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HPV and host factors in juvenile onset recurrent respiratory papillomatosis

Award Number: R01CA287486
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/05/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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HPV and host factors in juvenile onset recurrent respiratory papillomatosis - ABSTRACT. Patients with juvenile-onset recurrent respiratory papillomatosis (JoRRP) suffer from recurring epithelial papillomas along the respiratory tract caused by low-risk H PV viruses, predominantly H PV6. This most common benign neoplasm in children varies significantly in clinical course. Patients undergo an average of 4-5 surgeries in the first year post-diagnosis, and severe cases can result in hundreds of surgeries and progression to cancer. The lack of effective medications significantly lowers the quality of life for children with RRP, and highlights the need for new biomarkers and therapies. To develop therapeutics and prognostic markers requires overcoming a deep gap in knowledge of viral and host cell factors that produce papillomas (ie, candidate targets and markers). This is now possible thanks to the development of models of normal and JoRRP 3D stratified squamous epithelium (SE). Using fresh tumor and matched nondiseased (ND) tissue from children with JoRRP, we generated primary monolayer keratinocytes, which we then engineered into organotypic epithelial rafts. With this established pipeline of internally controlled 2D/3D models, we have made significant strides. Our global transcriptome analyses of 2D JoRRP/ND keratinocytes defined a JoRRP-specific EMT-like disease signature, which we validated in rafts and patient specimens. Single-cell RNA sequencing (scRNAseq) of HPV6+ RRP specimens (vs matched HPV- ND controls) further uncovered 16 transcriptionally distinct keratinocyte subpopulations (clusters C0-15). CS bears striking similarity to our recently published cancerassociated HI ODEN subpopulation induced by high-risk HPV16. Both are located in superficial layers where H PV amplification occurs, and both share biomarkers including the ELF3 transcription factor, which is required for HIDDEN formation. Our new data show that the HPV16 E6/E7 oncogenes are sufficient to induce HI ODEN, suggesting that conserved HPV6 E6/E7 activities might induce analogous subpopulations at the epithelial surface. In Aim1, we test whether and how HPV6 E6 and/or E? induce CS, and whether CS is required for viral progeny production. Our scRNAseq data also revealed striking abundance of HPV6 E5γ and δ transcripts across clusters, indicating importance for viral processes and/or keratinocyte phenotypes. While functions of low-risk HPV E5γ/δ proteins are unstudied in translational disease models, HPV6 E5γ was reported to bind the EGFR and ERBB2 receptor tyrosine kinases. In Aim2, we test whether HPV6 E5γ and/or E5δ sustain JoRRP phenotypes, and whether they do so, at least in part, via EGFR/ERBB2 signaling.


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: 2026 ( Subtotal = $1,340,183 )
2026	2026	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cancer Biology Research	003	3	9/18/2026	EXTENSION WITH OR WITHOUT FUNDS	$0
2026	2026	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cancer Biology Research	001	3	6/19/2026	EXTENSION WITH OR WITHOUT FUNDS	$1,340,183
2026	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cancer Biology Research	002	2	8/31/2026	NON-COMPETING CONTINUATION	$0
2026	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cancer Biology Research	000	2	6/18/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,340,183

Issue Date FY: 2025 ( Subtotal = $446,728 )
2025	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cancer Biology Research	000	2	6/18/2025	NON-COMPETING CONTINUATION	$446,728
														Subtotal = $446,728

Issue Date FY: 2024 ( Subtotal = $446,728 )
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cancer Biology Research	000	1	7/5/2024	NEW	$446,728
														Subtotal = $446,728

Grand Total All Awards = $2,233,639

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HPV and host factors in juvenile onset recurrent respiratory papillomatosis

Award Number: R01CA287486

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/05/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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