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OVERCOMING THE PROTECTIVE BARRIERS OF BREAST CANCER IN BONE MARROW WITH TARGETED PRODRUG NANOTHERAPY

Award Number: R01CA216840
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/12/2018
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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OVERCOMING THE PROTECTIVE BARRIERS OF BREAST CANCER IN BONE MARROW WITH TARGETED PRODRUG NANOTHERAPY - Women have a 1 in 8 lifetime risk of breast cancer making it their second highest oncogenic cause of mortality behind lung cancer. Thirty percent of patients with stage I to III disease have silent bone marrow (BM) micro-metastases, which increase their likelihood of cancer recurrence as well as complications, such as pathological fractures, and related to the osteolytic nature of the disease. Even patients with limited early-stage disease, who responded well to chemo- or hormonal therapy at the primary site, may relapse years later when dormant bone marrow micro-metastases, previously protected within the bone marrow niche, recrudesce. Our research has recently revealed that breast cancer metastasis in the presence of bone marrow stromal cells, in vitro and in vivo, up-regulated αvβ3-integrin expression, leading to marked diminished sensitivity to systemic chemotherapy. Moreover, these data indicated that TGF-β3 sequestered in the bone microstroma was liberated to induce αvβ3-integrin up-regulation. Utilizing this bone BC target, αvβ3-targeted mixed micelles (~15nm) incorporating Sn2 lipase-labile docetaxel (DTX) prodrug (DTX-PD) (αvβ3-DTX-PD MP) were developed to rapidly and homogeneously penetrate into the tumor shown and deliver DTX therapy directly into the cell through a novel approach, termed Contact Facilitated Drug Delivery (CFDD). αvβ3-DTX-PD MP markedly reduced bone marrow BC tumor burden and osteolytic damage with negligible off-target effects, whereas systemic DTX at up to 4-fold higher doses had no impact on tumor progression yet elicited hepatic and hematologic toxicity. However, many patients with bone BC likely will have previously received DTX. From this perspective and recognizing the stem cell nature of breast cancer bone metastases, a camptothecin (CPT) Sn2 lipase-labile prodrug (CPT-PD) was developed to offer a new patient-naive treatment. CPT is a topoisomerase 1 (TOPO 1) inhibitor with powerful hypoxia-inducible factor 1-alpha (HIF-1α) inhibitor that is cytotoxic to cancer stem cells. This proposal investigates the efficacy and safety the αvβ3-CPT-PD-MP or αvβ3-DTX-PD MP nanosystems against the bone BC tumors, micro-metastases, dormant tumor cells to provide potent therapy to bone and to reduce the risk of breast cancer relapse from micrometastases. This proposal addresses the unmet therapeutic challenge and medical need posed by BC bone metastases. This project will delineate the bone BC efficacy and safety of αvβ3-Sn2-prodrug micelles and also elucidate the impact of key bone microstroma constituents such as TGF-β and αvβ3+ tumor associated macrophages (M2 TAMS) and αvβ3+ osteoclasts on treatment responses. The translational overarching goals are to more effectively treat patients with Stage 4 breast cancer in bone (Aims 1& 2), and to increase the enduring cure rate for Stage 1 to 3 BC patients by treating occult breast cancer micro-metastases to diminish disease relapse (Aim 3).


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 = -$203 )
2025	2022	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	000	5	4/15/2025	NON-COMPETING CONTINUATION	-$203
														Subtotal = -$203

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Cancer Treatment Research	000	5	5/22/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $610,502 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	001	5	5/19/2022	NON-COMPETING CONTINUATION	$49,838
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	000	5	12/23/2021	NON-COMPETING CONTINUATION	$560,664
														Subtotal = $610,502

Issue Date FY: 2021 ( Subtotal = $622,961 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	001	4	1/25/2021	NON-COMPETING CONTINUATION	$31,148
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	000	4	12/18/2020	NON-COMPETING CONTINUATION	$591,813
														Subtotal = $622,961

Issue Date FY: 2020 ( Subtotal = $622,961 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	000	3	12/24/2019	NON-COMPETING CONTINUATION	$560,664
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	001	3	1/14/2020	NON-COMPETING CONTINUATION	$62,297
														Subtotal = $622,961

Issue Date FY: 2019 ( Subtotal = $604,272 )
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	000	2	12/28/2018	NON-COMPETING CONTINUATION	$604,272
														Subtotal = $604,272

Issue Date FY: 2018 ( Subtotal = $622,961 )
2018	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	000	1	1/12/2018	NEW	$622,961
														Subtotal = $622,961

Grand Total All Awards = $3,083,454

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OVERCOMING THE PROTECTIVE BARRIERS OF BREAST CANCER IN BONE MARROW WITH TARGETED PRODRUG NANOTHERAPY

Award Number: R01CA216840

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/12/2018

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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