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 removeneurofibromas is the main treatment for MPNST, its complete surgical removal is almost impossible. For unresectable ormetastatic diseases, chemotherapeutic drugs are only marginally effective (with a response rate of <21%), and initialresponses to therapy are usually short-lived with a recurrence rate of 40-65%, followed by rapid progression and death. Assuch, 5-year overall survival rates remain low (the 5-year survival is <50%). Currently, there are no effective systemictherapies for MPNST patients. Therefore, novel efficacious therapeutic approaches are urgently needed. The Ras pathwayis frequently activated in MPNST patients. In our published literature, we demonstrated that galectin-1 (Gal-1) isupregulated in human MPNST and that Gal-1 knockdown leads to the suppression of the Ras pathway, thereby inhibitingcancer cell proliferation. To target Gal-1, we developed a novel inhibitor LLS2 which was able to induce apoptosis inMPNST cells and suppress the growth of MPNST xenografts in vivo. Given these results, we reason that Galectin-1 is anexcellent therapeutic target against MPNST, and that LLS2 is an excellent lead compound for the development of noveltherapeutics against MPNST. To improve the potency and bioavailability of LLS2, we synthesized a focus library of LLS2analogs according to predicted bioavailability. We have identified a new Gal-1 inhibitor, LLS30, which is more potent andsafer than LLS2. Our preliminary studies have demonstrated that LLS30 suppresses tumor growth in vitro and in vivo againstMPNST with no evidence of toxicity. In this SBIR Phase I proposed research, we will focus on the preclinical validation ofLLS30 as a novel potent therapeutic agent against MPNST. Completion of these studies will allow us to demonstrate thatLLS30 effectively suppresses MPNST growth in the orthotopic xenograft mouse model without adverse effects on thesurrounding 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 INDapplication to FDA for a human Phase I clinical trial. If successful, our small molecule inhibitor of Gal-1, LLS30, representsa first-in-class targeted cancer therapy that will have a tremendous impact on the improvement of survival rate and qualityof life of patients with MPNST.
Public Health Relevance Statement: PROJECT NARRATIVE
Currently, there are no effective systemic therapies for malignant peripheral nerve sheath tumor (MPNST), an
aggressive form of cancer of the connective tissue surrounding nerves. MPNST is a malignant tumor with low survival rate
(5-year survival of <50%). We have demonstrated that inhibition of a key cancer signaling molecule, Galectin-1, is a
promising therapeutic approach against MPNST. Kibio is investigating a novel Galectin-1 inhibitor which is non-toxic and
efficacious in an MPNST xenograft model, which we will study further in this project. This novel Galectin-1 inhibitor has
potential to be a promising antitumor agent for MPNST therapy.
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