ETV1 inhibitor takes lead in combination approach to clinical trials

/ETV1 inhibitor takes lead in combination approach to clinical trials

ETV1 inhibitor takes lead in combination approach to clinical trials

By |2013-06-18T12:58:08-04:00May 20th, 2013|News, Research|

Memorial Sloan-Kettering Cancer Center (MSKCC) is preparing for what it calls “a breakthrough clinical trial” that will test a new drug that uses a MEK inhibitor to target ETV1 in combination with imatinib on a small group of newly diagnosed GIST patients with advanced disease.

We hope to begin recruitment in August, said Dr. William Tap, Section Chief of Sarcoma Oncology at MSKCC. The Phase II trial will be small, with only about 45 participants, and will only have one site at MSKCC in New York City, he said. That’s because “we just want to show that this approach works,” before recruiting for a larger scale trial, Dr. Tap said. There will be a Phase I portion of the trial to define the Phase II doses of the combination regimen.

The trial is unique because most new GIST clinical trials recruit patients that already have taken imatinib, sunitinib or other drugs and have already developed resistance to those drugs. This trial will try to show that treatment with a combination of imatinib and the MEK inhibitor from the start will be even more effective in combating GIST and will reduce the likelihood of secondary mutations that cause resistance.

Novartis Pharmaceuticals is co-developing the MEK inhibitor, MEK162, with Array Biopharma. MEK162 has been through Phase I trials and recently completed a Phase II trial in NRAS-mutant melanoma.

tapDr. Tap said the research that opened the way to this new approach was led by his colleague at MSKCC, Dr. Ping Chi. She was able to show that ETV1, a transcription factor, was essential to the survival of GIST; while it was hard to target ETV1 because it didn’t have molecule-binding pockets that could be blocked by drugs, she found a way around this problem by discovering that MEK inhibitors could do that job.

“MEK inhibitors alone doesn’t seem to be great, but by doing combination therapy with imatinib we get a dramatic response,” Dr. Chi said. ETV1 is a master regulator that is highly expressed in all GISTS.

“Ping’s discovery is one of the major discoveries that we have seen in GIST research since the discovery of KIT,” Dr. Tap said.

In 2010, Dr. Chi published a study she led, “ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours,” in Nature.

In a review of the study in Nature, LRG Research Team members Michael Heinrich and Christopher Corless wrote: “Whether the survival of GIST stem/progenitor cells depends on ETV1 is therefore a pertinent question. If so, targeting ETV1 in GISTs may produce the cure that currently eludes KIT inhibitors such as imatinib.”

Since 2010, Dr. Chi and her colleagues have been working on a way of finding a practical application for their findings. And now they think they have one.

“We were interested in developing novel approaches to GIST because of the imatinib resistance, and we stumbled upon ETV1, which is a transcription factor,” Dr. Chi explained. She said ETV1 plays a role in other cancers, also driving the pathogenic process, but in GIST it is the master regulator in the development of cancer cells. That means it regulates a group of target genes, called the transcriptional targets, which in turn are required for the proper development, specification and survival of a particular cell lineage, such as the Interstitial Cells of Cajal that play a role in GIST.

She said that by conventional thinking, targeting ETV1 was thought to be difficult because it doesn’t have the molecule-binding pockets that you could design a drug for. However, she found that the protein stability of ETV1 is controlled by MEK signaling. “So we thought, aha, maybe we could target the signaling pathways. We thought that if we could inhibit the MEK pathway we could destroy the ETV1 protein.”

Although using the MEK inhibitor alone didn’t produced great results, Dr. Chi said, when they tried using MEK inhibitors in combination with imatinib in vivo “we saw really dramatic responses.” Studies in mice have also yielded positive results.

“The hard thing was trying to find the right drug to target this clinically,” Dr. Tap said. “That’s what Ping and I have been working on for well over a year now. We’ve spent a lot of time with Novartis (Pharmaceuticals) sharing Ping’s data, and they’ve been very supportive about moving forward with the clinical trial.”

Dr. Tap said that while imatinib has been a great drug for GIST, many patients inevitably develop resistance and their tumors begin to grow again.

“We know that their tumors become much more complex on a genetic level, and because of that we often don’t see the results we would like to see” in clinical trials for new drugs, Dr. Tap said. “What we’re trying to do is bring the combination up front in newly diagnosed patients where we can have the greatest impact.”

He said if the small trial “shows this principle works, we’d really like to move it forward into a larger trial.”

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