No abstract

Ninety percent of deaths from cancer are caused by metastasis. miRNAs are critical players in biological processes such as proliferation, metastasis, apoptosis, and self-renewal. We and others have previously demonstrated that miRNA-10b promotes metastatic cell migration and invasion. Importantly, we also showed that miR-10b is a critical driver of metastatic cell viability and proliferation. To treat established metastases by inhibiting miR-10b, we utilized a therapeutic, termed MN-anti-miR10b, composed of anti-miR-10b antagomirs, conjugated to iron oxide nanoparticles, that serve as delivery vehicles to tumor cells in vivo and a magnetic resonance imaging (MRI) reporter. In our previous studies using murine models of metastatic breast cancer, we demonstrated the effectiveness of MN-anti-miR10b in preventing and eliminating existing metastases. With an outlook toward clinical translation of our therapeutic, here we report studies in large animals (companion cats) with spontaneous feline mammary carcinoma (FMC). We first investigated the expression and tissue localization of miR-10b in feline tumors and metastases and showed remarkable similarity to these features in humans. Next, in the first case study involving this therapeutic we intravenously dosed an FMC patient with MN-anti-miR10b and demonstrated its delivery to the metastatic lesions using MRI. We also showed the initial safety profile of the therapeutic and demonstrated significant change in miR-10b expression and its target HOXD10 after dosing. Our results provide support for using companion animals for further MN-anti-miR10b development as a therapy and serve as a guide for future clinical trials in human patients.

Despite many advances in cancer treatment, metastatic disease is estimated to be responsible for 90% of all cancer-related deaths. Current treatments for metastatic disease target various aspects of carcinogenesis but not specifically the metastatic process, representing a major unmet clinical need. MicroRNA-10b, a small non-coding RNA, offers tremendous potential as a treatment target for metastatic disease. It is implicated in invasion, migration, and viability of metastatic cells across a variety of cancer types, and it is upregulated in metastases compared to their matched primary tumor, establishing miR-10b as a potential treatment target unique to metastatic niche. We have previously developed a therapeutic targeting miR-10b in metastases and tested it in murine models of metastatic breast cancer. This therapeutic, consisting of an anti-miR-10b antisense oligonucleotide conjugated to iron oxide-based nanoparticles, prevents metastasis and eradicates pre-existing metastases in murine breast cancer models. With an outlook to clinical translation of our approach, we seek to test our therapeutic strategy in larger animal models. Feline mammary carcinomas are considered by most to be the best large animal model for human breast cancer due to similarities such as relative age of onset, histopathology, metastatic patterns, and treatment response. To support the use of this model with our therapeutic, we investigated the characteristics of miR-10b expression in spontaneous metastatic breast cancer in companion cats. Archival blocks of matched primary tumors and metastatic lymph nodes from companion cats diagnosed with mammary carcinoma (n=9, 44%TNBC, 56%HER2+) were obtained from the tissue bank of the Michigan State University (MSU) Veterinary Diagnostic Laboratory (VDL). Tissues were analyzed for miR-10b and its target HOXD10 expression using qRT-PCR and in situ hybridization. qRT-PCR revealed that miR-10b expression was significantly upregulated in 55.5% of lymph node metastases compared to their matched primary tumor, mirroring findings in human metastatic cancer. This was validated by qRT-PCR for HOXD10 gene expression (a direct target of miR-10b), which was significantly downregulated in these metastases compared to their matched primary tumor. In situ hybridization demonstrated that miR-10b expression was increased at the invasive edge of tumors and in actively invading cells, suggesting miR-10b plays a similar role in invasion in feline breast cancer as it does in human breast cancer. Altogether, these findings support the use of feline mammary carcinomas as a model of human breast cancer and as an excellent candidate for treatment with our therapeutic. Citation Format: Alan Halim, N. Anna Savan, Paulo Vilar Saavedra, Vilma Yuzbasiyan-Gurkan, Matti Kiupel, Lorenzo Sempere, Anna Moore. Prospective Use of Feline Mammary Carcinomas to Study MiR-10b and Metastasis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-08-02.