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Discoidin Domain Receptor Tyrosine Kinase 2 in bladder cancer progression

Award Number: R01CA075115
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/1997
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Discoidin Domain Receptor Tyrosine Kinase 2 in bladder cancer progression - PROJECT SUMMARY Even with immune checkpoint blockade therapy (ICBT), most patients with metastatic bladder cancer (BC) die of their disease. In the previous funding period, we studied CD24, a metastasis driver and prognostic marker. Our most translationally significant finding is induction of CD24 expression by Discoidin Domain Receptor Tyrosine Kinase 2 (DDR2), a collagen-activated receptor that is therapeutically actionable. In human BC, DDR2 expression was associated with poor patient prognosis, the aggressive and ICBT insensitive basal squamous tumor subtype (BSS), TGFβ signaling, immunosuppressive (M2) macrophages (Mφ) and a fibroblast-enriched, tumor microenvironment. These results raised the intriguing possibility that DDR2 is a lynchpin driver of both metastasis and ICBT resistance. To explore this possibility, we developed an shRNA based functional screen in syngeneic murine BC models to probe DDR2 and other selected “druggable” targets evaluated in BC clinical trials for their synergism with αPD-1, a common ICBT in BC. We found the most robust tumor reduction with depletion of DDR2 and this was recapitulated with the Tyr kinase inhibitor, dasatinib. This result was compelling because it defined a novel synergistic combination therapy with αPD-1 that, unlike CD24 targeting, is actionable in the near term in patients. To begin elucidating the mechanisms DDR2 may use to drive tumor metastasis and ICBT resistance, we profiled DDR2-silenced murine BC tumors with RNA-seq. We identified 69 genes downregulated >2 fold by DDR2 depletion and used these to construct a DDR2 Effector Signature (DES). Low tumor DES scores of surgically or αPD-L1 treated patients associated with better outcome, supporting a role for DES genes in progression and αPD-L1 response. Remarkably, MMP10 or S100A2 expression each alone stratified outcome nearly as well as the DES score in surgery and αPD-L1 treatment and they were implicated in Mφ, TGFβ and fibroblast biology. These findings and the lack of genes associated with T-cell exhaustion in DES, lead us to propose our innovative Guiding Hypothesis that cancer cell DDR2 establishes the BSS and uses MMP10 and S100A2 to engage M2 Mφ and cancer-associated fibroblasts (CAFs) to promote metastasis and αPD-(L)1 resistance. Specific Aims test this hypothesis with the Objective to develop new effective treatments for metastatic BC. Aim 1 will use full and conditional DDR2-null mice exposed to chemical carcinogens to test the hypothesis that DDR2 expression in basal urothelial cells is necessary for BSS tumor development and progression. Aim 2 will treat murine tumors with alterations in DDR2, MMP10 and S100A2 expression grown in genetically engineered mice with fibroblast and Mφ defects, with αPD-1, to test the hypothesis that cancer cell DDR2 drives MMP10 and S100A2 and via their actions in Mφ and fibroblasts contribute to metastasis and αPD-1 resistance. Since even with DDR2+PD-1 blockade, not all tumors are cured, Aim 3 will test the hypothesis that inhibition DPP4, a peptidase and Coronavirus receptor we discovered as a potential driver of resistance to DDR2+PD-1 blockade, can improve effectiveness of such therapy.


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 = -$56,376 )
2025	2024	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Biology Research	001	25	9/23/2025	NON-COMPETING CONTINUATION	-$56,376
2025	2024	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Biology Research	000	25	9/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = -$56,376

Issue Date FY: 2024 ( Subtotal = $392,659 )
2024	2024	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Biology Research	000	25	7/10/2024	NON-COMPETING CONTINUATION	$392,659
														Subtotal = $392,659

Issue Date FY: 2023 ( Subtotal = $413,325 )
2023	2023	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Biology Research	000	24	5/3/2023	NON-COMPETING CONTINUATION	$413,325
														Subtotal = $413,325

Issue Date FY: 2022 ( Subtotal = $405,059 )
2022	2022	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Biology Research	002	23	7/19/2022	NON-COMPETING CONTINUATION	$405,059
2022	2021	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Biology Research	001	22	6/21/2022	COMPETING CONTINUATION	$4,736
2022	2019	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Biology Research	000	21	6/21/2022	NON-COMPETING CONTINUATION	-$4,736
														Subtotal = $405,059

Issue Date FY: 2021 ( Subtotal = $413,325 )
2021	2021	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cancer Biology Research	000	22	3/18/2021	COMPETING CONTINUATION	$413,325
														Subtotal = $413,325

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cancer Biology Research	000	21	4/30/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $391,637 )
2019	2019	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cancer Biology Research	004	21	3/29/2019	NON-COMPETING CONTINUATION	$391,637
2019	2018	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cancer Biology Research	000	20	12/3/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2019	2018	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Cancer Biology Research	002	19	12/21/2018	NON-COMPETING CONTINUATION	-$41,899
2019	2018	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cancer Biology Research	003	20	12/21/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$55,598
2019	2017	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Cancer Biology Research	001	18	12/21/2018	NON-COMPETING CONTINUATION	-$13,699
														Subtotal = $391,637

Issue Date FY: 2018 ( Subtotal = $399,843 )
2018	2018	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Cancer Biology Research	002	19	8/31/2018	NON-COMPETING CONTINUATION	-$327,414
2018	2018	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Cancer Biology Research	001	19	5/24/2018	NON-COMPETING CONTINUATION	$36,932
2018	2018	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Cancer Biology Research	000	19	3/14/2018	NON-COMPETING CONTINUATION	$332,381
2018	2018	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cancer Biology Research	003	20	8/31/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$357,944
														Subtotal = $399,843

Issue Date FY: 2017 ( Subtotal = $369,313 )
2017	2017	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Cancer Biology Research	002	18	6/7/2017	NON-COMPETING CONTINUATION	$36,932
2017	2017	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Cancer Biology Research	000	18	3/7/2017	NON-COMPETING CONTINUATION	$332,381
2017	2012	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Cancer Biology Research	001	15	5/8/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $369,313

Issue Date FY: 2016 ( Subtotal = $369,313 )
2016	2016	UNIVERSITY OF COLORADO DENVER	P.O. BOX 6508	AURORA	CO	80045	ADAMS	USA	Cancer Biology Research	000	17	6/23/2016	NON-COMPETING CONTINUATION	$369,313
														Subtotal = $369,313

Issue Date FY: 2015 ( Subtotal = $369,015 )
2015	2015	UNIVERSITY OF COLORADO DENVER	P.O. BOX 6508	AURORA	CO	80045	ADAMS	USA	Cancer Biology Research	000	16	4/9/2015	COMPETING CONTINUATION	$369,015
														Subtotal = $369,015

Issue Date FY: 2012 ( Subtotal = $340,613 )
2012	2012	UNIVERSITY OF COLORADO DENVER	P.O. BOX 6508	AURORA	CO	80045	ADAMS	USA	Cancer Biology Research	000	15	4/30/2012	NON-COMPETING CONTINUATION	$340,613
														Subtotal = $340,613

Issue Date FY: 2011 ( Subtotal = $340,613 )
2011	2011	UNIVERSITY OF COLORADO DENVER	P.O. BOX 6508	AURORA	CO	80045	ADAMS	USA	Cancer Biology Research	000	14	6/8/2011	NON-COMPETING CONTINUATION	$340,613
														Subtotal = $340,613

Issue Date FY: 2010 ( Subtotal = $351,338 )
2010	2010	UNIVERSITY OF COLORADO DENVER	P.O. BOX 6508	AURORA	CO	80045	ADAMS	USA	Cancer Biology Research	001	13	9/24/2010	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$351,338
2010	2009	UNIVERSITY OF VIRGINIA	PO BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	12	9/20/2010	NON-COMPETING CONTINUATION	$0
														Subtotal = $351,338

Issue Date FY: 2009 ( Subtotal = $345,801 )
2009	2009	UNIVERSITY OF VIRGINIA	P.O. BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	12	4/15/2009	NON-COMPETING CONTINUATION	$345,801
														Subtotal = $345,801

Issue Date FY: 2008 ( Subtotal = $383,926 )
2008	2008	UNIVERSITY OF VIRGINIA	PO BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	001	10	4/3/2008	SUPPLEMENT FOR EXPANSION	$38,125
2008	2008	UNIVERSITY OF VIRGINIA	PO BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	11	5/28/2008	COMPETING CONTINUATION	$345,801
														Subtotal = $383,926

Issue Date FY: 2007 ( Subtotal = $329,778 )
2007	2007	UNIVERSITY OF VIRGINIA	PO BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	10	2/13/2007	NON-COMPETING CONTINUATION	$329,778
														Subtotal = $329,778

Issue Date FY: 2006 ( Subtotal = $339,627 )
2006	2006	UNIVERSITY OF VIRGINIA	PO BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	9	3/1/2006	NON-COMPETING CONTINUATION	$339,627
														Subtotal = $339,627

Grand Total All Awards = $6,942,209

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Discoidin Domain Receptor Tyrosine Kinase 2 in bladder cancer progression

Award Number: R01CA075115

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/1997

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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