Mutations in the anaplastic lymphoma kinase (ALK) gene drive tumor formation in two new transgenic mouse models of neuroblastoma, according to independent reports published this month.
“These are very exciting,” said Yael Mossé, MD, Attending Physician at Children's Hospital of Philadelphia and Assistant Professor at the Perelman School of Medicine at the University of Pennsylvania, who was not involved in developing either model.
“They are proof of concept, proof of what we already knew: that ALK is important in familial neuroblastoma and a driver in this disease. Both of the papers prove that if you force expression of a particular mutation in ALK, you see development of neuroblastoma tumors.”
Perhaps more interesting for patients and clinicians, though, is that the models, reported in the July 10 issue of Cancer Cell (2012;21:362–373) and the July 4 issue of Science Translational Medicine (2012;4:141ra91), are already-proving valuable for preclinical testing of novel combinations. She said she expects a new combination trial to start within a year.
Monotherapy Not Quite Enough
Researchers made a key advance in 2008 when they discovered that activating mutations in the ALK gene occurred in familial neuroblastoma and in approximately 10 percent of sporadic cases. They quickly capitalized on those findings, launching a phase I trial with the first-generation ALK inhibitor, crizotinib.
Unfortunately, the most common ALK mutation in neuroblastoma patients, ALKF1174L, is relatively resistant to the drug. Even with doses substantially higher than those used to treat EML4-ALK-driven lung cancers in adult patients, the best response seen in neuroblastoma patients with ALKF1174L has been stable disease. (Mossé presented early trial results of the Children's Oncology Group trial at this spring at the ASCO Annual Meeting [OT, 6/25/12]).
New Models, New Combinations
Working with the new mouse model though, researchers have begun to see pathways that cooperate with ALK to drive the tumor. For example, in the Science Translational Medicine paper, Johannes H. Schulte's team from University Children's Hospital Essen in Germany, saw that one ALK-mutant mouse developed spontaneous secondary changes in the MYCN gene, which is frequently altered in patients as well. The double mutant strain developed tumors faster than the AKL-mutant mice
Meanwhile, a second group of researchers, co-led by Louis Chesler from the Institute of Cancer Research in the United Kingdom and Rani George of Dana-Farber Cancer Institute and Children's Hospital Boston, found similar results when they crossed their ALKF1174L strain with an existing MYCN transgenic strain. The double mutant animals developed tumors much more quickly than those carrying the MYCN alone, suggesting the ALK strengthens the impact of the MYCN mutation. (Unlike, Dr. Schulte's ALK-mutant mouse, the Chesler-George ALK mutant mouse did not form neuroblastoma tumors on its own.)
Moreover, when they started teasing apart the signaling pathways that were altered in the ALKF1174L/MYCN double mutant, they found that the PI3K/AKT/mTOR and MAPK pathways were activated.
The researchers then tested a combination of an mTOR inhibitor and crizotinib and found that the combination prolonged survival in the mice, compared with either single agent.
Mossé has also been using the ALKF1174L/MYCN double mutant mouse to test drug combinations. She says her team has strong preliminary results with a second-generation ALK inhibitor, which is potentially more specific than crizotinib, and “a catalytic mTOR inhibitor that inhibits that whole mTOR/PI3K pathway.” The drugs, which she declined to name, have already been through phase I trials in adults.
Therefore, if all continues to go well, she expects a combination trial to open within a year for pediatric neuroblastoma patients.
Preclinical Testing Key
That said, Mossé emphasized during a phone interview that pediatric oncologists don't get many opportunities to test new agents or combinations because there are so few patients. “We can't test every ALK inhibitor. We can't test every combination. We really have to be very rigorous about the preclinical work to predict what is going to happen in the patient and move the right combination to the clinic.”
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