Abstract 1311: PET-MRI microdosing can determine the delivery of the experimental cancer therapeutic, MN-anti-miR10b, to metastatic lesions in a murine model of breast cancer

Abstract

Abstract Conventional therapies, which are effective against primary cancer, oftentimes are not successful at treating metastatic cancer. In our earlier work, we identified miRNA-10b as a master regulator of the viability of metastatic tumor cells. This knowledge allowed us to design a miR-10b inhibitor, termed MN-anti-miR10b, capable of delivery to metastatic sites via intravenous injection. In mouse models of breast cancer, we demonstrated that MN-anti-miR10b, when combined with a low-dose cytostatic, caused lifelong complete regressions of established metastases with no evidence of systemic toxicity. As a first step towards translating MN-anti-miR10b for the treatment of metastatic breast cancer, we needed to determine if MN-anti-miR10b, which is so effective in mice, will also accumulate in human metastases. Towards that goal, we developed a method to radiolabel MN-anti-miR10b with Cu-64, inject a microdose of the radiolabeled MN-anti-miR10b into murine models of metastatic breast cancer, and determine the uptake of the therapeutic by the metastatic lesions using positron emission tomography-magnetic resonance imaging (PET-MRI). Specifically, we injected a microdose of 64Cu-MN-anti-miR10b into mice bearing luciferase-expressing metastatic breast adenocarcinoma and performed in vivo bioluminescence (BLI) and PET-MRI to assess uptake by the metastatic lesions. The lesions were identified by BLI, based on their luciferase expression. PET-MRI clearly demonstrated uptake of 64Cu-MN-anti-miR10b, measurable at a microdose. Ex vivo PET-MRI confirmed that the activity was associated with the metastatic lesions, as identified at necropsy. Uptake by metastatic organs was also demonstrated by scintigraphy and shown to be significantly higher than in the same organs devoid of BLI-detectable metastatic lesions. Finally, 64Cu-MN-anti-miR10b injected as a non-carrier added microdose had comparable biodistribution to that injected at a standard therapeutic dose. The value of the current study is in setting the stage for clinical PET-MRI microdosing, which would be able to answer a key question on the path to drug development without the associated cost to do a full clinical trial – the question of delivery to the target organ sites. Since the PET technique is sensitive enough to determine the concentration of radiolabeled drug with sensitivity approaching the sub-picomolar range, as little as a microgram of the radiolabeled drug is sufficient to perform a PET-MRI study in humans. In addition to proving delivery, the microdosing studies will reveal the pharmacokinetic behavior of MN-anti-miR10b which will allow one to establish dosing during therapy. Finally, in clinical trials, one can use microdosing PET-MRI to select patients for treatment, based on which patients' metastases accumulate the therapeutic. Citation Format: Marianne Le Fur, Byunghee Yoo, Nicholas Rotile, Pamela Pantazopoulos, Alana Ross, Iris Zhou, Peter Caravan, Zdravka Medarova. PET-MRI microdosing can determine the delivery of the experimental cancer therapeutic, MN-anti-miR10b, to metastatic lesions in a murine model of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1311.