About 40,000 women die each year from breast cancer in the US due to development of chemoresistance. Although ER/PR-positive breast cancer patients are treated effectively with endocrine therapy, chemotherapy is still one of the most effective and widely used means of treating breast cancer The patients in the triple- negative breast cancer (TNBC) group are dependent on chemotherapy as the sole therapy and their prognosis is poor due to inherent resistance. Her2 positive breast cancer patients are commonly treated with Herceptin but only in combination with chemotherapy. In addition, a significant fraction of breast cancer patients with large locally advanced cancers receives neoadjuvant therapy. Thus, there is clear unmet need to overcome chemoresistance in breast cancer patients. It is known that most cancer cells primarily use glycolysis as their main source of energy (ATP). However, this paradigm is currently changing in light of new studies supporting critical roles for mitochondria respiration in promoting cancer metastasis and chemoresistance. Thus, mitochondria are now being incorporated as targets into cancer treatment strategies but the challenge is the development of effective modulators of mitochondrial respiration that have minimal toxicity. We have identified MCJ (DnaJC15) as a mitochondrial protein that acts as an endogenous brake of the mitochondria respiration. MCJ is the first identified endogenous negative regulator of Complex I of the electron transport chain (ETC). Loss of MCJ expression promotes Complex I activity and production of mitochondrial ATP without affecting glycolysis rate. We have shown that MCJ expression is lost or markedly reduced in drug- resistant breast cancer cell lines. Recently, we have shown that loss of MCJ causes chemoresistance in vivo and that low MCJ in breast tumors correlates with poor chemotherapy response. Together, these studies indicate that restoring MCJ function in those breast cancer cells that have lost or reduced MCJ could be a novel approach to overcome chemoresistance. We have developed MCJ mimetics and our preliminary studies support the utility of these compounds as potential therapeutic drugs to safely reverse chemoresistance in breast cancer. The goal of this exploratory/developmental R21 application is to demonstrate that MCJ mimetics reverse resistance to a variety of standard chemotherapeutic drugs for breast cancer in vitro and in vivo using different mouse models, and cause no toxicity. We will determine: 1) the efficacy of MCJ mimetics in overcoming chemoresistance in vitro (Aim 1); the efficacy of MCJ mimetics in overcoming chemoresistance in vivo in mouse models (Aim 2) .
About 40,000 women die each year from breast cancer in the US due to development of chemoresistance. Chemotherapy is still one of the most effective and widely used means of treating breast cancer. More than one third of the breast cancer patients are dependent on chemotherapy as the only available treatment (including those who are already diagnosed with metastatic cancer). Thus, there is clear unmet need to overcome chemoresistance in breast cancer patients. One of the mechanism by which breast cancer cells become resistant to chemotherapy is the use of drug efflux pumps that send the chemotherapeutic drugs outside of the cells to protect them from death. These pumps (called ABC transporters) use a lot of energy in the form of ATP to pump drugs outside of the cells. Our recent studies indicate that the ATP used as source of energy for these pumps is generated by mitochondria, intracellular organelles that act as engine of the cells. Thus, to overcome chemoresistance we propose to reduce the energy (ATP) produced by mitochondria (engine of the cancer cells). We have recently discovered that some cancer cells have lost a new molecule, MCJ, that we have identified as a brake for mitochondria. As a result, the engine (mitochondria) of those MCJ- deficient cancer cells has more power, makes more ATP (energy) and as a consequence the drug efflux pumps are more active and the cells are more resistant. We have developed new compounds (MCJ mimetics) that restore MCJ function in those cells that have lost it. Basically MCJ mimetics act as alternative brakes of the mitochondria, to reduce the ATP used by the pumps. Our preliminary studies support that these MCJ mimetics could be used as therapeutics to overcome chemoresistance to standard chemotherapeutic drugs used for breast cancer patient treatment.
