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

Award Number: UH3CA244687
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $770,000 )
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	5	8/25/2023	NON-COMPETING CONTINUATION	$770,000
														Subtotal = $770,000

Issue Date FY: 2022 ( Subtotal = $770,001 )
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	001	4	7/8/2022	NON-COMPETING CONTINUATION	$608,196
2022	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	3	12/20/2021	EXTENSION WITH OR WITHOUT FUNDS	$161,805
														Subtotal = $770,001

Issue Date FY: 2021 ( Subtotal = $770,000 )
2021	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	3	9/10/2021	EXTENSION WITH OR WITHOUT FUNDS	$770,000
														Subtotal = $770,000

Grand Total All Awards = $2,310,001

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

Award Number: UH3CA244687

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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