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A novel role of IGFBP7 in the microenvironment of hepatocellular carcinoma

Award Number: R01CA240004
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2024

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A novel role of IGFBP7 in the microenvironment of hepatocellular carcinoma - Summary Evasion from immune surveillance is an important mechanism facilitating tumorigenesis. Identification of regulators of anti-tumor immunity will help exploit this mechanism to develop effective therapeutic strategies. Oncogenic insulin-like growth factor (IGF) signaling is suggested to dampen anti-tumor immune surveillance in hepatocellular carcinoma (HCC). However, there is a gap of knowledge in in- depth understanding of the underlying mechanism. Insulin-like growth factor binding protein-7 (IGFBP7) inhibits IGF-I signaling and functions as a tumor suppressor in HCC. An Igfbp7 knockout (Igfbp7-/-) mouse exhibits constitutive activation of IGF signaling and develops spontaneous multi- organ tumors and markedly accelerated carcinogen-induced HCC compared to +/+ or +/- mice. Igfbp7 expression was significantly higher in stromal cells, such as liver macrophages, versus hepatocytes, and activated macrophages were increased in Igfbp7-/- mice, suggesting a previously unrecognized function of Igfbp7 in modulating the tumor microenvironment (TME). A significant inhibition in expression of immune surveillance regulating genes and a corresponding decrease in antigen presentation by dendritic cells were observed in Igfbp7-/- mice compared to +/+. Increased tumorigenesis in Igfbp7-/- mice was associated with decreased tumor infiltration by CD8+ and CD4+ T cells while Igfbp7-overexpression caused growth inhibition of mouse HCC cells in syngeneic mice, dependent on the presence of CD8+ and CD4+ T cells. These results suggest that IGFBP7 exhibits pleiotropic anti-tumor activities and that modulation of an immune response may be an important component of the tumor suppressor function of IGFBP7, which has not been previously reported. The long-term objectives of our laboratory are to identify key players regulating HCC and translate this knowledge into novel and effective targeted therapies. Our recent findings strongly suggest a novel role of IGFBP7 in regulating the TME and anti-tumor immune response. We hypothesize that activation of IGF signaling in the absence of IGFBP7 promotes HCC by augmenting cancer cell proliferation and survival, modulating tumor-microenvironment crosstalk, and impairing tumor immune surveillance. Therapeutically, administration of IGFBP7 will not only inhibit cancer cell survival, but also promote immune recognition of tumors, resulting in more effective eradication of tumors and metastases. We will perform in-depth molecular, biochemical, immunological, and therapeutic studies using relevant mouse models to establish our hypotheses. Successful completion of the present studies will help transition IGFBP7 to therapeutic application and thereby help save lives of scores of HCC patients for whom no effective therapy currently exists.


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: 2025 ( Subtotal = $0 )
2025	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Biology Research	000	5	10/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $476,580 )
2023	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Biology Research	000	5	5/31/2023	NON-COMPETING CONTINUATION	$476,580
														Subtotal = $476,580

Issue Date FY: 2022 ( Subtotal = $476,580 )
2022	2022	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Biology Research	000	4	5/26/2022	NON-COMPETING CONTINUATION	$476,580
														Subtotal = $476,580

Issue Date FY: 2021 ( Subtotal = $486,305 )
2021	2021	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Biology Research	000	3	5/25/2021	NON-COMPETING CONTINUATION	$486,305
														Subtotal = $486,305

Issue Date FY: 2020 ( Subtotal = $486,305 )
2020	2020	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Biology Research	000	2	4/28/2020	NON-COMPETING CONTINUATION	$486,305
														Subtotal = $486,305

Issue Date FY: 2019 ( Subtotal = $500,003 )
2019	2019	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Biology Research	000	1	5/8/2019	NEW	$500,003
														Subtotal = $500,003

Grand Total All Awards = $2,425,773

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A novel role of IGFBP7 in the microenvironment of hepatocellular carcinoma

Award Number: R01CA240004

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2024

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