Two pathways have long been of interest to researchers studying colon cancer: Notch and MAPK. But drugs designed to target either pathway have proven disappointing. Now a team of researchers in Germany has made a discovery that sheds light on those disappointments—and provides insight that could improve colon cancer treatment.
The team, from Ludwig-Maximilians-Universität (LMU) in Munich, studied more than 300 patient samples and discovered that colon cancers are made of two different types of cell that can replace each other if one is killed off, according to a statement. Cells in the middle of colon tumors had active Notch signaling but reduced MAPK signaling, and are highly proliferative, the researchers said. On the other hand, cells at the tumor edge had active MAPK signaling but low Notch activity and seemed to be in the first stages of metastasis.
They tried attacking each pathway in mouse models but found that the single-target approach was an incomplete solution. AstraZeneca/Array's experimental MAPK inhibitor selumetinib quickly rid the mice of MAPK-active cells. But then the Notch cells multiplied, compensating for the loss. Stopping the treatment allowed some of the Notch cells to form new metastasis-ready MAPK cells along the tumor edge.
Treating the mice with the Notch-blocking chemical dibenzazepine had the opposite effect: It cleared the Notch-active cells, leaving the MAPK cells behind to multiply and give rise to new Notch cells when the treatment was stopped. Targeting Notch alone could be harmful to colon cancer patients, as it increases the number of MAPK-active cancer cells that are about to start spreading. The findings appear in the Journal of Experimental Medicine.
"This suggests that colon cancers may evade targeted treatment against MAPK or Notch signaling by a reversible shift in the predominating pathway activity," said David Horst, deputy director of the Pathologisches Institut at LMU, in the statement. "However, when combining both therapies to target both cell populations, we found strong repressive effects on tumor cell proliferation and increased cell death, resulting in slower tumor growth and prolonged survival times compared to either treatment alone."
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Scientists working on Notch-targeting drugs have run into selectivity problems that cause dose-limiting side effects. OncoMed called off a phase 2 trial of its Notch drug, tarextumab, in pancreatic cancer due to worsening response rates and a "low likelihood" of improving overall survival. But challenges in the field have not deterred Ayala Pharmaceuticals, which raised $17 million in April to advance a gamma secretase inhibitor licensed from Bristol-Myers Squibb into phase 2. The Israeli biotech is developing it as a precision medicine for patient populations with diseases affected by Notch activating mutations, including cancer.
The German team argues that its data support "specific and simultaneous targeting" of the divergent cells found in colon tumors, Horst said. "Further preclinical and clinical trials may therefore reveal if combined MAPK and Notch inhibition, in addition to established chemotherapeutic protocols, can improve therapy response in patients with colorectal cancer."