Speaker: Liyang Cui, Stanford
Program Description:
Breast cancer is the number two cause of death among all types of cancers in women. The deadliest subtype of breast cancer, triple-negative, carries the highest metastatic risk and poorest outcome due to the resistance to current therapeutic methods. Triple-negative breast cancer (TNBC) is an intrinsically heterogeneous disease. Targeting single biomarker or oncogene often yields unsatisfactory therapeutic outcome in TNBC treatment. To achieve a broader therapeutic benefit, our starting point is copper ion, one critical metal ion that plays irreplaceable roles in a broad range of biochemical reactions. Copper excess in serum and cancerous tissues has been long recognized in breast cancer patients. Dysregulation of copper metalloproteins is found to be involved in uncontrolled growth, invasion, dissemination of cancer cells, angiogenesis and secondary tumor formation at distant sites. Despite the well-recognized importance, successful attempts to treat cancer with copper chelation are rather limited.
We develop a mitochondrial copper depleting strategy that exploits the potential metabolic vulnerability of TNBC. We formulate a copper-depleting nanoplatform (CDN), a positively charged copper depleting complex that targets mitochondria and deprives the cytochrome c oxidase of its copper co-factor. CDN inhibits electron transport chain complex IV, decreases the oxygen consumption and abrogates oxidative phosphorylation of TNBC cells. Shutdown of oxidative phosphorylation significantly reduces the energy production and induces a unique metabolic switch to glycolysis. Together with energy deficiency, compromised mitochondrial membrane potential and elevated oxidative stress result in TNBC cell apoptosis after CDN treatment. CDN reports its copper depleting status through multimodal optical signal changes. Strategic administrations of CDN based on the imaging results effectively decrease copper level in TNBC tumors and inhibit tumor growth with low toxicity and significantly prolonged survival.
