Trials Explore a Synergistic Therapeutic Combination for Head and Neck, Lung Cancer

A Kaplan-Meier plot comparing survival in cohorts of SCCHN patients with high and normal 
expression of Aurora kinase A, based on data from The Cancer Genome Atlas. Inhibiting the activity of Aurora kinase A is expected to improve survival for patients with elevated levels of Aurora kinase A.

A Kaplan-Meier plot comparing survival in cohorts of SCCHN patients with high and normal expression of Aurora kinase A, based on data from The Cancer Genome Atlas. Inhibiting the activity of Aurora kinase A is expected to improve survival for patients with elevated levels of Aurora kinase A.

Epidermal growth factor receptors (EGFRs) are proven to be effective molecular targets for anti-cancer drugs, but what happens when EGFRs are targeted in conjunction with a lesser-studied enzyme — Aurora kinase A? Clinical trials underway at Fox Chase are exploring the effectiveness of this “two-hit” therapeutic approach in head and neck cancer as well as lung cancer.

Igor Astsaturov, MD, PhD

Igor Astsaturov, MD, PhD

EGFR inhibitors are a commonly used treatment in a variety of cancers because of their effectiveness at rapidly shrinking tumors, but tumors are likely to develop resistance to these drugs over time.

This resistance led researchers at Fox Chase to search for a more effective approach than EGFR inhibitors alone — work that has led to two Phase I clinical trials now under way at Fox Chase.

The original research, led by deputy chief scientific officer Erica A. Golemis, PhD, and medical oncologist Igor Astsaturov, MD, PhD, and reported in Science Signaling, used siRNA screens to determine which proteins are required by cells to survive despite the presence of an EGFR inhibitor.

“We were searching for drugs and pathways that would enhance the potency of EGFR inhibition,” Astsaturov says.

One such protein was Aurora kinase A, which the team felt had the biggest therapeutic potential because of its synergism with EGFR.

Hossein Borghaei, DO

Hossein Borghaei, DO

Astsaturov and Roger B. Cohen, MD, of the Abramson Cancer Center at the Hospital of the University of Pennsylvania, designed a trial which adds MLN8237, an oral Aurora kinase A inhibitor, to radiation and cetuximab, the standard treatment for locally advanced squamous cell carcinoma of the head and neck (SCCHN). The trial continues to recruit participants (see opposite page for more information) with the eventual goal of moving into a randomized Phase II study.

“We believe this combination has the potential to be very synergistic,” Astsaturov says. “It was successful in animal models and we are hoping for humans the same will be true.”

Further exploring the role of Aurora kinase in head and neck cancers, Astsaturov and a team of colleagues led by medical oncologist Ranee Mehra, MD, reviewed potential drug combination trials and biomarkers to use with Aurora kinase inhibitors in SCCHN. Their work was published in The Lancet Oncology in September 2013.

MLN8237, known commercially as alisertib and produced by Millennium Pharmaceuticals, is also being explored by Fox Chase researchers as a potential treatment for patients with recurrent or metastatic non-small cell lung cancer. In a trial being led by Hossein Borghaei, DO, chief of thoracic medical oncology, the drug is combined with the EGFR inhibitor erlotinib (see opposite page).

Results from the trial, reported by Borghaei at the AACR Annual Meeting in April 2014, are too early to judge whether or not the combination is effective, so he plans to analyze tumors post-study to look for a marker that would predict response to treatment. ■