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 avß3-integrin expression, leading to marked diminished sensitivity to
systemic chemotherapy. Moreover, these data indicated that TGF-ß3 sequestered in the bone microstroma
was liberated to induce avß3-integrin up-regulation. Utilizing this bone BC target, avß3-targeted mixed micelles
(~15nm) incorporating Sn2 lipase-labile docetaxel (DTX) prodrug (DTX-PD) (avß3-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). avß3-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-1a) inhibitor that is cytotoxic to cancer stem cells.
This proposal investigates the efficacy and safety the avß3-CPT-PD-MP or avß3-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 avß3-Sn2-prodrug micelles and also
elucidate the impact of key bone microstroma constituents such as TGF-ß and avß3+ tumor associated
macrophages (M2 TAMS) and avß3+ 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).