Drug Developed at Fox Chase Holds Promise for Gastroesophageal Cancer

Above, ligand-dependent activation of HER3 and its subsequent dimerization with HER2 leads to potent activation of the PI3K/Akt pathway, a signaling cascade that plays essential roles in regulating cellular homeostasis. Inappropriate signaling through the HER2/HER3 heterodimer is linked to the formation and progression of a number of cancers, including gastric and breast cancers. MM-111, an anti- HER2/anti-HER3 bispecific antibody, blocks signaling through this critical receptor pair and inhibits the growth of HER2/HER3-driven cancer cells.

Above, ligand-dependent activation of HER3 and its subsequent dimerization with HER2 leads to potent activation of the PI3K/Akt pathway, a signaling cascade that plays essential roles in regulating cellular homeostasis. Inappropriate signaling through the HER2/HER3 heterodimer is linked to the formation and progression of a number of cancers, including gastric and breast cancers. MM-111, an anti- HER2/anti-HER3 bispecific antibody, blocks signaling through this critical receptor pair and inhibits the growth of HER2/HER3-driven cancer cells.

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Crystal Denlinger, MD

A first-of-its-kind drug that emerged from research at Fox Chase Cancer Center is now moving into an important new area: gastroesophageal cancer. “This is a drug that could provide new therapeutic options in a disease that doesn’t have many,” says medical oncologist Crystal Denlinger, MD, who is leading a worldwide study to test the compound’s effectiveness in cancers of the stomach and esophagus.

At the time of the drug’s initial conception, scientists were developing therapies for lung, breast, and bladder cancers that targeted cells making an excess of the HER2 protein, which is associated with both tumor growth and a poor prognosis. Therapies targeting HER2-positive cells alone, however, weren’t producing optimal results. Greg Adams, PhD, director of biological research and therapeutics at Fox Chase and Louis M. Weiner, MD, then chairman of medical oncology at Fox Chase, decided to pursue a therapy that would block both HER2 and another protein that promotes cancer growth, HER3. Weiner is now director of the Lombardi Comprehensive Cancer Center at Georgetown University.

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Greg Adams, PhD

To accomplish this, a novel bispecific antibody was engineered by Eva Horak in Adams’ lab in collaboration with James Marks, MD, PhD, of the University of California San Francisco. The antibody features two binding sites — one that attaches to HER3 and one to HER2. This prevents HER3 from binding with a growth factor, which would in turn trigger HER3 to pair with HER2, activating both; this single compound therefore shuts down two cancer-promoting activation pathways. Matthew Robinson, PhD, an assistant professor in Fox Chase’s Developmental Therapeutics Program, then guided the new antibody through a series of preclinical assays that validated its specificity and function.

To further test the approach, Fox Chase and UCSF partnered with Merrimack Pharmaceuticals, Inc., which licensed the lead antibody and modified it to improve its pharmacokinetics. The resulting drug is known as MM-111. Merrimack then turned to Fox Chase and South Texas Accelerated Research Therapeutics to assess the safety of MM-111 in patients with HER2-positive cancers. Those results, initially reported by Denlinger at the San Antonio Breast Cancer Symposium in December 2010, showed tolerable side effects, none of which were unexpected. Fox Chase also participated in another safety trial examining MM-111 when combined with multiple chemotherapy drugs.

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Matthew Robinson, PhD

When initial studies demonstrated that Herceptin (trastuzumab), an existing HER2-targeting drug, had some effect against HER2-positive gastroesophageal cancers when combined with chemotherapy, Denlinger wondered whether MM-111 might be an effective treatment for these cancers. Eventually, that thought led to a global clinical trial involving 60 centers. The current study, for patients with advanced esophageal, gastroesophageal junction, and gastric cancer, targets tumors that have moderate or high expression of the HER2 protein on the surface of the cancer cells. The trial combines MM-111 with standard chemotherapy treatment.

From the development of the drug through first-in-human trials to efficacy studies for gastric cancer and other diseases, Fox Chase scientists have had the unique experience of shepherding MM-111 through its entire development. “This came out of Fox Chase, went to a company, and came back to Fox Chase,” says Robinson, “which is the ideal situation.” ■