Entremed (ENMD)

[silver bullet]

new spin on June 2 pr from U of C....June 15, 2010.....New drug kills colorectal cancer, even when key mutations are present

Dr. John Tentler
Collaborator with Drs. Eckhart, Tan and Pitts

Key finding: ENMD-2076 is anti-angiogenic, anti-proliferative and anti-metabolic in advanced colorectal cancer

University of Colorado Cancer Center researchers have shown that a new drug, ENMD-2076, kills colorectal cancer cells and inhibits new tumors from growing in animal models—even when the tumor has specific gene mutations that have been previously hard to target.

John Tentler, PhD, associate professor of medical oncology at the University of Colorado School of Medicine, was the lead researcher on the study, which was published in the June 1 issue of Clinical Cancer Research.

For years, patients with colorectal cancer were given cetuximab, a drug that works to block EGFR, which is overexpressed 60 to 80 percent of colorectal tumors. But study after study has found that about 40 percent of colorectal cancer patients also have a mutation of genes that lie downstream of EGFR—KRAS and BRAF.

Give those patients with metastatic colorectal cancer cetuximab, and only those without KRAS mutation will have benefit. That means people with the KRAS mutation have few good treatments.

“There’s an urgent need to find a new treatment for people with KRAS-mutant colorectal cancer,” Tentler said. “We think that ENMD-2076 may be one of those new good drugs.”

ENMD-2076 has been through early clinical trials at UCCC and other centers, and shows favorable results against solid tumors, such as ovarian cancer (now being tested in Phase II trials) and colorectal cancer.

Tentler’s paper gets at how—and why—the drug works. The preclinical studies showed that ENMD-2076 worked against key biological processes:cell proliferation, angiogenesis and tumor metobolism.

“This drug blocks cancer cell growth by targeting Aurora kinase and VEGFR2,” he said. “We took advantage of the Cancer Center’s excellent technology and expertise of their core facility to use non-invasive imaging, such as PET scans and MRIs, to follow the tumors over time during treatment with ENMD-2076. We were able to gather information about blood vessels and metabolic activity in the tumors. The hope is to make the blood vessels that feed these tumors shrivel up and die.”

Tentler’s experiments, done in xenograft models, show that the drug works well against colorectal cancer regardless of KRAS mutation status—a fact that, if it carries forward to human patients, will be critical for the approximately 60,000 of 150,000 Americans who will be diagnosed with colorectal cancer this year for whom standard treatment may not work.

“We’re essentially doing a clinical trial in mice using these direct patient samples,” he said. “We showed the drug actually caused the tumor stop growing and in some cases to get smaller. That’s a great sign in this model that we hope will prove true in future human clinical trials.”