Novel small-molecule therapeutics for malignant peripheral nerve sheath tumor

项目摘要 恶性周围神经鞘膜瘤是一种罕见的肿瘤，预后相当差（5年生存率 <50%），并且是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的主要治疗手段，手术切除几乎不可能。对于不可切除或 对于转移性疾病，化疗药物仅略微有效（响应率<21%），并且初始 对治疗的反应通常是短暂的，复发率为40 - 65%，随后是快速进展和死亡。作为 因此，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 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，我们证明了半乳糖凝集素-1（Gal-1）是 Gal-1在人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，我们开发了一种新的抑制剂LLS2，它能够诱导细胞凋亡， MPNST细胞和抑制体内MPNST异种移植物的生长。考虑到这些结果，我们推断半乳糖凝集素-1是一种 LLS2是针对MPNST的极好的治疗靶点，并且LLS2是用于开发新的药物的极好的先导化合物。 治疗MPNST。为了提高LLS2的效力和生物利用度，我们合成了LLS2的焦点文库 根据预测的生物利用度。我们已经确定了一种新的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在体外和体内抑制肿瘤生长， MPNST，无毒性证据。在这项SBIR I期拟议研究中，我们将重点关注以下方面的临床前验证： LLS30作为一种新的有效的治疗剂对MPNST。这些研究的完成将使我们能够证明， LLS30有效地抑制原位异种移植小鼠模型中的MPNST生长，而对MPNST的生长没有不利影响。 周围的正常组织在后续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、规模扩大生产或cGMP生产）、制剂开发和IND- 使药理学和毒理学研究成为可能。第二阶段项目的最终可交付成果将是提交IND 向FDA申请进行人体I期临床试验。如果成功，我们的小分子Gal-1抑制剂LLS30， 一流的靶向癌症治疗，将对提高生存率和质量产生巨大影响 MPNST患者的寿命。

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.