Novel small-molecule therapeutics for malignant peripheral nerve sheath tumor

恶性周围神经鞘瘤的新型小分子疗法

基本信息

批准号：
10546921
负责人：
Tsung-Chieh Shih
金额：
$ 40万
依托单位：
KIBIO INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10546921
关键词：
Adverse effects Agreement Animals Apoptosis Award Binding Biological Assay Biological Availability Blood Brain California Cell Line Cell Proliferation Cessation of life Chemistry Clinic Clinical Clinical Data Comparative Pathology Connective Tissue Cyclic GMP Data Data Set Development Disease Dose Excision FDA approved Formulation Funding Galectin 1 Growth Guanosine Triphosphate Heart Histologic Human In Vitro Kidney Laboratories Lead Legal patent Libraries Literature Liver Lung Malignant Neoplasms Mass Spectrum Analysis Maximum Tolerated Dose Modeling Monitor Mus NOD/SCID mouse Nerve Nerve Tissue Neurofibromatosis 1 Neurofibrosarcoma Normal tissue morphology Operative Surgical Procedures Organ Pathway interactions Patients Pharmaceutical Preparations Pharmacology and Toxicology Phase Phase I Clinical Trials Prognosis Publishing Quality of life Rare Diseases Recurrence Research Role Route Schwann Cells Signal Transduction Signaling Molecule Small Business Innovation Research Grant Spleen Structure-Activity Relationship Survival Rate Systemic Therapy Therapeutic Therapeutic Agents Time Tissue Sample Toxic effect Tumor Cell Line Universities Unresectable Validation Western Blotting Xenograft Model Xenograft procedure analog antitumor agent attenuation cancer cell castration resistant prostate cancer clinically relevant cytotoxic cytotoxicity efficacy study first-in-human follow-up improved in vivo in vivo evaluation inhibitor innovation intraperitoneal invention knock-down manufacturing scale-up mouse model neoplastic cell neurofibroma new therapeutic target novel novel therapeutics overexpression patient derived xenograft model phase 2 study pre-clinical preclinical study rare cancer response scale up sciatic nerve small molecule small molecule inhibitor small molecule therapeutics targeted agent targeted cancer therapy therapeutic target treatment response tumor growth tumor progression tumor xenograft

项目摘要

PROJECT SUMMARY Malignant peripheral nerve sheath tumor (MPNST) is a rare tumor with a fairly poor prognosis (5-year survival of <50%) and is a leading cause of increased death for Neurofibromatosis type 1 patients. Although surgery to remove neurofibromas is the main treatment for MPNST, its complete surgical removal is almost impossible. For unresectable or metastatic diseases, chemotherapeutic drugs are only marginally effective (with a response rate of <21%), and initial responses to therapy are usually short-lived with a recurrence rate of 40-65%, followed by rapid progression and death. As such, 5-year overall survival rates remain low (the 5-year survival is <50%). Currently, there are no effective systemic therapies for MPNST patients. Therefore, novel efficacious therapeutic approaches are urgently needed. The Ras pathway is frequently activated in MPNST patients. In our published literature, we demonstrated that galectin-1 (Gal-1) is upregulated in human MPNST and that Gal-1 knockdown leads to the suppression of the Ras pathway, thereby inhibiting cancer cell proliferation. To target Gal-1, we developed a novel inhibitor LLS2 which was able to induce apoptosis in MPNST cells and suppress the growth of MPNST xenografts in vivo. Given these results, we reason that Galectin-1 is an excellent therapeutic target against MPNST, and that LLS2 is an excellent lead compound for the development of novel therapeutics against MPNST. To improve the potency and bioavailability of LLS2, we synthesized a focus library of LLS2 analogs according to predicted bioavailability. We have identified a new Gal-1 inhibitor, LLS30, which is more potent and safer than LLS2. Our preliminary studies have demonstrated that LLS30 suppresses tumor growth in vitro and in vivo against MPNST with no evidence of toxicity. In this SBIR Phase I proposed research, we will focus on the preclinical validation of LLS30 as a novel potent therapeutic agent against MPNST. Completion of these studies will allow us to demonstrate that LLS30 effectively suppresses MPNST growth in the orthotopic xenograft mouse model without adverse effects on the surrounding normal tissue. In the follow-up SBIR Phase II study, we will focus on LLS30 optimization, Chemistry, Manufacturing, and Control (CMC) activities (e.g., the development of master and working banks, purification development, CMC analytical development, scale-up manufacturing, or cGMP manufacturing), formulation development, and IND- enabling pharmacology and toxicology studies. The final deliverable of the Phase II project will be to submit an IND application to FDA for a human Phase I clinical trial. If successful, our small molecule inhibitor of Gal-1, LLS30, represents a first-in-class targeted cancer therapy that will have a tremendous impact on the improvement of survival rate and quality of life of patients with MPNST.

项目摘要恶性周围神经鞘肿瘤（MPNST）是一种罕见的肿瘤，预后较差（5年生存期的生存期5年 <50％），是神经纤维瘤病1型患者死亡增加的主要原因。尽管手术要去除神经纤维瘤是MPNST的主要治疗方法，几乎不可能进行完全的手术去除。对于无法切除或转移性疾病，化学治疗药物仅略有效（缓解率<21％），初始对治疗的反应通常是短暂的，复发率为40-65％，其次是快速进展和死亡。作为这样的5年总生存率仍然很低（5年生存率<50％）。目前，没有有效的系统性 MPNST患者的疗法。因此，迫切需要新颖的有效治疗方法。 RAS路径在MPNST患者中经常被激活。在我们发表的文献中，我们证明了galectin-1（gal-1）是在人类MPNST中上调，GAL-1敲低导致RAS途径的抑制，从而抑制癌细胞增殖。为了靶向gal-1，我们开发了一种新型的抑制剂LLS2，能够诱导凋亡 MPNST细胞并抑制体内MPNST异种移植的生长。鉴于这些结果，我们认为Galectin-1是优秀的针对MPNST的治疗靶标，而LLS2是开发新颖的铅化合物针对MPNST的治疗学。为了提高LLS2的效力和生物利用度，我们合成了LLS2的焦点库根据预测的生物利用度。我们已经确定了一种新的GAL-1抑制剂LLS30，该抑制剂更有效，并且比LLS2更安全。我们的初步研究表明，LLS30抑制了体外和体内肿瘤的生长 mpnst，没有毒性的证据。在SBIR阶段我提出的研究中，我们将重点介绍 LLS30是一种针对MPNST的新型有效治疗剂。这些研究的完成将使我们能够证明 LLS30有效地抑制了原位异种移植小鼠模型中的MPNST生长周围正常组织。在后续SBIR II期研究中，我们将重点介绍LLS30优化，化学，制造和控制（CMC）活动（例如，硕士和工作银行的发展，净化开发， CMC分析开发，扩大制造或CGMP制造），配方开发和索引启用药理学和毒理学研究。第二阶段项目的最终交付将是提交IND 应用于FDA进行人类I期临床试验。如果成功，我们的小分子抑制剂是Gal-1，LLS30，代表一流的目标癌症治疗，将对生存率和质量的提高产生巨大影响 MPNST患者的寿命。