Notch Signaling Inhibitor Shows Promise as Treatment for Colon, Other Cancers, Study Shows

Notch Signaling Inhibitor Shows Promise as Treatment for Colon, Other Cancers, Study Shows

A new treatment for colon and other cancers that addresses mutations of the Notch signaling pathway is showing promise, researchers say.

“Notch signalling is an important contributor to the development of a variety of cancers,” said Dr. Kapil Dhingra, who presented the results of a Phase 1 trial of the treatment at the 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, in Munich, Germany. “However, successful development of drugs against this pathway has been challenging, in part due to unacceptable side effects,” Dhingra said in a news release.

“While preliminary, the results of the Phase 1 study of LY3039478 show evidence of anti-tumor activity in a number of different tumor types with a manageable safety profile, added Dhingra, a managing member of KAPital Consulting in the US. “These results warrant further investigation of this drug in clinical trials.”

The Notch signaling pathway regulates processes that differentiate cells in embryos and people. Mutations of the pathway are associated with several cancers, however.

“Research suggests that the Notch signalling pathway plays a role in helping cancer cells to grow, divide and spread around the body; it is also involved in angiogenesis, the process by which tumors grow new blood vessels, and it may contribute to tumors becoming resistant to chemotherapy,” said Dr. Christophe Massard, a senior medical oncology consultant and chair of the Early Drug Development program at the Institut Gustave Roussy Cancer Campus in Paris. “Notch signalling that is unregulated due to mutations in the Notch protein is implicated in a number of cancers.”

Scientists have tried other treatments to block the pathway in cancer patients, with promising results in lymphoma and rare cancers. But the therapies caused such severe gastrointestinal toxicity that they were put on hold.

Researchers tried the new Notch inhibitor, LY3039478, on 103 cancer patients in a Phase 1 trial (NCT01695005). The participants had tumors of the colon, breast, and salivary glands, and sarcoma.

Participants received LY3039478 orally three times a week for two 28-day cycles. Gastrointestinal specialists watched for toxic effects of the treatment.

LY3039478, which inhibits all four Notch receptors, shrank the tumor of one breast cancer patient and stopped the progression of the disease in 29 patients. PET scans showed that the treatment had also shrunk the tumors of a patient with adenoid cystic sarcoma and another patient with testicular cancer.

The most common side effects were diarrhea (48%), vomiting (40%), nausea (38%), loss of strength (25%) and loss of appetite (21%), but they were considered manageable. Some patients also reported weight loss, hair loss, and dry skin and mouth.

In a dose-escalating part of the trial, researchers were able to identify the recommended dose for the Phase 2 trial: 50 mg three times a week, for 28-day cycles, until the disease begins progressing or there is an unacceptable toxicity level.

Researchers plan another trial to assess LY3039478 in combination with other investigational or approved cancer drugs: talategib for breast cancer, abemaciclib for colon cancer, Platinol (cisplatin) for cholangiocarcinoma, and Gemzar (gemcitabine) and Paraplatin (carboplatin) in soft-tissue sarcoma.

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