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Interplay between PDGFRA, oxygen-regulated translation and KSHV in Kaposi's sarcomagenesis

Award Number: R01CA136387
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2010
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Interplay between PDGFRA, oxygen-regulated translation and KSHV in Kaposi's sarcomagenesis - In spite of our understanding of KSHV pathogenesis and the implementation of rationally designed therapies based on these advances, advanced KS is mostly an incurable disease and many of the most promising new therapies continue to have major roadblocks and implementation problems in the setting of ART. We have shown that 1) KSHV lytic genes; and particularly the vGPCR oncogene can induce- PDGF mediated activation of PDGFRA and that this is the most prominently activated RTK in AIDS-KS and it is an oncogenic driver and a therapeutic target in KS. 2) We identified PDGFRA (+) mesenchymal stem cells as KS progenitors; and PDGFRA, as an enabler of KSHV oncogenesis in an angiogenic KS like environment and we developed of a new KSHV infection-to-tumorigenesis system that allows to dissect the effect of the angiogenic microenvironment and the contribution of viral and host mechanisms to oncogenesis 3) We found that the ability of the virus to regulate the oxygen sensing machinery allowed the virus to coopt the hypoxia-regulated alternative translation initiation machinery eIF4EH activated by HIF2a and mediated by eIF4E2 alternative cap-binding. This was essential for KSHV replication, for escaping the viral shut-off and for PDGFRA driven pathogenesis in MSCs. The importance of this discovery is that through its regulation of the oxygen sensing machinery the virus access to translation initiation plasticity, defined as the ability for KSHV to alternatively initiate protein synthesis using both the initiation complex eIF4E bearing a cap-binding regulated by the PI3K- AKT-mTOR -HIF1a (eIF4E1 cap-binding) axis or the eIF4EH (eIF4E2 cap-binding) regulated by the HIF2a. We hypothesize that this provides the virus with several adaptive advantages that we will study: 1) Allows the virus to maximize replication in different oxygen levels corresponding to variety of tissues and pathophysiological conditions and it may allow the virus to bypass the stress and innate immunity-related kinases targeting eIF2a inhibition 2) It may be employed by viral oncogenes such as vGPCR and/or by its host-cell signaling mediators such as PDGFRA for proliferation and the induction of direct and paracrine oncogenesis 3) Could allow the transformed host cell to be plastic and adaptive in the context of AIDS-KS therapies targeting PDGFRA such as Imatinib, which are known to target the PDGFRA-AKT-mTOR-E1-HIF1a pathway. We will employ the MSC based de novo oncogenesis to tumorigenesis models, an induction reactivation model and two natural infections systems and AIDS-KS samples from different repositories to test these hypotheses. Aim 1: Study how KSHV regulation of the oxygen sensing machinery (O2SM) leading to HIF2a activation of translational initiation by eIF4EH contributes to KSHV replication and innate immunity evasion. Aim 2: Study mechanisms whereby KSHV regulation of the oxygen sensing machinery leading to HIF2a activation of translational initiation by eIF4EH contributes to KSHV oncogenesis in mouse MSC and human MSCs. Aim 3: Role of translation initiation plasticity in mediating resistance to PDGFRA targeted therapies.


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 = $452,653 )
2024	2024	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Cancer Biology Research	000	15	5/29/2024	NON-COMPETING CONTINUATION	$452,653
														Subtotal = $452,653

Issue Date FY: 2023 ( Subtotal = $514,386 )
2023	2023	UNIVERSITY OF MIAMI	1400 NW 10TH AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Biology Research	001	14	2/16/2023	NON-COMPETING CONTINUATION	$452,653
2023	2023	UNIVERSITY OF MIAMI	1400 NW 10TH AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Biology Research	002	14	2/20/2023	SUPPLEMENT FOR EXPANSION	$61,733
2023	2022	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Biology Research	000	13	11/22/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $514,386

Issue Date FY: 2022 ( Subtotal = $514,386 )
2022	2022	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Biology Research	002	13	3/4/2022	SUPPLEMENT FOR EXPANSION	$61,733
2022	2022	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Biology Research	003	13	5/16/2022	NON-COMPETING CONTINUATION	-$9,053
2022	2022	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Biology Research	004	13	5/16/2022	SUPPLEMENT FOR EXPANSION	-$1,234
2022	2022	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Biology Research	001	13	3/4/2022	NON-COMPETING CONTINUATION	$61,733
2022	2022	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Biology Research	000	13	2/28/2022	NON-COMPETING CONTINUATION	$390,920
2022	2022	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Biology Research	005	13	5/17/2022	NON-COMPETING CONTINUATION	$9,053
2022	2022	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Biology Research	006	13	5/17/2022	SUPPLEMENT FOR EXPANSION	$1,234
														Subtotal = $514,386

Issue Date FY: 2021 ( Subtotal = $491,223 )
2021	2021	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Biology Research	000	12	2/8/2021	NON-COMPETING CONTINUATION	$452,653
2021	2021	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Biology Research	001	12	9/14/2021	SUPPLEMENT FOR EXPANSION	$38,570
														Subtotal = $491,223

Issue Date FY: 2020 ( Subtotal = $512,133 )
2020	2020	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Biology Research	001	11	4/28/2020	SUPPLEMENT FOR EXPANSION	$59,481
2020	2020	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Biology Research	000	11	2/28/2020	COMPETING CONTINUATION	$452,652
2020	2020	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Biology Research	003	11	9/2/2020	COMPETING CONTINUATION	$57
2020	2019	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Cause and Prevention Research	002	10	9/2/2020	SUPPLEMENT FOR EXPANSION	-$57
														Subtotal = $512,133

Issue Date FY: 2019 ( Subtotal = $495,721 )
2019	2019	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Cause and Prevention Research	000	10	2/13/2019	NON-COMPETING CONTINUATION	$443,506
2019	2019	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Cause and Prevention Research	001	10	2/15/2019	SUPPLEMENT FOR EXPANSION	$52,215
														Subtotal = $495,721

Issue Date FY: 2018 ( Subtotal = $564,881 )
2018	2018	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Cause and Prevention Research	003	9	5/24/2018	SUPPLEMENT FOR EXPANSION	$5,383
2018	2018	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Cause and Prevention Research	000	9	1/31/2018	NON-COMPETING CONTINUATION	$411,501
2018	2018	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Cause and Prevention Research	002	9	5/21/2018	NON-COMPETING CONTINUATION	$99,551
2018	2018	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Cause and Prevention Research	001	9	2/8/2018	SUPPLEMENT FOR EXPANSION	$48,446
														Subtotal = $564,881

Issue Date FY: 2017 ( Subtotal = $487,559 )
2017	2017	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Cause and Prevention Research	000	8	2/17/2017	NON-COMPETING CONTINUATION	$411,500
2017	2017	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Cause and Prevention Research	001	8	6/7/2017	NON-COMPETING CONTINUATION	$45,723
2017	2017	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Cause and Prevention Research	002	8	9/11/2017	SUPPLEMENT FOR EXPANSION	$30,336
														Subtotal = $487,559

Issue Date FY: 2016 ( Subtotal = $457,223 )
2016	2016	UNIVERSITY OF MIAMI	P.O. BOX 248106	CORAL GABLES	FL	33124	MIAMI-DADE	USA	Cancer Cause and Prevention Research	001	7	1/27/2016	NON-COMPETING CONTINUATION	$457,223
2016	2015	UNIVERSITY OF MIAMI	POST OFFICE BOX 248106	CORAL GABLES	FL	33124	MIAMI-DADE	USA	Cancer Cause and Prevention Research	000	6	1/7/2016	COMPETING CONTINUATION	$0
														Subtotal = $457,223

Issue Date FY: 2015 ( Subtotal = $457,223 )
2015	2015	UNIVERSITY OF MIAMI	P.O. BOX 248106	CORAL GABLES	FL	33124	MIAMI-DADE	USA	Cancer Cause and Prevention Research	000	6	2/25/2015	COMPETING CONTINUATION	$457,223
														Subtotal = $457,223

Issue Date FY: 2014 ( Subtotal = $406,962 )
2014	2014	UNIVERSITY OF MIAMI	P.O. BOX 248106	CORAL GABLES	FL	33124	MIAMI-DADE	USA	Cancer Cause and Prevention Research	000	5	2/28/2014	NON-COMPETING CONTINUATION	$377,594
2014	2014	UNIVERSITY OF MIAMI	P.O. BOX 248106	CORAL GABLES	FL	33124	MIAMI-DADE	USA	Cancer Cause and Prevention Research	001	5	4/17/2014	NON-COMPETING CONTINUATION	$29,368
														Subtotal = $406,962

Issue Date FY: 2013 ( Subtotal = $395,903 )
2013	2013	UNIVERSITY OF MIAMI	P.O. BOX 248106	CORAL GABLES	FL	33124	MIAMI-DADE	USA	Cancer Cause and Prevention Research	000	4	2/11/2013	NON-COMPETING CONTINUATION	$189,529
2013	2013	UNIVERSITY OF MIAMI	P.O. BOX 248106	CORAL GABLES	FL	33124	MIAMI-DADE	USA	Cancer Cause and Prevention Research	001	4	6/28/2013	NON-COMPETING CONTINUATION	$206,374
														Subtotal = $395,903

Issue Date FY: 2012 ( Subtotal = $437,003 )
2012	2012	UNIVERSITY OF MIAMI	P.O. BOX 248106	CORAL GABLES	FL	33124	MIAMI-DADE	USA	Cancer Cause and Prevention Research	000	3	3/20/2012	NON-COMPETING CONTINUATION	$437,003
														Subtotal = $437,003

Issue Date FY: 2011 ( Subtotal = $438,640 )
2011	2011	UNIVERSITY OF MIAMI	P.O. BOX 248106	CORAL GABLES	FL	33124	MIAMI-DADE	USA	Cancer Cause and Prevention Research	001	2	5/13/2011	NON-COMPETING CONTINUATION	$19,445
2011	2011	UNIVERSITY OF MIAMI	P.O. BOX 248106	CORAL GABLES	FL	33124	MIAMI-DADE	USA	Cancer Cause and Prevention Research	000	2	3/1/2011	NON-COMPETING CONTINUATION	$419,195
														Subtotal = $438,640

Grand Total All Awards = $7,086,232

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Interplay between PDGFRA, oxygen-regulated translation and KSHV in Kaposi's sarcomagenesis

Award Number: R01CA136387

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2010

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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