Modulation of Breast Cancer Metastasis Using Bone-Targeted Delivery of a Small Anti-Cancer Peptide - PROJECT SUMMARY Breast cancer, the most commonly diagnosed cancer and the second cause of women’s cancer mortality remains a global public health problem. Breast cancer can eventually metastasize to the bone, lungs, liver, brain, and soft tissues in more than 20-40% of cases over decades after the primary diagnosis. This phenomenon is particularly prominent in ER+ BC, as it remains dormant for years. Triple-negative breast cancer (TNBC) accounts for 10–20% of all breast cancer cases and carries a poor prognosis due to its highly aggressive nature, high incidence of relapse, and metastasis. TNBC is refractory to treatments with a higher mortality rate. Despite their severe adverse effects, cytotoxic chemotherapy remains the treatment mainstay. TNBC frequently metastasizes to bone and other tissue where systemic therapies fail to penetrate adequately. Previous studies showed that Angiotensin 1-7 (Ang1-7) inhibits cancer cell proliferation and metastasis in culture and xenograft animal models and presents a favorable safety profile. Yet, Ang1-7’s biological activity is hampered by poor pharmacokinetics (PK) and short half-life (t1/2). Thus, improving its t1/2 and PK profile and explicitly targeting primary and secondary cancer sites is vital to recovering Ang1-7 anti-cancer efficacy. A novel bone-targeting Ang1-7 conjugate (Ang Conj) has been developed in our laboratory. Our innovative strategy to address these goals is to target Ang1-7 to the bone. Since bone is one of the most common sites of metastasis in TNBC patients, targeting the anti-cancer peptide Ang1-7 to the bone will create a drug depot on the bone with sustained delivery of adequate levels of Ang1-7 to inhibit tumor metastasis in the bone and other tissues. Indeed, our preliminary studies demonstrate that the Ang Conj has >10-fold greater t1/2, favorable bone tissue distribution, and significantly increased anti-cancer effects in vitro and in vivo. Our long-term goal is to advance the application of this novel and safe Ang Conj to prevent and treat metastatic TNBC and to provide an effective alternative to the current invasive and highly toxic treatment modalities. Expected outcomes: Ang Conj will prove safe and effective in models of metastatic TNBC. Our approach will prevent tumor metastasis to the bone by targeting the site and providing sustained plasma concentration of active peptides to protect other tissue. Advancing this strategy to the clinic would offer a much-needed alternative to traditional toxic chemotherapy in TNBC that could be applied to different types of refractory cancers, such as lung, colorectal, and prostate cancers. Page 1 of 1
