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Targeting the colchicine binding site in tubulin for cancer therapy

Award Number: R01CA148706
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2011
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Targeting the colchicine binding site in tubulin for cancer therapy - Despite recent advances in both targeted therapy and immunotherapy, the overall survival (OS) for metastatic prostate cancer (PCa) remains low. This renewal application is to continue our productive efforts to develop a new tubulin inhibitor that can overcome drug resistance associated with FDA approved tubulin inhibitors, and will therefore, increase OS in PCa and other types of cancers where anti-tubulin drugs are used. The support from the previous periods of funding has resulted in a new drug candidate, Veru-111, which is under Phase 2 clinical trials for metastatic PCa. While Veru-111 is on a promising path to gain future FDA approval, there are significant room for improvement. The goals of this renewal are: (1) to develop the next generation of Veru-111 to proactively address its anticipated drug resistance; and (2) to develop targeted Veru- 111 drug conjugates to increase drug accumulation in prostate tumors and to target PCa bone metastasis. Aim 1. Develop a new generation of Veru-111, that can overcome both taxane resistance and the anticipated Veru-111 resistance. Preliminary data: We have discovered a hybrid scaffold based on Veru-111 and Azixa, represented by SHIP-216, that can overcome resistances to both taxanes and Veru-111. Approaches: Guided by high-resolution X-ray crystal structures, we will optimize the SHIP-216 scaffold to further improve its potency and drug-like properties. New analogs will be evaluated against a panel of PCa cell lines, including both taxane- and Veru-111-resistant cell lines to select the best five analogs for in vivo efficacy studies in Aim 3. Aim 2. Conjugate Veru-111 with PSMA targeting moieties to increase drug accumulation in PCa tumors and conjugate Veru-111 with bisphosphonates for more efficacious targeting of bone metastasis. Preliminary data: we have demonstrated Veru-111 itself can significantly reduce bone metastasis in a PDX model. We have also developed linkers for conjugating Veru-111 with PSMA targeting moieties or bisphosphonates. Approaches: we will optimize the length and composition of the linkers to PSMA targeting moieties and use different bisphosphonates in conjugation, to generate focused sets of Veru-111 drug conjugates. These conjugates will be first evaluated in vitro for stability and activation to select the best four conjugates (two in PMSA and two in bisphosphonates conjugates) for further in vivo efficacy studies in Aim 3. Aim 3. We will determine the maximum tolerable dose (MTD), pharmacokinetics (PK), and in vivo efficacy of the selected nine compounds from Aims 1-2 in both PCa cell line models and a PDX model to select the overall best compound to support subsequent clinical trials in the Veru-111 portfolio. Preliminary data: we have already shown that SHIP-216 as a new Veru-111 analog is highly efficacious against multiple xenograft models, including the 22Rv1 PCa and the Veru-111 resistant DU-145/VxR PCa models. Approaches: We will evaluate all selected new compounds for their designed ability to treat prostate tumors using both cell line and PDX models in vivo.


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 = $389,817 )
2025	2025	UNIVERSITY OF TENNESSEE	62 S DUNLAP ST	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	000	15	7/28/2025	NON-COMPETING CONTINUATION	$389,817
														Subtotal = $389,817

Issue Date FY: 2024 ( Subtotal = $370,326 )
2024	2024	UNIVERSITY OF TENNESSEE	62 S DUNLAP ST	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	001	14	7/19/2024	NON-COMPETING CONTINUATION	$370,326
2024	2023	UNIVERSITY OF TENNESSEE	62 S DUNLAP ST	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	000	13	3/15/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $370,326

Issue Date FY: 2023 ( Subtotal = $389,817 )
2023	2023	UNIVERSITY OF TENNESSEE	62 S DUNLAP ST	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	000	13	9/8/2023	NON-COMPETING CONTINUATION	$389,817
														Subtotal = $389,817

Issue Date FY: 2022 ( Subtotal = $382,020 )
2022	2022	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	002	12	8/8/2022	NON-COMPETING CONTINUATION	$382,020
2022	2021	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	001	11	12/2/2021	COMPETING CONTINUATION	$49,195
2022	2020	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	000	10	12/2/2021	NON-COMPETING CONTINUATION	-$49,195
														Subtotal = $382,020

Issue Date FY: 2021 ( Subtotal = $403,307 )
2021	2021	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	002	11	9/21/2021	COMPETING CONTINUATION	$5,096
2021	2021	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	001	11	7/29/2021	COMPETING CONTINUATION	$398,211
2021	2020	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	000	10	7/23/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $403,307

Issue Date FY: 2020 ( Subtotal = $365,493 )
2020	2020	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	000	10	12/16/2019	NON-COMPETING CONTINUATION	$328,942
2020	2020	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	001	10	1/23/2020	NON-COMPETING CONTINUATION	$36,551
														Subtotal = $365,493

Issue Date FY: 2019 ( Subtotal = $354,527 )
2019	2019	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	000	9	1/14/2019	NON-COMPETING CONTINUATION	$354,527
														Subtotal = $354,527

Issue Date FY: 2018 ( Subtotal = $365,493 )
2018	2018	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	001	8	5/22/2018	NON-COMPETING CONTINUATION	$36,551
2018	2018	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	000	8	12/14/2017	NON-COMPETING CONTINUATION	$328,942
2018	2016	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	003	6	9/12/2018	COMPETING CONTINUATION	$6
2018	2015	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	002	5	9/12/2018	NON-COMPETING CONTINUATION	-$6
														Subtotal = $365,493

Issue Date FY: 2017 ( Subtotal = $365,493 )
2017	2017	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET RM 300	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	000	7	12/15/2016	NON-COMPETING CONTINUATION	$328,942
2017	2017	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	001	7	6/7/2017	NON-COMPETING CONTINUATION	$36,551
														Subtotal = $365,493

Issue Date FY: 2016 ( Subtotal = $391,361 )
2016	2016	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	000	6	1/15/2016	COMPETING CONTINUATION	$391,361
														Subtotal = $391,361

Issue Date FY: 2015 ( Subtotal = $307,100 )
2015	2015	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	001	5	1/23/2015	NON-COMPETING CONTINUATION	$30,710
2015	2015	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	000	5	12/24/2014	NON-COMPETING CONTINUATION	$276,390
														Subtotal = $307,100

Issue Date FY: 2014 ( Subtotal = $297,887 )
2014	2014	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	001	4	4/22/2014	NON-COMPETING CONTINUATION	$21,497
2014	2014	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	000	4	12/19/2013	NON-COMPETING CONTINUATION	$276,390
														Subtotal = $297,887

Issue Date FY: 2013 ( Subtotal = $288,674 )
2013	2013	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	000	3	11/30/2012	NON-COMPETING CONTINUATION	$153,550
2013	2013	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	001	3	6/6/2013	NON-COMPETING CONTINUATION	$135,124
														Subtotal = $288,674

Issue Date FY: 2012 ( Subtotal = $307,100 )
2012	2012	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	001	2	5/2/2012	NON-COMPETING CONTINUATION	$30,710
2012	2012	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	000	2	12/30/2011	NON-COMPETING CONTINUATION	$276,390
														Subtotal = $307,100

Issue Date FY: 2011 ( Subtotal = $307,100 )
2011	2011	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	000	1	12/17/2010	NEW	$307,100
														Subtotal = $307,100

Grand Total All Awards = $5,285,515

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Targeting the colchicine binding site in tubulin for cancer therapy

Award Number: R01CA148706

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2011

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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