Novel small-molecule therapeutics for malignant peripheral nerve sheath tumor

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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.