David Jablons, MD

First Appeared Thursday, 27 July '06

UCSF Researchers Fingerprint Lung Tumors, Test New Drug Candidate

Adding their own contributions to a rapidly advancing field, UCSF researchers - along with colleagues from Incyte Corporation and the University of Texas Southwestern Medical Center - have described new targets in lung cancer and evaluated a promising new drug candidate that halts growth signals in tumor cells grown in the lab. Their report is featured in the July issue of the scientific journal Cancer Cell.

Stopping tumor growth is a never-ending challenge for oncologists. But thanks to improved research tools and researchers' deeper understanding of cancer biology, the challenge is leading to better drugs, better matching of drugs with patients and, for some, much better outcomes.

"We're emerging from an era when we lumped all tumors together," says study author David Jablons, MD, head of the UCSF Comprehensive Cancer Center's Thoracic Oncology Program. "It used to be that a pathologist would look under a microscope, confirm a diagnosis - nonsmall cell carcinoma, for instance - and those patients would all get the same platinum drug for treatment.

"Van Leeuwenhoek could have made the call," rues Jablons, referring to the 17th-century microscope whiz who first viewed living cells.

Today, researchers and clinicians alike want to know which molecules are contributing to uncontrolled cell growth in cancer. These abnormalities vary among tumors, even among tumors that arise in the same organ. They also want to know whether certain drugs work better against tumors in which cells exhibit a particular pattern of genetic or other molecular abnormalities. An increasing number of drugs target specific molecular aberrations in tumors. The one-drug-suits-all approach is coming to an end.

For the research reported in Cancer Cell, Jablons, Biao He, PhD, a doctoral scientist and assistant adjunct professor of surgery at UCSF, and their academic and industry colleagues focused on growth signaling through the EGFR pathway.

Common Molecular Abnormality in Lung Cancer

EGFR is a protein "receptor" molecule that spans the outer membrane of the cell. From the outside of the cell, it hooks up with growth factors. EGFR then relays a growth signal - through a series of protein intermediaries - to the nucleus of the cell, where the DNA that makes up genes resides. In response to EGFR signaling, genes are switched on and off - new proteins are made or destroyed. Depending on how the cell weighs the signal, along with other signals it is receiving, it may grow or divide.

However, an abnormally high amount of EGFR is present in roughly 80 percent of lung tumors. The excess is believed to be responsible for driving abnormal growth. Unfortunately, clinical trials of two drugs that target EGFR - Tarceva and Iressa - were somewhat disappointing. The drugs were designed to prevent EGFR from relaying its growth signal inside the cell. When tested on the most common category of lung cancer, nonsmall cell lung cancer, neither drug caused tumors to shrink in a majority of advanced-stage cases. In various trials, tumors shrank by 50 percent or more only in about 9 percent to 18 percent of patients.

As those results suggest, there is still much more to learn about the role of the EGFR signaling pathway in lung cancer. The Cancer Cell study marks further progress. Basically, the researchers concluded that lung cancers may often be evading the effects of EGFR inhibition by sending growth signals into cancer cells along slightly altered routes.

A Family of Related Receptors and a Cancer Drug That Stymies Them

Biao He probed molecules within lung tumor samples from UCSF's tissue bank. He found that a receptor related to EGFR, called HER3, was overabundant in most of the 14 lung tumors examined. There also was excessive production of a growth factor - called heregulin - which is secreted by the same tumor cells. Heregulin attaches to HER3 from outside the cell and activates the receptor.

After EGFR inhibitors were first developed, researchers learned that one of the requirements for EGFR signaling is for two receptors to pair up at the cell surface and work together. EGFR can pair with itself, but it also can meet the requirement by pairing with one of its sibling receptors, HER2 or HER3. Even without EGFR, HER2 and HER3 - when activated by heregulin and similar growth factors - can pair up to trigger growth signaling.

The research collaborators on the Cancer Cell study also conducted preclinical tests on a new type of drug, called a selective ADAM inhibitor. Taking yet another step upstream along the signaling pathway, the specific drug candidate tested - called INCB3619 - inhibits a protein called ADAM17. ADAM17 activates the growth factors that in turn activate any of the EGFR-like receptors. In the lab studies, INCB3619 - by preventing activation of heregulin and its ilk - inhibited HER3 growth signaling in Tarceva-resistant tumor cells. The drug also augmented the inhibitory effect of Tarceva in nonresistant tumors.

Tailoring Treatment to Tumors

Certain subsets of patients are the most likely to benefit from EGFR inhibitor treatment. Studies from around the world have found that mutations in the EGFR gene were almost always observed in lung cancers that shrank in response to treatment. These mutations have been observed in roughly half of nonsmokers, East Asians and women, but rarely in other groups of lung cancer patients.

However, even though EGFR mutation has been associated with response to treatment, it has not been strongly associated with increased survival.

By the same token, some patients with advanced lung cancer whose tumors do not shrink in response to Tarceva nonetheless survive longer than patients who receive placebo. For instance, men with the squamous cell type of nonsmall cell lung cancer who smoked at some point in their lives appear to survive longer on average with Tarceva treatment, despite a very low tumor response rate. Smokers with other types of lung cancer did not have the same benefit from treatment.

So far, at least one molecular measure does appear related to survival. Last year, researchers reported in the Journal of the National Cancer Institute that extra copies of the EGFR gene - not necessarily mutated - appear to improve the chances that patients with advanced lung cancer will respond to Tarceva treatment and live longer than they would without the additional treatment.

New Molecular Fingerprinting Tests in the Offing

There already are tests to detect EGFR mutations. UCSF Comprehensive Cancer Center member Fred Waldman, MD, PhD, now is developing a test to enable clinical researchers to quickly gauge how many copies of the EGFR gene are present in tumor tissue. A similar test for a related protein, called HER2, already is used to determine which breast cancer patients should receive a drug, Herceptin, which is targeted against HER2.

EGFR plays a role in several types of solid tumors, not just lung cancer, so the test should be quite popular, and even more so as additional targeted treatments become available.