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Defining the role of isoprenylated xanthones from the mangosteen for enhancing degradation of full length and variant forms of androgen receptor in prostate cancer

Award Number: R37CA227101
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Defining the role of isoprenylated xanthones from the mangosteen for enhancing degradation of full length and variant forms of androgen receptor in prostate cancer - PROJECT SUMMARY Clinically there are examples of small molecules including finasteride and dutasteride that can reduce the risk of prostate cancer and potentially may be effect in minimal low risk disease. AR targeting drugs can prove extremely beneficial for a patient, however, the benefit is short as many of these agents are only effective for approximately 1 year. In our data collected during the initial 5-year R37 MERIT award we are characterizing the AR degradation properties of α-mangostin against known AR polymorphisms associated with resistance. Briefly, PC3 cells were transfected with AR constructs expressing the following Polymorphisms including E256K, T818D, and T878A. A second biological target for prostate cancer we have evaluated during the initial 5-year R37 MERIT award was the role of binding immunoglobulin protein (BiP), also known as GRP78 or HSP70. Our central hypothesis is that xanthones including α-Mangostin from the mangosteen are SARDs that promote proteolytic degradation of the AR and this mechanism is critically regulated by the multi-functional chaperone protein BiP. Furthermore, the multi-functional BiP protein in addition to promoting AR degradation is able to serve as a receptor on the cell surface for the apoptotic ligand Isthmin-1. Importantly, we have observed that benign prostate epithelial cells when treated with alpha-mangostin do not increase the UPR pathway or the expression of BiP [2, 4]. Our objective in this proposal is identify opportunities to exploit the multi-functional properties of BiP that are involved in AR degradation and receptor properties of BiP when localized to the cell surface involved in apoptosis using xanthones and recombinant Ishthmin-1. Our objective herein will be to identify key domains of BiP that bind to AR in prostate cancer cells involved in AR degradation. A second objective will be to functionally characterize the interaction BiP and Isthmin-1 in prostate cancer in combination with xanthones from the mangosteen fruit. Our third objective will be to optimize the pro-apoptotic properties of the BiP ligand Isthmin-1 in combination with isoprenylated xanthones.


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 = $334,511 )
2025	2025	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cancer Cause and Prevention Research	001	7	4/2/2025	NON-COMPETING CONTINUATION	$334,511
2025	2023	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cancer Cause and Prevention Research	000	5	2/20/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $334,511

Issue Date FY: 2024 ( Subtotal = $371,677 )
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cancer Cause and Prevention Research	000	6	5/8/2024	EXTENSION WITH OR WITHOUT FUNDS	$371,677
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cancer Cause and Prevention Research	001	6	5/29/2024	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $371,677

Issue Date FY: 2023 ( Subtotal = $346,361 )
2023	2023	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Cause and Prevention Research	000	5	12/23/2022	NON-COMPETING CONTINUATION	$318,087
2023	2023	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Cause and Prevention Research	001	5	1/19/2023	NON-COMPETING CONTINUATION	$0
2023	2023	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Cause and Prevention Research	002	5	3/14/2023	NON-COMPETING CONTINUATION	$28,274
														Subtotal = $346,361

Issue Date FY: 2022 ( Subtotal = $353,430 )
2022	2022	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Cause and Prevention Research	001	4	6/17/2022	NON-COMPETING CONTINUATION	$35,343
2022	2022	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Cause and Prevention Research	000	4	1/31/2022	NON-COMPETING CONTINUATION	$318,087
														Subtotal = $353,430

Issue Date FY: 2021 ( Subtotal = $353,431 )
2021	2021	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Cause and Prevention Research	001	3	1/25/2021	NON-COMPETING CONTINUATION	$17,673
2021	2021	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Cause and Prevention Research	000	3	12/22/2020	NON-COMPETING CONTINUATION	$335,758
														Subtotal = $353,431

Issue Date FY: 2020 ( Subtotal = $352,420 )
2020	2020	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Cause and Prevention Research	000	2	12/20/2019	NON-COMPETING CONTINUATION	$317,178
2020	2020	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Cause and Prevention Research	001	2	1/13/2020	NON-COMPETING CONTINUATION	$35,242
														Subtotal = $352,420

Issue Date FY: 2019 ( Subtotal = $352,420 )
2019	2019	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Cause and Prevention Research	000	1	12/13/2018	NEW	$352,420
														Subtotal = $352,420

Grand Total All Awards = $2,464,250

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Defining the role of isoprenylated xanthones from the mangosteen for enhancing degradation of full length and variant forms of androgen receptor in prostate cancer

Award Number: R37CA227101

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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