Novel small-molecule therapeutics for malignant peripheral nerve sheath tumor

项目总结 恶性周围神经鞘瘤(MPNST)是一种罕见的肿瘤，预后较差。 50%)，是导致1型神经纤维瘤病患者死亡增加的主要原因。虽然要做手术切除 神经纤维瘤是MPNST的主要治疗方法，完全手术切除几乎是不可能的。对于不能切除或 对于转移性疾病，化疗药物仅有轻微疗效(应答率为21%)，最初 对治疗的反应通常是短暂的，复发率为40%-65%，紧随其后的是快速进展和死亡。AS 这样，5年总体存活率仍然很低(5年存活率为50%)。目前，还没有一个有效的系统 MPNST患者的治疗。因此，迫切需要新的有效的治疗方法。RAS途径 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MPNST中上调，Gal-1基因敲除导致RAS途径抑制，从而抑制 癌细胞增殖。针对Gal-1，我们开发了一种新的抑制剂LLS2，它能够诱导细胞凋亡 并在体内抑制MPNST移植瘤的生长。鉴于这些结果，我们推断Galectin-1是一种 抗MPNST的良好靶点，LLS2是开发新型药物的良好先导化合物 针对MPNST的治疗。为了提高LLS2的效价和生物利用度，我们合成了LLS2的焦点文库 根据预测的生物利用度进行类比。我们已经发现了一种新的Gal-1抑制剂LLS30，它更有效， 比LLS2更安全。我们的初步研究表明，LLS30在体外和体内都能抑制肿瘤的生长。 MPNST，没有毒性证据。在这项SBIR第一阶段拟议的研究中，我们将重点放在临床前验证 LLS30作为一种治疗MPNST的新型有效药物。这些研究的完成将使我们能够证明 LLS30有效抑制异种小鼠原位移植模型中MPNST的生长 周围的正常组织。在后续的SBIR第二阶段研究中，我们将重点关注LLS30优化、化学、 制造和控制(CMC)活动(例如，开发主银行和工作银行、净化开发、 CMC分析开发、放大制造或cGMP制造)、配方开发和工业- 使药理学和毒理学研究成为可能。第二阶段项目的最终交付成果将是提交IND 向FDA申请进行人体I期临床试验。如果成功，我们的Gal-1小分子抑制剂LLS30代表 一流的肿瘤靶向治疗，将对提高存活率和质量产生巨大影响 对MPNST患者生活质量的影响。

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.