Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Autophagy-mediated immune responses to oncolytic VSV

Award Number: R21CA192185
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2014
PERIOD OF PERFORMANCE END DATE: 11/30/2017

Group Awards By:

View Award Description

Autophagy-mediated immune responses to oncolytic VSV - ¿ DESCRIPTION (provided by applicant): We propose to investigate the role of autophagy in facilitating synergistic increase in oncolytic activity of vesicular stomatitis virus (VSV) in combination with the FDA-approved histone deacetylase inhibitor vorinostat. Vorinostat reversibly sensitizes hormone-refractory prostate cancer cells to oncolysis; transcriptome and biochemical analysis of PC3 prostate cancer cells identified NF-kB-mediated upregulation of the autophagic pathway as a potential mechanism responsible for suppression of the antiviral response and potentiation of VSV oncolysis (Shulak et al, J. Virol, 2014). Our hypothesis is that host genes involved in distinct stages of autophagosome formation contribute to vorinostat-mediated blocking of antiviral signalling, thus facilitating increased VSV replication and stimulation of adaptive immune responses during oncolysis. Our specific aims are: 1. To evaluate autophagosome formation and examine the role of key autophagic proteins in vorinostat-dependent potentiation of VSV oncolysis. Genes that regulate canonical stages of autophagosome formation - a) initiation, b) nucleation, c) elongation and closure, and d) recycling - will be knocked-down with siRNA to determine which steps of the autophagic pathway contribute to synergy. Following gene knockdown, cells will be treated with vorinostat and infected with VSV; mRNA levels of various pro-inflammatory cytokines and other molecules with roles in innate responses and autophagic pathway will be measured by a nanofluidic BioMarkTM assay. In addition, the crosstalk between autophagy and apoptosis will be assessed by examining the stability of the BCL-2/BECLIN1 complex using immunoprecipitation and by determining the effect of either knockdown or overexpression of BCL-2 and BECLIN1 on VSV oncolysis and innate immune responses. 2. To examine the contribution of autophagy to innate and adaptive immune responses in a murine model of prostate cancer. The contribution of vorinostat-induced autophagy to immune responses will be examined in the immunocompetent TRAMP-C2 model of prostate cancer. Co-administration of the autophagy inhibitor hydroxychloroquine (HCQ) will be used to inhibit autophagy in vivo. Immune responses to vorinostat + VSV +/- HCQ will be assessed by enumeration of tumor infiltrating immune cells and by measuring mRNA levels of antiviral proteins. Changes in adaptive immune responses will be assessed using tumor cell lysate- pulsed dendritic cells. Such cells will be used to measure T cell priming to tumor antigens in CD4+ T cells (IFNg production) and to measure cytolytic activity in CD8+ T cells by assessing the intracellular levels of perforin and granzyme B in treated mice. Altogether this project will define the role autophagy plays in potentiation of VS oncolysis and in modulation of innate and adaptive responses to vorinostat + VSV combination.


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: 2018 ( Subtotal = $0 )
2018	2017	ISTITUTO PASTEUR ITALIA FONDAZIONE CENCI BOLOGNETTI	VIALE REGINA ELENA 291	ROMA	ROMA	00161		ITA	Cancer Treatment Research	000	3	4/12/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $117,072 )
2017	2017	ISTITUTO PASTEUR ITALIA FONDAZIONE CENCI BOLOGNETTI	VIALE REGINA ELENA 291	ROMA	ROMA	00161		ITA	Cancer Treatment Research	001	3	6/7/2017	NON-COMPETING CONTINUATION	$11,708
2017	2017	ISTITUTO PASTEUR FONDAZIONE CENCI BOLOGNETTI	VIALE REGINA ELENA 291	ROMA	ROMA	00161		ITA	Cancer Treatment Research	000	3	11/21/2016	NON-COMPETING CONTINUATION	$105,364
														Subtotal = $117,072

Issue Date FY: 2016 ( Subtotal = $0 )
2016	2015	ISTITUTO PASTEUR FONDAZIONE CENCI BOLOGNETTI	VIALE REGINA ELENA 291	ROME				ITA	Cancer Treatment Research	001	2	6/24/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$75,284
2016	2015	VACCINE & GENE THERAPY INSTITUTE-FLORIDA	9801 SOUTHWEST DISCOVERY WAY	PORT SAINT LUCIE	FL	34987	SAINT LUCIE	USA	Cancer Treatment Research	000	1	6/24/2016	NEW	-$75,284
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $246,645 )
2015	2015	VACCINE & GENE THERAPY INSTITUTE-FLORIDA	9801 SOUTHWEST DISCOVERY WAY	PORT SAINT LUCIE	FL	34987	SAINT LUCIE	USA	Cancer Treatment Research	000	1	12/1/2014	NEW	$246,645
														Subtotal = $246,645

Grand Total All Awards = $363,717

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Autophagy-mediated immune responses to oncolytic VSV

Award Number: R21CA192185

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2014

PERIOD OF PERFORMANCE END DATE: 11/30/2017

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer