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Role of heat shock transcription factor HSF1 in tumorigenesis

Award Number: R01CA062130
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/1996
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Role of heat shock transcription factor HSF1 in tumorigenesis - Among human malignancies, primary liver tumors account for 9% of all cancer deaths worldwide and 12% in developing countries. HCC accounts for up to 85% of liver cancers and is one of the leading lethal malignancies worldwide. Chronic liver damage caused by viral infection (HBV and HCV), alcohol, non-alcoholic fatty liver disease (NAFLD)-associated chronic inflammation, fibrosis, cirrhosis, or a combination of these factors increases the risk for HCC. Notably, NAFLD, a hepatic manifestation of metabolic syndrome, affects nearly 25% of the US population, and its incidence is rapidly increasing since obesity and metabolic syndrome are growing epidemics worldwide. Although the risk factors are well defined, HCC is still an aggressive and difficult-to-treat malignant disease with poor outcome and limited therapeutic options. In fact, major obstacles for effective treatment of this cancer is that HCC is frequently resistant to chemotherapy and radiotherapy, and there is a high frequency of tumor recurrence after curative surgical resection. Currently, there is a strong rationale for immune intervention in HCC, but recent clinical trials have demonstrated that the benefits of immunotherapy are relegated to a small fraction (~20%) of cancer patients, including these with HCC. This prompts the need for greater understanding of the mechanisms underlying liver cancer cell plasticity and adaptation, as well as developing novel therapeutic approaches to achieve more effective and selective cure of this disease. Hsf1, as the master activator of the classical heat shock response and guardian of the proteome, has been implicated in the pathogenesis of cancer. We have discovered that genetic inactivation of Hsf1 in pre-clinical mouse cancer models leads to remarkable inhibition of HCC development. On the basis of published and preliminary studies we propose a novel pathogenic mechanism whereby Hsf1 activation promotes HCC development by stimulating both the protein folding capacity of the cell and regulating anabolic metabolic pathways, thus perpetuating chronic hepatic metabolic disease. Our recent research revealed that the Hsf1 transcriptional program enables malignant cells to escape immune surveillance. This may provide a new approach to improve HCC treatment by improving the anti-tumor immune capacity targeting Hsf1 activity. Our experimental strategy entails the following three major approaches: 1. Determine the impact of hsf1 deletion on liver cancer initiation and explore its therapeutic implications for advanced HCC, 2. Determine the metabolic and epigenetic mechanisms by which Hsf1 ablation induces an effective anti-tumor CD8+ T cell response, and 3. Investigate the impact of Hsf1 deletion on improved CD8+ T cell-based immunotherapy for HCC. In summary, the long-term translational goal of the project is to test the potential of Hsf1 targeting in human HCC. It will also provide proof-of-concept for targeting Hsf1-mediated metabolic programs for immunotherapeutic application of liver cancer.


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 = $0 )
2026	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	000	29	12/15/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $434,268 )
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	001	29	5/22/2025	NON-COMPETING CONTINUATION	$43,427
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	000	29	2/17/2025	NON-COMPETING CONTINUATION	$390,841
														Subtotal = $434,268

Issue Date FY: 2024 ( Subtotal = $96,017 )
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	000	28	4/1/2024	NON-COMPETING CONTINUATION	$96,017
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	001	28	4/18/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $96,017

Issue Date FY: 2023 ( Subtotal = $558,195 )
2023	2023	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	001	27	9/18/2023	NON-COMPETING CONTINUATION	$11,166
2023	2023	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	000	27	2/1/2023	NON-COMPETING CONTINUATION	$547,029
														Subtotal = $558,195

Issue Date FY: 2022 ( Subtotal = $547,029 )
2022	2022	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	001	26	5/31/2022	NON-COMPETING CONTINUATION	$44,657
2022	2022	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	000	26	1/31/2022	NON-COMPETING CONTINUATION	$502,372
														Subtotal = $547,029

Issue Date FY: 2021 ( Subtotal = $558,195 )
2021	2021	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	000	25	2/15/2021	NON-COMPETING CONTINUATION	$558,195
														Subtotal = $558,195

Issue Date FY: 2020 ( Subtotal = $555,929 )
2020	2020	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	001	24	2/14/2020	COMPETING CONTINUATION	$555,929
2020	2020	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	003	24	8/3/2020	COMPETING CONTINUATION	$151,263
2020	2018	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	002	23	8/3/2020	NON-COMPETING CONTINUATION	-$151,263
2020	2018	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	000	23	2/6/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $555,929

Issue Date FY: 2018 ( Subtotal = $556,510 )
2018	2018	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST # CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	000	23	8/13/2018	NON-COMPETING CONTINUATION	$556,510
														Subtotal = $556,510

Issue Date FY: 2017 ( Subtotal = $556,510 )
2017	2017	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST # CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	000	22	7/19/2017	NON-COMPETING CONTINUATION	$556,510
														Subtotal = $556,510

Issue Date FY: 2016 ( Subtotal = $698,630 )
2016	2016	GEORGIA REGENTS RESEARCH INSTITUTE INC	1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	001	21	8/2/2016	NON-COMPETING CONTINUATION	$556,510
2016	2016	GEORGIA REGENTS RESEARCH INSTITUTE INC	1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	000	20	3/24/2016	SUPPLEMENT FOR EXPANSION	$142,120
														Subtotal = $698,630

Issue Date FY: 2015 ( Subtotal = $307,800 )
2015	2015	GEORGIA REGENTS RESEARCH INSTITUTE INC	1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	000	20	7/23/2015	NON-COMPETING CONTINUATION	$307,800
														Subtotal = $307,800

Issue Date FY: 2014 ( Subtotal = $306,113 )
2014	2014	GEORGIA REGENTS RESEARCH INSTITUTE INC	1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	001	19	8/27/2014	COMPETING CONTINUATION	$306,113
2014	2013	GA Health Science University Research Institute, Inc	1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Treatment Research	000	18	8/22/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $306,113

Issue Date FY: 2013 ( Subtotal = $265,076 )
2013	2013	GA HEALTH SCIENCE UNIVERSITY RESEARCH INSTITUTE, INC	1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Treatment Research	001	18	6/28/2013	NON-COMPETING CONTINUATION	$198,807
2013	2013	GA HEALTH SCIENCE UNIVERSITY RESEARCH INSTITUTE, INC	1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Treatment Research	000	18	5/1/2013	NON-COMPETING CONTINUATION	$66,269
														Subtotal = $265,076

Issue Date FY: 2012 ( Subtotal = $281,996 )
2012	2012	MEDICAL COLLEGE OF GEORGIA, RESEARCH INSTITUTE	1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Treatment Research	000	17	4/16/2012	NON-COMPETING CONTINUATION	$281,996
														Subtotal = $281,996

Issue Date FY: 2011 ( Subtotal = $281,996 )
2011	2011	MEDICAL COLLEGE OF GEORGIA, RESEARCH INSTITUTE	1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Treatment Research	000	16	3/21/2011	NON-COMPETING CONTINUATION	$261,645
2011	2011	MEDICAL COLLEGE OF GEORGIA, RESEARCH INSTITUTE	1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Treatment Research	001	16	5/18/2011	NON-COMPETING CONTINUATION	$20,351
														Subtotal = $281,996

Issue Date FY: 2010 ( Subtotal = $290,717 )
2010	2010	MEDICAL COLLEGE OF GEORGIA, RESEARCH INSTITUTE	1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Treatment Research	000	15	4/26/2010	NON-COMPETING CONTINUATION	$290,717
														Subtotal = $290,717

Issue Date FY: 2009 ( Subtotal = $290,717 )
2009	2009	MEDICAL COLLEGE OF GEORGIA, RESEARCH INSTITUTE	1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Treatment Research	000	14	5/8/2009	COMPETING CONTINUATION	$290,717
														Subtotal = $290,717

Issue Date FY: 2008 ( Subtotal = $274,570 )
2008	2008	MEDICAL COLLEGE OF GEORGIA, RESEARCH INSTITUTE	RESEARCH INSTITUTE	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Treatment Research	000	13	4/8/2008	NON-COMPETING CONTINUATION	$274,570
														Subtotal = $274,570

Issue Date FY: 2007 ( Subtotal = $274,570 )
2007	2007	MEDICAL COLLEGE OF GEORGIA, RESEARCH INSTITUTE	RESEARCH INSTITUTE	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Treatment Research	000	12	4/18/2007	NON-COMPETING CONTINUATION	$274,570
														Subtotal = $274,570

Issue Date FY: 2006 ( Subtotal = $282,770 ) (Continued on the next page)
Grand Total All Awards = $9,456,343

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Role of heat shock transcription factor HSF1 in tumorigenesis

Award Number: R01CA062130

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/1996

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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