Overexpression of the HER2 (ErbB2) cell surface receptor has been reported in 10-25 percent of gastric and esophageal cancers. The HER2 receptor triggers tumor growth and survival when it binds together with an additional receptor known as HER3 (ErbB3) and another protein called heregulin. HER3 expression has been associated with poor prognosis in gastric cancer. MM-111 is designed to anchor to both receptors, HER2 and HER3, on the cell surface and block heregulin's ability to transmit tumor growth signals, thus inhibiting the tumor cell's ability to thrive.
"The protein heregulin can often cause resistance to standard chemotherapy and targeted treatments in gastric tumors that express both HER2 and HER3," said
Merrimack is initiating a Phase 2 study testing MM-111 in combination with paclitaxel or with paclitaxel and trastuzumab for the treatment of advanced gastric, esophageal and gastroesophageal junction (GEJ) cancers. Merrimack is also currently conducting a Phase 1 study of MM-111 across multiple HER2+ tumors, including breast, colorectal, gastric, esophageal and ovarian cancers.
Results of the preclinical study showed that the combination of MM-111 with trastuzumab is synergistic in a preclinical HER2-expressing gastric cancer model. Additionally, the study found that heregulin desensitizes gastric tumor cells to the effects of trastuzumab and paclitaxel. The addition of MM-111 to the paclitaxel and trastuzumab regimen, or the addition of MM-111 to either paclitaxel or trastuzumab, restored sensitivity of tumors to treatment in the model.
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