November 23, 2015
Simmons Cancer Center’s vast portfolio of lung cancer research includes projects focused on:
Assaults on KRAS
Researchers are finding new ways to neutralize the impact of the KRAS gene mutation, a notorious molecular villain in lung as well as other cancers.
Much like EGFR mutations and ALK rearrangements, KRAS mutations drive lung cancer development and growth. However, KRAS mutations, frequently seen in smokers, are more common—representing about 25 percent of lung adenocarcinomas, compared with 10 percent for EGFR and just 5 percent for ALK.
As part of an initiative to advance genomics- guided medicine, the laboratory of Professor of Cell Biology Dr. Mike White is carrying out massively parallel chemical toxicity screens in a group of molecularly and clinically annotated lung tumor cell lines. The efforts are defining new mechanistic subtypes of oncogenic KRAS-driven cancers, together with drug leads that specifically target those subtypes.
The initiative is just one of several at Simmons Cancer Center that are addressing the unique challenge of KRAS-driven cancers. “KRAS for decades has been considered undruggable,” notes lung cancer specialist Dr. David Gerber.
Yet there may be more than one way to drug the “undruggable.” For instance, one compound now in clinical trials at UT Southwestern takes aim at a KRAS accomplice—a downstream enzyme, called focal adhesion kinase (FAK), that impacts tumor growth at the behest of KRAS.
Research led by Associate Professor of Internal Medicine Dr. Pier Paolo Scaglioni has shown in a mouse model of human lung cancer that inhibiting FAK can effectively treat tumors with KRAS mutations and prolong survival. He and other Cancer Center scientists are striving to enhance the effectiveness of FAK inhibitors and also are testing in the lab whether the drugs work in lung cancers that do not carry KRAS mutations.
Based on that work, Drs. Scaglioni and Gerber have developed a trial testing defactinib (VS-6063), an oral FAK inhibitor, in patients with KRAS-mutant cancers. The trial, involving about 10 centers across the U.S., is nearing the end of phase II testing.
Meanwhile, the laboratory of radiation oncologist and lung cancer specialist Dr. Kenneth Westover has synthesized a molecule that directly inactivates the KRAS protein. X-ray crystallography and mass spectrometry showed that the molecule, SML-8-73-1, interferes selectively and irreversibly with KRAS molecules carrying the G12C mutation, a hallmark of tobacco associated lung cancer. The researchers are now chemically tweaking the molecule to make it more drug-like, to facilitate its study in living cancer cells and in animals.
“It’s the first step in a long journey,” Dr. Westover says.
Targeting neuroendocrine tumors
Cancer Center scientists are also tackling new challenges in lung neuroendocrine tumors— a category that includes small cell, carcinoid, and large cell neuroendocrine cancers of the lung. Pulmonary neuroendocrine tumors, for which no targeted “personalized,” treatment is yet available, account for about 40,000 new U.S. lung cancer cases each year.
Pioneering research led by Professor of Pharmacology Dr. Melanie Cobb, collaborating with Professor of Neuroscience Dr. Jane Johnson, is revealing that many neuroendocrine cancers in the lung and elsewhere are dependent on two related proteins that govern gene transcription. The proteins, ASCL1 and NeuroD1, are important in normal development but can go haywire and promote tumor growth.
The research effort has found that each transcription factor can influence at least 1,000 genes downstream and has cataloged how those genes differ in normal versus tumor tissue. The findings are helping to reveal which downstream genes might be targeted successfully with drugs to halt tumor growth.
Opening up clinical trials
Clinical trials can’t speed new knowledge to the bedside if they can’t accrue patients, and quickly. And trials can’t help individual patients who aren’t permitted to participate. To address these concerns, Cancer Center researchers have shined a spotlight on exclusion criteria for lung cancer clinical trials.
“Well under 5 percent of adult cancer patients are accrued to clinical trials,” notes Dr. Gerber, “and a major limiting factor is stringent eligibility criteria.”In one study of more than 50 lung cancer clinical trials, Dr. Gerber and colleagues found that about 80 percent of trials automatically excluded patients who had a previous cancer—even though the prior cancer seemed unlikely to interfere with the study treatment, conduct of the trial, or interpretation of the outcomes. For example, “you have patients who three years ago had prostate cancer surgery who can’t go on a clinical trial,” Dr. Gerber says.
In all, up to 18 percent of potential trial patients—perhaps more than 200 people in some studies—were excluded from the lung cancer studies, the research found. Exclusion of patients with a cancer history is likely only to increase over time.
“In the past 30 years, the number of cancer survivors in the U.S. has grown fourfold,” Dr. Gerber notes. Including more cancer survivors, he says, could lead to faster trials that better reflect the real-world population of lung cancer patients.
Newer work by the research team, which includes UT Southwestern’s Dr. Ethan Halm and Dr. Sandi Pruitt, studied more than 100,000 patients older than 65 who were diagnosed with stage IV lung cancer from 1992 to 2009. Almost 15 percent had a prior cancer, typically within five years of the lung cancer diagnoses, and about three-quarters of the prior cancers were diagnosed at stages I, II, or III.
Regardless of its type, stage, or timing, a previous cancer did not adversely impact survival in the advanced lung cancer patients, the study found. Lung cancer patients with previous cancers should therefore be considered candidates for clinical trials seeking new therapies, the researchers say.
A mechanism for metastasis
Research rooted at UT Southwestern is shedding new light on metastases, the major cause of death from cancer.
Collaborating with colleagues in China, Chief of Pulmonary and Critical Care Medicine Dr. Lance Terada, along with Cancer Center lung cancer researchers Dr. John Minna and Dr. Luc Girard, have characterized a protein—a transcription factor called Aiolos—that is important in the spread of cancer cells. Aiolos is frequently overexpressed in lung cancers and is a marker of poor prognosis.
Although the protein is also produced by normal blood cells, Aiolos is repurposed in cancer cells to allow them to circulate in the bloodstream and metastasize.
Aiolos promotes metastasis by interfering with normal adhesion that anchors tissue cells to their environment and by repressing another protein, p66Shc, that normally quashes metastatic activity.
“Cellular behaviors that are largely responsible for cancer mortality are poorly understood,” notes Dr. Terada. “Our study reveals a central mechanism by which cancer cells acquire blood cell characteristics to gain metastatic ability.”
Understanding this metastasis mechanism opens a door to finding new medicines to rein in tumors, Drs. Terada and Minna say.
Simmons Cancer Center members Dr. Darla Kendzor and Dr. Michael Businelle are testing ways to help safety-net and homeless patients break their smoking addiction.
People living in poverty are less likely to quit smoking than people of greater means, even though both groups try to quit about as frequently, note Drs. Businelle and Kendzor, faculty at the University of Texas School of Public Health Dallas Regional Campus. “Although the prevalence of smoking has declined to 18 percent among U.S. adults,” Dr. Kendzor says, “nearly 30 percent of those living below the poverty threshold and over 70 percent of those who are homeless continue to smoke.”
In one of their recent studies at the Parkland Hospital Tobacco Cessation Clinic, patients who were randomized to receive standard care plus small weekly financial incentive were twice as likely to remain abstinent four and 12 weeks later, compared with patients who received standard care alone. The cost of the incentives averaged $63 per participant. Given that the first year of lung cancer treatment costs about $70,000, preventing a single case of lung cancer would cover the cost of at least five years of the financial incentives program.
In another Parkland-based nicotine cessation study, the team is testing whether delivering messages via smartphone can help patients quit smoking and avoid relapse. The messages are tailored in real-time based upon patients’ responses to select questions.
The researchers have also recently evaluated the effects of offering a small financial incentive for nicotine cessation among clients at The Bridge homeless recovery center in Dallas. Weekly incentives during the first month after quitting—costing an average of $42 per participant—markedly increased abstinence rates at four weeks.
Earlier work by the team shed light on the difficulties that homeless shelter residents face when trying to quit, leading to a smoking ban in a large area of the shelter campus. “Homeless adults are less likely to quit smoking partially due to a shelter culture that is permissive of smoking and results in exposure to over 40 other smokers each day,” Dr. Businelle says. Residents’ support for the no-smoking area was high, and tests of exhaled carbon monoxide indicated that smoking may have declined after the change was implemented.