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Georgetown Team Planning Human Trial after Finding Targetable Marker of EGFR Inhibitor Resistance

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NEW YORK (GenomeWeb) — A team led by researchers from the National Cancer Institute and Georgetown University has discovered that overexpression of the protein CRIPTO-1 is associated with intrinsic resistance to EGFR inhibition, and shown in early in vitro and in vivo experiments that targeting CRIPTO-1 using available or investigational drugs could improve patients' responses to anti-EGFR therapies.

The team published the results, collected from numerous experiments in cell lines, animal models, and human tumor samples, in the Journal of Clinical Investigation earlier this month.

Based on these early results, the group is now planning a human trial combining the EGFR inhibitor erlotinib (Roche/Genentech's Tarceva) with an inhibitor of the oncogenic tyrosine-protein kinase SRC, which is activated by CRIPTO-1.

Giuseppe Giaccone, the study's senior author and associate director for clinical research at Georgetown Lombardi Comprehensive Cancer Center, told PGx Reporter this week that the AstraZeneca SRC inhibitor that showed promise in his team's initial experiments is no longer manufactured so the group is now considering two alternative drugs for the trial — either another AstraZeneca compound, AZD0424, or an approved drug for chronic myelogenous leukemia, bosutinib (Pfizer's Bosulif), which targets both SRC and BCR-ABL.

Giaccone said the group is planning to recruit 40 patients for an initial trial to establish whether combining erlotinib with one of these SRC inhibitors is tolerable. If it is, and if the researchers see evidence of better efficacy, they would then expand to a randomized trial.

The hope, Giaccone said, is that targeting SRC/CRIPTO-1 can increase the number of patients who respond initially to EGFR inhibition by decreasing intrinsic resistance to the drug.

But the path ahead is likely to be hard, as early-stage genomic associations often fail to translate into clinically meaningful results. For example Roche announced earlier this year that it would stop a late-stage trial of the MET inhibitor onartuzumab in combination with Tarceva (erlotinib) as a NSCLC treatment for patients with abnormal MET signaling. MET had been previously marked as a potential promoter of resistance to EGFR-inhibiting drugs.

Roche pursued its Phase III strategy after a Phase II study showed that the combination with Tarceva tripled median survival in patients with high MET expression compared to those receiving just Tarceva, but these results were not borne out in the later trial.

Both intrinsic resistance, in which patients fail to respond at all or respond for a very short period, and acquired resistance, in which patients relapse after a longer period of sensitivity, are issues in EGFR inhibition. Based on results so far, the Georgetown group has been able to show clearly that CRIPTO-1 is associated with intrinsic resistance, although because of complications in using cell lines and other experimental systems, there is no way to know for sure that the marker isn't also implicated in acquired resistance.

Regardless, Giaccone said, reducing intrinsic resistance to these drugs and thus increasing the number of patients who can benefit initially from treatment could have significant clinical impact.

"About 10 to 20 percent of patients progress on EGFR inhibitor treatment — they really don’t benefit at all — while another 20 percent or so have stable disease but only for a short time," Giaccone said.

"We have to do a better job up front of having more patients who are sensitive to these drugs," he added.

A first step will be the group's upcoming combination therapy trial, which Giaccone said the team has provided rationale for in its JCI study.

CRIPTO-1 is involved in the epithelial-to-mesenchymal transition, which has been shown to be a potential mechanism of resistance to EGFR inhibitors in previous research. Based on this, Giaccone said, he and his colleagues decided to investigate whether and how CRIPTO-1 might be associated with this resistance.

In in vitro and in vivo experiments, the team was able to tease out how EGFR and CRIPTO-1 are connected. According to the study, the data indicated that, at least in non-small cell lung cancer, EGFR-mutated cells without CRIPTO-1 expression are sensitive to EGFR inhibition. However, cells with higher CRITPO-1 expression show downregulation of microRNA-205, which then leads to activation of SRC signaling, which offsets the impact of EGFR inhibition on cell viability.

By targeting SRC, the group increased the efficacy of EGFR inhibition, suggesting that combining both types of drug may be a promising strategy for overcoming CRIPTO-1-induced intrinsic EGFR resistance.

To boost this evidence and provide a more direct link to human biology, the group also studied samples from cancer patients, and found that CRIPTO-1 expression was significantly higher in EGFR-mutated tumors of NSCLC patients who did not respond to EGFR inhibition compared to those who did.

Giaccone said that it is not yet clear how much of intrinsic EGFR inhibitor resistance may be explained by CRIPTO-1 and SRC.

"We don't know if it is more important than other [pathways that might be discovered]," he said. "But with intrinsic EGFR resistance there is so little known, we thought it was important to do this work."

Although the group's evidence so far points to the influence of CRIPTO-1 being exclusive to intrinsic resistance, Giaccone said that the researchers are also interested in further investigating whether it might also extend to acquired resistance by examining serial samples from patients who became resistant to EGFR inhibitors to see if levels of CRIPTO-1 may increase in tandem.

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