ER/PR-Positive (HER2 negative)
MM-121 and exemestane-containing regimen
Subclasses of breast cancer are often described based on the presence or absence of specific receptors. In the case of ER-positive breast cancer, cancer cells that express the Estrogen Receptor (ER) are stimulated to grow by estrogen through the associated activation of downstream growth signaling pathways. Depriving tumor cells of estrogen, through administration of anti-hormonal drugs such as exemestane, has emerged as an effective way to treat ER-positive breast cancer patients. Exemestane functions by blocking the enzyme aromatase, which is responsible for the production of estrogen, thereby resulting in a reduction in ER signaling.
Although many patients respond positively to exemestane treatment, this effect can be reduced in patients who have been previously treated with an anti-hormonal agent, and patients ultimately become resistant to this therapy. One proposed mechanism by which tumor cells become resistant is through activation of the HER3 receptor and its associated signaling pathways. HER3 signaling is believed to be a central mechanism by which cancer cells in general acquire resistance to anti-hormonal therapy, as well as other targeted therapies and many chemotherapies (Schoeberl et al., 2010). Ligand- induced signaling of HER3 activates signaling pathways that promote the development, growth, and progression of cancer and that mediate cell survival in the face of chemical stress. MM-121 is a HER3-targeted antibody that functions by inhibiting heregulin-induced signaling through HER3 (Schoeberl et al., 2010; Schoeberl et al., 2009). This mechanism of action is designed to inhibit cancer growth directly, restore sensitivity to drugs to which a tumor has become resistant, and delay the development of resistance to other agents.
MM-121 is currently being tested clinically in combination with exemestane in postmenopausal women with hormone receptor-positive breast cancer. By directly inhibiting activation of the estrogen receptor through the administration of exemestane, and simultaneously inhibiting HER3-mediated growth and resistance through the administration of MM-121, we hope to block tumor growth and the development of resistance to exemestane. Collectively, this combined approach is necessary to block both the key pathway driving cancer growth as well as a key pathway that is used to escape growth inhibition.
It is our hypothesis that MM-121 has the potential to help patients in multiple indications. To continue our learning and to identify new ways this treatment can benefit patients, we are analyzing several potential biomarkers in connection with our MM-121 clinical trials. Through this approach, we hope to generate additional knowledge on how ErbB3 signaling affects response to therapy and then apply this understanding to identify patients that will most likely benefit from treatment regimens that include MM-121.