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

• 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
• 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

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.

项目概要 恶性周围神经鞘瘤（MPNST）是一种罕见的肿瘤，预后相当差（5 年生存率） <50%），是 1 型神经纤维瘤病患者死亡增加的主要原因。虽然手术切除 神经纤维瘤是MPNST的主要治疗方法，其完全手术切除几乎是不可能的。对于不可切除或 转移性疾病、化疗药物仅具有微弱效果（有效率<21%），并且初始治疗 对治疗的反应通常是短暂的，复发率为 40-65%，随后迅速进展并死亡。作为 因此，5年总生存率仍然很低（5年生存率<50%）。目前尚无有效的系统性措施 MPNST 患者的治疗。因此，迫切需要新的有效的治疗方法。 Ras途径 MPNST 患者中经常被激活。在我们发表的文献中，我们证明半乳糖凝集素-1 (Gal-1) 是 在人类 MPNST 中表达上调，Gal-1 敲低会导致 Ras 通路受到抑制，从而抑制 癌细胞增殖。为了靶向 Gal-1，我们开发了一种新型抑制剂 LLS2，它能够诱导细胞凋亡 MPNST 细胞并抑制体内 MPNST 异种移植物的生长。鉴于这些结果，我们推断 Galectin-1 是一种 抗 MPNST 的优秀治疗靶点，LLS2 是开发新型药物的优秀先导化合物 针对 MPNST 的治疗。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的类似物。我们已经鉴定出一种新的 Gal-1 抑制剂 LLS30，它更有效且更有效。 比 LLS2 更安全。我们的初步研究表明，LLS30 可在体外和体内抑制肿瘤生长 MPNST 没有毒性证据。在本次 SBIR 第一阶段拟议研究中，我们将重点关注以下药物的临床前验证： LLS30 作为一种新型有效的 MPNST 治疗剂。完成这些研究将使我们能够证明 LLS30 有效抑制原位异种移植小鼠模型中的 MPNST 生长，而不会对 周围正常组织。在后续的SBIR II期研究中，我们将重点关注LLS30优化、化学、 制造和控制 (CMC) 活动（例如，主库和工作库的开发、净化开发、 CMC 分析开发、放大生产或 cGMP 生产）、配方开发和 IND- 促进药理学和毒理学研究。第二阶段项目的最终成果将是提交 IND 向 FDA 申请人体 I 期临床试验。如果成功，我们的 Gal-1 小分子抑制剂 LLS30 代表 一流的靶向癌症治疗将对生存率和质量的提高产生巨大影响 MPNST 患者的生活。