Tumor Antigen Targeted Nanoparticle Therapy for Glioblastoma (GBM)

肿瘤抗原靶向纳米颗粒治疗胶质母细胞瘤 (GBM)

• 批准号: 10706449
• 负责人: JON Owen NAGY
• 金额: $ 40万
• 依托单位: NANOVALENT PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-08 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10706449
• 关键词: Adult; Age; Animals; Antibodies; Antibody-drug conjugates; Antigen Targeting; Antigens; Antineoplastic Agents; Binding; Biological Availability; Blood - brain barrier anatomy; Body Weight; Bone Marrow; Brain; Brain Neoplasms; Cancer Patient; Caring; Cause of Death; Cell surface; Cells; Central Nervous System Neoplasms; Cerebrovascular system; Chemotherapy-Oncologic Procedure; Circulation; Clinic; Cytotoxic agent; Data; Dose; Drug Delivery Systems; Drug Targeting; Drug toxicity; Drug usage; Encapsulated; Extracellular Domain; Failure; Formulation; Gender; Glioblastoma; Goals; Hour; Human; Hybrids; Implant; In Vitro; Incidence; Injections; Legal patent; Life; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Metastatic malignant neoplasm to brain; Methods; Mission; Morbidity - disease rate; Mus; Nanotechnology; Neoplasm Metastasis; Normal tissue morphology; Patients; Pediatric Neoplasm; Pharmaceutical Preparations; Phase; Plasma; Primary Neoplasm; Reproducibility; Resistance; Resources; SEER Program; SN-38; Safety; Small Business Technology Transfer Research; Surface; Survival Rate; Systemic Therapy; Technology; Therapeutic; Time; Tissues; Toxic effect; Transcript; Translating; Tumor Antigens; Tumor Burden; Xenograft procedure; antibody conjugate; antitumor effect; blood-brain barrier crossing; blood-brain barrier penetration; blood-brain tumor barrier; cBioPortal; cancer cell; cancer therapy; care costs; chemotherapeutic agent; chemotherapy; comparative efficacy; cost; curative treatments; effective therapy; epidermal growth factor receptor VIII; high risk; human model; improved; in vivo; irinotecan; manufacture; mortality; mouse model; nanoparticle; nanoparticle drug; nanopolymer; nanoscale; neoplastic cell; novel; particle; pharmacokinetics and pharmacodynamics; preclinical development; prevent; small molecule; success; targeted treatment; therapeutic nanoparticles; tumor; tumor growth; tumor heterogeneity

Project Summary The goal of this Fast Track STTR project is to determine proof-of-principle and efficacy of a novel blood brain barrier (BBB) penetrating therapeutic nanoparticle for the potential treatment of otherwise intractable brain tumors like glioblastoma multiforme (GBM). This project seeks to demonstrate that novel, targetable nanoparticles can delivery therapeutic substances to human brain tumor cells and reduce tumor burden in brain cancer and prolong patient survival. The therapeutic cargos are encapsulated cytotoxic drugs for otherwise intractable brain tumors. After exiting the brain vasculature, upon recognition by the tumor cell, the nanoparticle binds, gets taken into the cell (endocytosed) and the nanoparticle cargo is released, ultimately allowing availability of the drug to kill the cancer cell. This project fits well within the mission of the NCI, to develop new nanotechnology-based therapeutics, especially for high-risk tumors. Historically successful cancer chemotherapy, while vastly increasing survival in non- CNS tumors, has failed to do so for brain tumors in children and adults alike. GBM remains the most malignant primary central nervous system tumor, where the median overall survival is 15–23 months and 5-year survival is less than 6%. The incidence of brain metastases is increasing with an estimated 69,950 adults age 40+ in 2021 in the US alone. Brain tumors represent the highest per-patient initial cost of care for any cancer group. Estimations from Surveillance, Epidemiology, and End Results (SEER) on annualized mean net cost of care approach $150,000 per patient. These patients have the highest annualized mean net costs for last-year-of-life care, relative to other cancers, at $135,000 to $210,000 (depending on age and gender). There us thus dramatic unmet need to prevent morbidity and mortality while improving an otherwise dismal survival rate. Treatment-resistant metastases are the ultimate cause of death in most cancer patients. For brain cancer treatment, systemic therapy for metastases is generally ineffective due to the inability to get therapeutic doses across the blood brain barrier. A reliable, low- toxic, highly effective therapy is urgently needed to treat patients with primary tumors and treatment-resistant metastases. The specific aims of this proposal are therefore efficient encapsulation cancer drugs inside the targeted HPLNs that cross the blood brain barrier, demonstrate safety and efficacy in killing cancer cells in a spectrum of humanized xenograft mouse models of human GBM. NanoValent's goal, at the conclusion of the Fast Track proposal is to have a promising optimized formulation that can be that can ultimately be GMP manufactured and submitted for IND approval with the FDA.

项目摘要 这个快速通道STTR项目的目标是确定原理验证和有效性 一种新的血脑屏障（BBB）穿透治疗纳米粒子的潜力 治疗其他难治性脑肿瘤，如多形性胶质母细胞瘤（GBM）。这 该项目旨在证明，新的，可靶向的纳米粒子可以提供 治疗物质对人脑肿瘤细胞的作用，并减少脑中的肿瘤负荷 癌症和延长患者生存期。治疗货物是包封的细胞毒性 治疗难治性脑肿瘤的药物在离开脑血管系统后， 被肿瘤细胞识别后，纳米颗粒结合，进入细胞 （内吞）并且纳米颗粒货物被释放，最终允许纳米颗粒的可用性。 杀死癌细胞的药物该项目非常符合NCI的使命， 开发基于纳米技术的新疗法，特别是针对高危肿瘤。 历史上成功的癌症化疗，同时大大提高了非癌症患者的生存率， 中枢神经系统肿瘤，没有这样做的脑肿瘤在儿童和成人一样。GBM 仍然是最恶性的原发性中枢神经系统肿瘤， 总生存期为15-23个月，5年生存率低于6%。的发生率 脑转移正在增加，2021年估计有69，950名40岁以上的成年人， 我们清静一点.脑肿瘤代表了任何疾病中最高的每位患者初始护理成本。 癌症组。监测、流行病学和最终结果（SEER） 年平均净护理成本接近每名患者150，000美元。这些患者具有 相对于其他癌症，最后一年护理的最高年平均净成本， $135，000至$210，000（视年龄及性别而定）。我们就这样戏剧性地 需要预防发病率和死亡率，同时提高本来就很低的存活率。 耐药转移是大多数癌症患者死亡的最终原因。 对于脑癌的治疗，由于肿瘤的转移，全身治疗通常是无效的。 治疗剂量无法通过血脑屏障一个可靠的，低- 目前，对原发性肿瘤患者的治疗迫切需要一种毒性高、疗效好的治疗方法 和耐药转移。因此，这项建议的具体目标是 在穿过血液的靶向HPLN内有效封装癌症药物 脑屏障，证明在杀死癌细胞的范围内的安全性和有效性。 人GBM的人源化异种移植小鼠模型。NanoValent的目标，在 快速通道建议的结论是具有有希望的优化配方， 最终可以进行GMP生产并提交IND批准， FDA。