# Novel small-molecule therapeutics for malignant peripheral nerve sheath tumor

> **NIH NIH R43** · KIBIO INC. · 2022 · $400,000

## Abstract

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.

## Key facts

- **NIH application ID:** 10546921
- **Project number:** 1R43CA271932-01A1
- **Recipient organization:** KIBIO INC.
- **Principal Investigator:** Tsung-Chieh Shih
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $400,000
- **Award type:** 1
- **Project period:** 2022-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10546921

## Citation

> US National Institutes of Health, RePORTER application 10546921, Novel small-molecule therapeutics for malignant peripheral nerve sheath tumor (1R43CA271932-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10546921. Licensed CC0.

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