Platinum-resistant / refractory
MM-121 plus paclitaxel-containing regimen
Many factors can contribute to the development of breast and ovarian cancer. One characteristic of the development of breast and ovarian cancer cells is the accelerated rate at which they divide and grow. To date, the most effective therapies have been cytotoxic chemotherapies that preferentially induce cellular stress and death in cancer cells relative to normal cells. Platinum-containing treatment regimens, as well as taxane-containing regimens, have been the most effective in treating this type of cancer. Taxanes are a class of chemotherapy routinely used for the treatment of breast and ovarian cancer patients that have previously received platinum-based regimens. Taxanes function by inhibiting the ability of tumor cells to properly divide, resulting in cellular stress and ultimately cell death. Despite this mechanism of action, cancer cells have the potential to adapt to overcome the anti-cancer effects of taxanes and it is believed that one way in which cells become resistant is by upregulating prosurvival signaling through ErbB3 (HER3). HER3 is a key tumorigenic protein in many types of cancers. Heregulin, the key ligand of HER3, activates the HER3 pathway, thereby promoting the development, growth, and progression of cancer. Compensatory activation of HER3 is also believed to be a central mechanism by which cancer cells acquire resistance to targeted therapies, as well as many chemotherapies (Schoeberl et al., 2010). MM-121 is a HER3-targeted antibody that functions by inhibiting ligand-induced signaling through HER3 (Schoeberl et al., 2010; Schoeberl et al., 2009). MM-121 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 being tested clinically in combination with paclitaxel for the treatment of platinum-resistant ovarian cancer. By abrogating potential HER3 escape mechanisms through MM-121, the intent is to lower the threshold necessary for cell death, rendering a cancer cell more sensitive to the toxic effects of paclitaxel. We believe that the addition of MM-121 to a paclitaxel regimen may result in a treatment with increased opportunity for tumor toxicity and an improved potential benefit. It is our hypothesis that MM-121 has the potential to help many patients in multiple indications. To continue our learning and to identify new ways this treatment can benefit patients, we are analyzing potential biomarkers in connection with 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.