# Recurrent Tumor-Specific Alternately Processed Transcripts as a Source of Neoantigens for NF1-associated Malignant Peripheral Nerve Sheath Tumor Immunoprevention

> **NIH NIH UG3** · UNIVERSITY OF MINNESOTA · 2020 · $761,618

## Abstract

Abstract/Summary
Neurofibromatosis type 1 (NF1) syndrome is an autosomal dominant tumor predisposition syndrome that is
caused by loss-of-function mutations of NF1 gene encoding neurofibromin. Among patients with NF1, loss of
the non-mutant allele of NF1 in a rare Schwann cell or precursor, along with other ill-defined factors, leads to
benign dermal or plexiform neurofibromas. The main cause of death among NF1 patients is the malignant
peripheral nerve sheath tumor (MPNST), a highly aggressive soft tissue sarcoma that most likely develops
from plexiform neurofibroma, in particular the so-called “atypical” plexiform neurofibroma. Approximately half of
MPNSTs are NF1-associated, and NF1 patients have 10-15% lifetime risk of developing this terrible cancer.
MPNSTs metastasize early and are often resistant to radiotherapy and chemotherapy. The main treatment for
MPNSTs is surgical resection but, despite radical excision with wide surgical margins, followed by
chemoradiation, 5-year survival rates are poor due to metastases as well as local recurrence. NF1 patients
could greatly benefit from prophylactic vaccination that would prevent the malignant transformation of benign
plexiform neurofibromas into “atypical” plexiform neurofibromas and to MPNSTs. We aim to determine if the
mutations that govern the development of “atypical” plexiform neurofibroma (NF1 loss followed by CDKN2A
loss) and MPSNT (NF1, CDKN2A, and SUZ12 loss) lead to the expression of recurrent alternately processed
transcripts, such as transcriptionally-induced chimeras, that could express neoantigens and be used as targets
for prophylactic vaccines. Such transcripts can be translated to produce novel peptides downstream of
frameshift mutations caused by coding exon read-through into introns, mis-splicing from a coding exon to a
non-canonical splice acceptors or splice acceptors in other genes. In most cases, a premature termination
codon (PTC) will be rapidly encountered by the ribosome translating such transcripts. Therefore, we
furthermore hypothesize that these alternately processed transcripts can express what we call “cryptic”
neoantigens when treated with drugs that suppress utilization of premature codons such as Ataluren or
gentamycin. In such a way, we could administer a prophylactic vaccine and induce conditionally active immune
response that would eliminate nascent tumors only when drug treatment is used.

## Key facts

- **NIH application ID:** 10023258
- **Project number:** 5UG3CA244687-02
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** DAVID ANDREW LARGAESPADA
- **Activity code:** UG3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $761,618
- **Award type:** 5
- **Project period:** 2019-09-25 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10023258

## Citation

> US National Institutes of Health, RePORTER application 10023258, Recurrent Tumor-Specific Alternately Processed Transcripts as a Source of Neoantigens for NF1-associated Malignant Peripheral Nerve Sheath Tumor Immunoprevention (5UG3CA244687-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10023258. Licensed CC0.

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