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Nanoparticle-mediated treatment for bone metastasis

Award Number: R01CA206189
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/04/2016
PERIOD OF PERFORMANCE END DATE: 04/30/2024

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Nanoparticle-mediated treatment for bone metastasis - DESCRIPTION (provided by applicant): Advanced-stage prostate cancer often metastasizes to bone but becomes incurable due to poor biodistribution of intravenously administered anticancer drugs within bone. Bisphosphonates are currently used to reduce the risk of skeleton-related events and to ameliorate bone pain, but they do not improve survival. Injected drugs or drug-loaded nanocarriers conjugated to bone-seeking agents remain inefficient in treating bone metastasis. In this proposal, as a therapy for bone metastasis, we explore a new route for nanoparticle (NP)-mediated drug delivery to bone - the intracellular clefts between endothelial cells in bone marrow. PEGylated NPs, because of their hydrophilic surface, remain in the circulation rather than efficiently extravagating through the fenestrations in bone-marrow capillaries. Our novel approach has been to design non-PEGylated NPs and rationalize their characteristics (size, charge, and surface composition) so that following their intravenous administration, these NPs do extravagate through the openings of the marrow's sinusoidal capillaries. In a preliminary study using a PC-3M-luc cell-induced osteolytic intraosseous mouse model of prostate cancer, (a) after intravenous injection, these NPs demonstrated focal accumulation in bone marrow within metastatic sites and (b) a single dose of paclitaxel-loaded NPs significantly inhibited the progression of bone metastasis and completely prevented bone loss In this proposal, our objective is to evaluate these NPs in a clinically relevant model of bon metastasis, induced by intracardiac injection of PC-3M-luc cells. We will test the efficacy of denosumab in NPs (DNmb- nano). DNmb is a monoclonal antibody that binds to receptor activator of nuclear factor-κB ligand (RANKL). Over expression of RANKL in the bone microenvironment drives the vicious destructive cycle of progression of bone metastasis and bone resorption. We will also explore DNmb as a targeting ligand against RANKL and use docetaxel loaded in NPs (TXT-nano), as TXT has proven more potent than paclitaxel for treating prostate cancer. We hypothesize that using our NPs, which effectively localize to bone, and the combination of DNmb and TXT with their complementary mechanism of action could inhibit progression of bone metastasis and prevent bone loss. The specific aims are: AIM 1: Delineate the parameters critical for efficient localization of NPs to metastatic sites in a prostate tumor model of advanced-stage bone metastasis. AIM 2: Evaluate the efficacy of the combination of docetaxel- and denosumab-loaded NPs (TXT-nano and DNmb-nano) to inhibit progression of bone metastasis and the resulting bone loss. AIM 3: Determine the pharmacokinetics and pharmacodynamics of drug distribution and tolerance to drug treatment by use of NPs. Impact: Since bone is a common site for metastasis in a number of human cancers, with devastating consequences, an effective drug-delivery strategy could potentially have considerably broader implications.


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 = $0 )
2024	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Treatment Research	000	6	7/19/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Treatment Research	000	6	4/14/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $268,394 )
2021	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Treatment Research	000	6	4/23/2021	NON-COMPETING CONTINUATION	$268,394
														Subtotal = $268,394

Issue Date FY: 2020 ( Subtotal = $44,168 )
2020	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Treatment Research	000	5	5/13/2020	NON-COMPETING CONTINUATION	$44,168
														Subtotal = $44,168

Issue Date FY: 2019 ( Subtotal = $303,185 )
2019	2019	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Treatment Research	000	4	4/19/2019	NON-COMPETING CONTINUATION	$303,185
														Subtotal = $303,185

Issue Date FY: 2018 ( Subtotal = $312,562 )
2018	2018	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Treatment Research	000	3	4/18/2018	NON-COMPETING CONTINUATION	$312,562
														Subtotal = $312,562

Issue Date FY: 2017 ( Subtotal = $312,562 )
2017	2017	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Treatment Research	001	2	6/7/2017	NON-COMPETING CONTINUATION	$31,257
2017	2017	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Treatment Research	000	2	4/27/2017	NON-COMPETING CONTINUATION	$281,305
														Subtotal = $312,562

Issue Date FY: 2016 ( Subtotal = $312,562 )
2016	2016	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Treatment Research	000	1	5/4/2016	NEW	$312,562
														Subtotal = $312,562

Grand Total All Awards = $1,553,433

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Nanoparticle-mediated treatment for bone metastasis

Award Number: R01CA206189

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/04/2016

PERIOD OF PERFORMANCE END DATE: 04/30/2024

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