Breast cancer is expected to be the most diagnosed cancer in the United States in 2024, with a predicted 310,000 new diagnoses. Hormone and targeted therapies, as well as earlier detection, have greatly improved the outlook for the majority of breast cancer patients. Unfortunately, there is still an unmet clinical need for the breast cancer subtypes that are not receptive to these therapies and, more importantly, the metastases that may arise if the cancer is allowed to progress, as their effect on vital function is reported to be the cause of up to 90% of cancer-related deaths. Current standard of care for metastatic disease includes treatments based on the subtyping of the primary tumor and chemotherapy; however, these treatments fail to appreciate the changes cancer cells undergo during the metastatic process and the differences that may exist between metastases and the primary tumor they originate from, which can include a change in subtype.The discovery of miR-10b, a small noncoding RNA that acts as a translational repressor for select targets, as a driver of breast cancer metastasis provided a target for the design of therapeutics tailormade against the metastatic process; and with reports that metastases have greater miR-10b expression than their matched primary tumors, these therapeutics may also be effective in treating existing metastases. Our lab developed one such therapeutic by conjugating anti-miR-10b antisense oligonucleotides to a Magnetic iron oxide Nanoparticle (MN) core, collectively named MN-anti-miR10b. In previous studies using a mouse model of spontaneously metastatic breast cancer, intravenous administration of MN-anti-miR10b has already demonstrated the ability to prevent onset of metastasis and to halt the growth of existing metastases. While not able to induce regression of metastases as a monotherapy, combination therapy with doxorubicin – a chemotherapeutic commonly used in the treatment of breast cancer – reproducibly eradicated metastases in both immunocompromised and immunocompetent mouse models of spontaneously metastatic breast cancer. Within this work, I showcase several of the contributions I made in advancing MN-anti- miR10b toward the clinic. I begin by consolidating the literature on miR-10b in breast cancer, highlighting many of the properties it has been associated with conferring and discussing its potential applications as a clinical marker and therapeutic target. Then, I demonstrate the modalities through which MN delivery to target metastatic tissues can be monitored, which is a major advantage when working to treat widespread metastatic disease that may present in otherwise undetectable or sensitive locations. These techniques are applied to a new study in which I investigate how miR-10b expression changes in mouse metastatic tissues as a function of the number of doses of MN-anti-miR10b administered. After showing that miR-10b can be almost completely suppressed in these tissues in as little as two treatments, I use RNA sequencing to identify the transcriptional effects of miR-10b inhibition in breast cancer cell lines, producing what I believe to be the first public dataset of its kind in this type of cancer. The sequencing results indicate the activation of developmental processes in response to miR-10b inhibition, which I then use to establish a link between miR-10b and stem-like cancer cells and further validate by finding that stemness is reduced in breast cancer cells upon treatment with MN-anti-miR10b. Lastly, I summarize work I contributed to in which a companion cat with spontaneous metastatic breast cancer recapitulating human disease was treated with MN-anti-miR10b. This work is part of translational studies that the Moore Lab is conducting with the aim of bringing this therapeutic into the clinic. The findings from this study support the clinical applications of MN-anti-miR10b as a therapy for metastatic breast cancer in humans in different ways, bringing the drug one step closer toward filling this urgent need.
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