SUN-300 - Inhibition of Creatine Kinase Activity Represses Breast Cancer Brain Metastasis

Dysregulated tumor cell metabolism is a hallmark of cancer progression and therapeutic resistance. We previously identified creatine kinase brain isoform (CKB) as a direct Hypoxia-Inducible Factor (HIF)-dependent gene that promotes invasion and metastasis in triple-negative breast cancer models. Knockdown of CKB also reduced intracellular ATP levels by inhibiting oxidative phosphorylation and glycolytic flux. The small molecule cyclocreatine (cCr), a creatine analog and creatine kinase substrate that inhibits creatine kinase activity, has been shown to inhibit breast cancer lung metastasis, prostate cancer progression and metastasis, and colorectal cancer metastasis to the liver. cCr is also known to cross the blood-brain barrier (BBB). We have tested the anti-metastatic activity of cCr in two luciferase reporter-labeled brain-enriched breast cancer metastasis models that produce concurrent extracranial metastases following intracardiac injection, 231-BrM2 (TNBC) and JIMT (HER2+). Whereas cCr (0.75 g/kg, daily, IP, in saline) repressed both brain and bone metastasis in the BrM2 model, it had no effect on either brain or extracranial metastasis in the JIMT model. To expand these studies to additional brain metastasis models, we have serially passaged the taxane-refractory, HCI-10 TNBC PDX model from the mammary fat pad to the brain (over three rounds) to generate a novel, brain metastasis-enriched subline of HCI-10 that develops brain metastases with 100% penetrance after intracardiac injection. New data from ongoing studies assessing the efficacy of cCr in the HCI-10 brain-metastasis model will also be presented.

This work was sponsored by Metavivor, the Mary Kay Ash Foundation, and the Department of Defense (BC220493).

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