疗靶点 在18种转移性癌症类型的100多项临床研究中。这种方法依赖于一种治疗方法， 在转移性细胞中特异性抑制microRNA-10 b的试剂。治疗（称为MN-抗- miR 10 b）由超小的葡聚糖包被的氧化铁纳米颗粒（MN）组成，其缀合至 靶向miRNA-10 b的药物。在我们的临床前研究中，我们发现， 在静脉内给药后，淋巴结、肺、骨和脑中的转移性肿瘤细胞贪婪地 注射我们证明了miR-10 b抑制治疗可以引起持久的消退， 淋巴结和远处转移的小鼠乳腺癌模型，没有全身性 毒性具体地说，仅用MN-抗miR 10 b与低剂量的miR 10 b联合治疗4至6周， 剂量化疗导致可检测到的转移完全消退。在消除 转移，停止治疗。在自然寿命内未观察到复发。 动物在本申请中，我们建议进行关键的翻译实验，包括IND- 启用和IND支持的成像研究，将评估MN-抗-miR 10 b的摄取， 在乳腺癌患者中，放射学证实的转移性病变，作为进入 I期临床试验。

项目成果

Radiolabeling and PET-MRI microdosing of the experimental cancer therapeutic, MN-anti-miR10b, demonstrates delivery to metastatic lesions in a murine model of metastatic breast cancer.

实验性癌症治疗剂 MN-anti-miR10b 的放射性标记和 PET-MRI 微剂量显示在转移性乳腺癌小鼠模型中可递送至转移性病灶。

• DOI: 10.1186/s12645-021-00089-5
• 发表时间: 2021
• 期刊: Cancer nanotechnology
• 影响因子: 5.7
• 作者: LeFur,Mariane;Ross,Alana;Pantazopoulos,Pamela;Rotile,Nicholas;Zhou,Iris;Caravan,Peter;Medarova,Zdravka;Yoo,Byunghee
• 通讯作者: Yoo,Byunghee