# IGNITE: Development of novel cyclophilin B/PIKfyve inhibitors for treatment of Malignant Peripheral Nerve Sheath Tumors

> **NIH NIH R61** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2020 · $1,005,666

## Abstract

PROJECT SUMMARY
Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are highly aggressive soft tissue sarcomas that arise
from peripheral nerves or the cells associated with nerve sheaths. They develop with high frequency in patients
with neurofibromatosis (NF1), and also sporadically in the general population or as a secondary malignancy
following radiation treatment. These tumors have high rates of metastasis to distant organs, and do not
respond adequately to standard chemotherapy or radiation. The only curative method involves wide surgical
excision. However, MPNSTs typically reside in close proximity to critical structures or present with metastatic
disease, and therefore are not often amenable to surgical cure. Improved therapies for MPNSTs are urgently
needed to improve survival rates and quality of life.
We previously reported that the intracellular chaperone cyclophilin B (CypB) plays a critical role in supporting
the survival of many tumors, particularly those of the nervous system, including Glioblastoma multiforme
(GBM). Knockdown or small molecule inhibition of CypB caused tumor cell death through a non-apoptotic
mechanism characterized by massive cytosolic vacuolization. In new work, we have conducted a high
throughput screen to search for novel CypB binding compounds with improved anti-cancer activity. One
compound, “MLS042”, was significantly more effective than previously characterized CypB inhibitors, and was
used as a lead compound to generate a family of related molecules. The most active, “SBI298”, forms the
basis for this proposal. MLS042 and SBI298 have selective cytotoxic activity against a range of tumor cell
types. Of the tumor types we have tested to date, MPNST cells have the highest sensitivity to cell killing by
MLS042 and SBI298. Preliminary tests in mice reveal that these compounds are relatively well tolerated, thus
leading to the central hypothesis of this application that SBI298 will prove to be safe and effective as a new
therapeutic agent for treatment of MPNST in preclinical testing. The goal of this proposal is to conduct
preclinical in vitro and in vivo testing of SBI298 and a focused set of related analogs to demonstrate that it has
sufficient biological activity to warrant further development for treatment of MPNST. We anticipate that these
studies will validate the significant roles of CypB and PIKfyve in tumor cell survival, and will lead to a new,
highly effective therapeutic for MPNST and potentially for other malignancies, as well.
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## Key facts

- **NIH application ID:** 9878705
- **Project number:** 1R61NS111085-01A1
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** Richard J Bram
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,005,666
- **Award type:** 1
- **Project period:** 2019-12-15 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878705

## Citation

> US National Institutes of Health, RePORTER application 9878705, IGNITE: Development of novel cyclophilin B/PIKfyve inhibitors for treatment of Malignant Peripheral Nerve Sheath Tumors (1R61NS111085-01A1). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/9878705. Licensed CC0.

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