Saturday, September 7, 2024 9/7/2024

High-risk HPV E6: dysregulation of immortalization, growth, and differentiation through protein partnerships in HPV-associated cancers

Award Number: R01CA172742
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By:

View Award Abstract

PROJECT SUMMARY/ABSTRACT High-risk human papillomaviruses (HR HPVs) cause 5% of all cancers. There are preventive vaccines against HPV, but less than 2% of the world's target population has received them. This leaves millions of women and men at risk for HPV-associated cervical, anogenital, and head and neck cancers. We need to understand how HR HPV establishes and maintains an active infection, while also driving cancer development, in order to guide focused therapeutic interventions to prevent, arrest, and reverse disease. The greatest clinical risk factor for cervical cancer is a persistent HR HPV infection. This persistence occurs through coordinated dysregulation of cellular pathways, which both support the infection and foster cancer development. Underlying this dysregulation is the requirement that the HPV oncogenes E6 and E7 partner with cellular proteins. Our work has focused on the E6 oncogene from HPV type 16 (16E6), the most common HR HPV type in cancers. Previously, we found that 16E6 required the cellular protein NFX1-123, and its protein partners cytoplasmic poly(A) binding proteins (PABPCs), to fully activate telomerase and the immortalization pathway. Our current studies revealed that NFX1-123 is highly expressed in cervical cancers, and together 16E6, NFX1-123, and PABPCs amplify telomerase, cellular growth, and longevity over time. We also discovered that NFX1-123 is increased during differentiation and, together with 16E6, augments cellular differentiation cascades and their host and viral gene targets while simultaneously protecting against concomitant cellular arrest and senescence. These findings create a sightline for a new level of investigation that will uncover the connectivity and control of growth and differentiation and the temporal changes driving and accelerating immortalization by PABPCs, NFX1-123, and 16E6. These results will also delineate targets for future treatments that specifically disrupt universal pathways required for HPV and its cancers. Our specific aims are: (1) Determine how 16E6, NFX1-123, and PABPCs work together in co-regulating growth and differentiation to better establish a persistent infection. We will mimic the initial steps of establishing a HR HPV infection to identify the way in which these proteins function to permit both differentiation and growth in concert during the initial, foundational steps of a HR HPV infection. (2) Elucidate the mechanism of longitudinal, sequential increases of hTERT and telomerase by 16E6, NFX1-123, and PABPCs. Telomerase activation leads to cellular immortalization. We will leverage long-term cellular studies to determine the sequential changes to hTERT, the catalytic subunit of telomerase, due to 16E6 with NFX1-123 and PABPCs and to create a roadmap of molecular oncogenic progression that mirrors clinical chronology. Our proposed studies will elucidate the temporal and interwoven dysregulation of oncogenic pathways by 16E6 and its host protein partners; they will also provide foundational data on the oncogenic etiology and progression of increasingly common HPV- associated cancers.


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: 2024 ( Subtotal = $425,778 )
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	000	11	6/17/2024	NON-COMPETING CONTINUATION	$357,616
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	001	11	6/18/2024	SUPPLEMENT FOR EXPANSION	$68,162
														Subtotal = $425,778

Issue Date FY: 2023 ( Subtotal = $439,224 )
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	000	10	4/25/2023	NON-COMPETING CONTINUATION	$368,909
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	001	10	5/1/2023	SUPPLEMENT FOR EXPANSION	$70,315
														Subtotal = $439,224

Issue Date FY: 2022 ( Subtotal = $436,042 )
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	000	9	5/13/2022	NON-COMPETING CONTINUATION	$368,909
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	001	9	8/24/2022	SUPPLEMENT FOR EXPANSION	$67,133
														Subtotal = $436,042

Issue Date FY: 2021 ( Subtotal = $376,438 )
2021	2021	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	002	8	5/19/2021	NON-COMPETING CONTINUATION	$376,438
2021	2020	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	001	7	10/16/2020	COMPETING CONTINUATION	$85,269
2021	2018	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Cause and Prevention Research	000	6	10/16/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$85,269
														Subtotal = $376,438

Issue Date FY: 2020 ( Subtotal = $376,438 )
2020	2020	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	000	7	5/13/2020	COMPETING CONTINUATION	$318,779
2020	2020	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	003	7	6/17/2020	COMPETING CONTINUATION	$57,659
2020	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND PT WAY NE	SEATTLE	WA	98105	KING	USA	Cancer Cause and Prevention Research	001	5	6/2/2020	NON-COMPETING CONTINUATION	-$85,269
2020	2018	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Cause and Prevention Research	002	6	6/2/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$85,269
														Subtotal = $376,438

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Cause and Prevention Research	001	6	2/7/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$314,843
2019	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Cancer Cause and Prevention Research	000	5	2/7/2019	NON-COMPETING CONTINUATION	-$314,843
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $402,550 )
2018	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Cancer Cause and Prevention Research	000	5	4/20/2018	NON-COMPETING CONTINUATION	$402,550
														Subtotal = $402,550

Issue Date FY: 2017 ( Subtotal = $402,550 )
2017	2017	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Cancer Cause and Prevention Research	000	4	5/22/2017	NON-COMPETING CONTINUATION	$402,550
														Subtotal = $402,550

Issue Date FY: 2016 ( Subtotal = $402,550 )
2016	2016	SEATTLE CHILDREN`S HOSPITAL	4800 SAND POINT WAY NORTHEAST	SEATTLE	WA	98105	KING	USA	Cancer Cause and Prevention Research	000	3	4/21/2016	NON-COMPETING CONTINUATION	$402,550
														Subtotal = $402,550

Issue Date FY: 2015 ( Subtotal = $402,550 )
2015	2015	SEATTLE CHILDREN`S HOSPITAL	4800 SAND POINT WAY NORTHEAST	SEATTLE	WA	98105	KING	USA	Cancer Cause and Prevention Research	000	2	4/6/2015	NON-COMPETING CONTINUATION	$402,550
														Subtotal = $402,550

Issue Date FY: 2014 ( Subtotal = $402,550 )
2014	2014	SEATTLE CHILDREN`S HOSPITAL	4800 SAND POINT WAY NORTHEAST	SEATTLE	WA	98105	KING	USA	Cancer Cause and Prevention Research	000	1	6/4/2014	NEW	$402,550
														Subtotal = $402,550

Grand Total All Awards = $4,066,670

Top

All Categories

About

Search

Reports

Data Submission

Award Information

High-risk HPV E6: dysregulation of immortalization, growth, and differentiation through protein partnerships in HPV-associated cancers

Award Number: R01CA172742

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer