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 ?v?3-integrin expression, leading to marked diminished sensitivity to systemic chemotherapy. Moreover, these data indicated that TGF-?3 sequestered in the bone microstroma was liberated to induce ?v?3-integrin up-regulation. Utilizing this bone BC target, ?v?3-targeted mixed micelles (~15nm) incorporating Sn2 lipase-labile docetaxel (DTX) prodrug (DTX-PD) (?v?3-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). ?v?3-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-1?) inhibitor that is cytotoxic to cancer stem cells. This proposal investigates the efficacy and safety the ?v?3-CPT-PD-MP or ?v?3-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 ?v?3-Sn2-prodrug micelles and also elucidate the impact of key bone microstroma constituents such as TGF-? and ?v?3+ tumor associated macrophages (M2 TAMS) and ?v?3+ 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).

Public Health Relevance

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) disseminated tumor cells (DTCs), 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 bone metastasis in the presence of TGF? in bone , in vitro and in vivo, up-regulated ?v?3-integrin expression, leading to marked diminished sensitivity to systemic chemotherapy. Utilizing this bone BC target, ?v?3-targeted mixed micelles incorporating Sn2 lipase-labile docetaxel prodrug (DTX-PD) (?v?3-DTX-PD MP) were developed and found to rapidly and homogeneously penetrate into BC bone tumors and deliver DTX therapy directly into the cell through a novel approach, termed 'Contact Facilitated Drug Delivery' (CFDD). ?v?3-DTX-PD MP markedly reduced bone marrow BC tumor burden and bone 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. Of note, many patients with bone metastasic breast cancer likely will have previously received DTX, so we propose to utilize and test additional non-cross resistant chemotherapies for use in the ?v?3-micelles. From this perspective and recognizing the 'stem cell' nature of breast cancer bone metastases, a camptothecin (CPT) Sn2 lipase-labile prodrug (CPT-PD) has been developed to offer a new patient-naive treatment. Overall, this project will delineate the efficacy and safety of ?v?3-Sn2-prodrug micelles for BC bone metastases and also elucidate the impact of key bone microstroma constituents such as TGF-? and ?v?3+ tumor associated macrophages (M2 TAMS) and ?v?3+ 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).

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA216840-02
Application #
9625105
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Fu, Yali
Project Start
2018-01-12
Project End
2022-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130