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On the path to the clinic: Lead optimization and pathway analysis of the pancreatic cancer-selective drug conjugate SW V-49

Award Number: R01CA163764
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2012
PERIOD OF PERFORMANCE END DATE: 03/31/2022

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On the path to the clinic: Lead optimization and pathway analysis of the pancreatic cancer-selective drug conjugate SW V-49 - Pancreatic cancer is a devastating disease that is refractory to standard chemotherapies, as demonstrated by the low five-year survival rate of 8%. The objective of this proposal is to assess a novel, highly promising therapeutic for the treatment of pancreatic cancer, employing comprehensive in vitro and preclinical in vivo testing prior to clinical evaluation studies. The sigma-2 (S2) receptor is overexpressed in pancreatic cancer, and small molecule ligands to this receptor localize to these tumors. In addition, PDAC cancer cells rapidly internalize selected sigma-2 ligands. This finding prompted us to explore the possibility of using these ligands to deliver additional therapeutic payloads to PDAC tumor cells via chemical linkage with our ligands. We have successfully used S2 ligands to deliver structurally diverse compounds including both peptides and small molecule therapeutics (classic chemotherapeutics [rapamycin] and peptidomimetics), into the cancer cells both in vitro and in vivo. In each case, the activity profiles of the conjugates were far greater than the isolated components or their equimolar combinations. Based on this delivery concept, we combined the tumor selectivity of the S2 ligand SV119 with a promising drug cargo that induces cell death selectively in PDAC (dm-Erastin), by creating a single small molecule conjugate (SW V-49). We have shown that this conjugate efficiently kills tumor cells in stroma-rich pancreatic cancer models with only limited signs of systemic toxicity. The key tasks of this project involve pharmacology and toxicity drug testing employing PDAC cell lines in vitro (murine and human), primary patient-derived 3D organoid in vitro cultures as well as syngeneic (mouse) and patient-derived xenograft models (PDX) of pancreatic 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: 2022 ( Subtotal = $0 )
2022	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	000	10	9/8/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $381,250 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	000	10	3/19/2021	NON-COMPETING CONTINUATION	$381,250
														Subtotal = $381,250

Issue Date FY: 2020 ( Subtotal = $381,250 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	000	9	3/4/2020	NON-COMPETING CONTINUATION	$381,250
														Subtotal = $381,250

Issue Date FY: 2019 ( Subtotal = $369,812 )
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	000	8	3/25/2019	NON-COMPETING CONTINUATION	$369,812
														Subtotal = $369,812

Issue Date FY: 2018 ( Subtotal = $381,250 )
2018	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	002	7	3/27/2018	NON-COMPETING CONTINUATION	$343,125
2018	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	003	7	5/23/2018	NON-COMPETING CONTINUATION	$38,125
2018	2017	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	001	6	11/8/2017	COMPETING CONTINUATION	$2,470
2018	2016	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	000	5	11/8/2017	EXTENSION WITH OR WITHOUT FUNDS	-$2,470
														Subtotal = $381,250

Issue Date FY: 2017 ( Subtotal = $381,250 )
2017	2017	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	002	6	8/16/2017	COMPETING CONTINUATION	$100,231
2017	2017	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	000	6	1/30/2017	COMPETING CONTINUATION	$381,250
2017	2016	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	001	5	8/16/2017	EXTENSION WITH OR WITHOUT FUNDS	-$100,231
														Subtotal = $381,250

Issue Date FY: 2016 ( Subtotal = $371,287 )
2016	2016	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Cancer Treatment Research	000	5	3/31/2016	EXTENSION WITH OR WITHOUT FUNDS	$371,287
														Subtotal = $371,287

Issue Date FY: 2015 ( Subtotal = $371,287 )
2015	2015	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Cancer Treatment Research	000	4	3/13/2015	NON-COMPETING CONTINUATION	$371,287
														Subtotal = $371,287

Issue Date FY: 2014 ( Subtotal = $360,148 )
2014	2014	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Cancer Treatment Research	000	3	6/25/2014	NON-COMPETING CONTINUATION	$360,148
														Subtotal = $360,148

Issue Date FY: 2013 ( Subtotal = $337,151 )
2013	2013	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Cancer Treatment Research	000	2	3/4/2013	NON-COMPETING CONTINUATION	$161,402
2013	2013	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Cancer Treatment Research	001	2	6/27/2013	NON-COMPETING CONTINUATION	$175,749
														Subtotal = $337,151

Issue Date FY: 2012 ( Subtotal = $375,271 )
2012	2012	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Cancer Treatment Research	000	1	4/26/2012	NEW	$375,271
														Subtotal = $375,271

Grand Total All Awards = $3,709,956

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On the path to the clinic: Lead optimization and pathway analysis of the pancreatic cancer-selective drug conjugate SW V-49

Award Number: R01CA163764

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2012

PERIOD OF PERFORMANCE END DATE: 03/31/2022

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