By Andrea Crawford
In the clinic where Balazs Halmos, MD, treats patients twice a week, individuals who have been smokers confront their diagnosis with a sense of guilt, while those with advanced diagnoses believe they have been given a death sentence and think clinicians throw toxic treatments at them to no real effect.
“Now, that mindset has totally changed for me,” says Dr. Halmos, section chief of thoracic oncology. “It’s time to educate practitioners, support staff, patients, and families. We need to become more optimistic, more positive, and more proactive about lung cancer treatments.”
With lung cancer among the most lethal of cancer diagnoses—its five-year survival rate is lower than 15 percent—Dr. Halmos’ shift in attitude represents nothing short of a revolution, for the field and for Dr. Halmos himself. Only a year ago, he published a moving essay in The Oncologist, likening his haunted feelings about caring for dying patients to the dark tale of Bluebeard in the opera written by Béla Bartók, a composer from his native Hungary. But in the past decade, the field of cancer care has been transformed by a greater understanding of the molecular drivers of tumors and propelled by an expansion of the ability to leverage that insight in the clinic.
Dr. Halmos joined P&S in 2009 to build a research program around thoracic oncology. In the intervening five years, clinical studies involving molecular oncology— precision medicine—to treat lung cancer have gone at Columbia from zero to some 15 studies under way at any given time. “Every single patient who comes to Columbia with a lung cancer diagnosis now is triaged,” says Dr. Halmos, associate professor of medicine. “Without any delays, our pathology lab runs a very specific panel of molecular tests so that within the shortest period of time, we can define the best treatment for that individual patient.” Molecular testing of biopsied lung tumors allows clinicians to identify genetic vulnerabilities within each cancer and thereby determine which combination of therapies may be most effective for a particular patient.
Dr. Halmos was a medical resident in 1997 when the first generation of targeted therapies delivered modest response. The earliest known target was the epidermal growth factor receptor (EGFR), a cell-surface protein involved in cell growth and division that is overexpressed in about 10 percent of lung cancers. A few years later, as improved sequencing technologies helped identify precise mutations, Dr. Halmos was treating patients with a therapy targeted to EGFR when he noticed that in some patients, after an initial response during which cancer growth was completely suppressed, the disease rebounded. By studying samples from these patients as tumor resistance developed, he found that the cause was a change in a single base pair of the cancer’s DNA, research he published in 2005 in the New England Journal of Medicine.
Dr. Halmos likens those base pairs of DNA to the bricks used to construct a building: Shift just a single brick among the 3 billion found in human DNA, and the resulting modification in the amino acid sequence of the EGFR protein blocks a previously effective drug from fitting into the protein’s binding pocket. “As a result of this little change, the medicine has no value any longer,” he says. “The cancer becomes completely resistant based on just a single DNA event that occurs in one cancer cell.”
Understanding that single amino acid change has propelled Dr. Halmos’ quest to identify compounds that can overcome such resistance, each targeting a specific mutation while leaving the normal protein alone. “These new medications are much more successful against the mutant protein that drives the cancer and also have a lot fewer side effects,” he says. While patients generally tolerate older medications that target EGFR, he explains, some people develop diarrhea and skin rashes as a result of the protein’s role in bowel function and the growth of skin cells.
Dr. Halmos’ investigation of the process by which EGFR resistance emerges has also shed light on the evolutionary pressure exerted by targeted drugs. He identified new mechanisms by which cancer cells become resistant to drugs, by turning on new pathways that bypass the drug’s effect—work first reported in Nature Genetics in 2012—and is now collaborating with several industry partners and planning clinical trials to use this new knowledge to develop more effective combinations that can overcome and prevent such bypassing events. “The new information we gain about how the cancer changes allows us now to stay ahead of the cancer in the long term by predicting what changes could occur,” he says. In this way, the future of cancer treatment resembles that of current successful HIV and tuberculosis therapies, where a combination of several agents successfully targets multiple weaknesses of the cells.
As understanding of those weaknesses continues to emerge, more patients benefit. In recent years, scientists have found targets in addition to EGFR that drive lung cancers, and Dr. Halmos’ team is investigating a number of compounds to affect these genetic alterations as well. “Now, for 40 to 50 percent of all lung cancers, we can identify some genetic abnormalities where we have a clinical study for a novel drug,” Dr. Halmos says. “The list is ever expanding, and the percentage of patients impacted is larger and larger.”
Lung cancers in smokers appear to be excellent targets for immunotherapies, because the tumors have many more genetic abnormalities than other types of lung cancer.The emerging field of immunotherapeutics may hold the key to further expansion of the portfolio of treatment options available to combat lung cancer. Although researchers long assumed that the immune system played no role in pulmonary oncology, immune cells have the ability to recognize lung cancer cells though sometimes they get outsmarted.
“These cancer cells can develop ways whereby they prevent the immune system from being able to recognize and attack them,” says Dr. Halmos. “There’s a very particular pathway that the lung cancers can utilize to paralyze—basically Taser—immune cells as they patrol the body in their attempt to eradicate cells recognized as foreign, such as cancer cells.” Key to the subterfuge is a protein expressed on the cancer-cell surface that engages with a protein on the surface of the immune cell, rendering it ineffective. Now new medicines are being investigated in the clinic that can disrupt this interaction, thereby turning off the Taser and allowing the immune cells to kill the cancer cells.
Lung cancers that develop among people who smoke tobacco appear to be excellent targets for immunotherapies, because smoking-related variants of the disease have many more genetic abnormalities than other types of lung cancer. “The lung cancer of a smoker has at least 200 to 300 different mutations, and many of them change the proteins of the cancer cell to the point that when it’s present on the cell surface, it looks foreign to the immune system,” he says. This, too, is a positive development; the majority of lung cancer patients fall into this category and, until now, many of the advances in targeted treatments have not been applicable to them. In collaboration with industry partners, Dr. Halmos’ team is assessing novel therapies that block the pathway most often affected in these patients.
Meanwhile, Dr. Halmos’ research team also has discovered ways to make tumors more susceptible to conventional chemotherapeutics, as he showed in a paper published in Carcinogenesis. “The reality is that there are still a very large number of patients who need to receive chemotherapy agents and radiation and benefit, often greatly,” he says.
In the case of Stage 3 lung cancer, for example, the current standard of care is not targeted therapy or surgery, but combined chemotherapy and radiation. That protocol has not changed in 30 years, but it works long term in only 20 percent of patients. To better understand how tumors become resistant to this approach, Dr. Halmos has partnered with Simon K. Cheng, MD, PhD, assistant professor of radiation oncology, to develop a functional genomic screen that assesses every gene in the cancer cell. Says Dr. Halmos, “We can get a sense of how every single gene—depending on whether it’s under-functioning or over-functioning—might contribute to the development of resistance against these classes of agents.” This has resulted in a short list of lead candidates, including the YAP gene. “By blocking its function in the laboratory, we can enhance the activity of radiation and chemotherapy quite significantly,” he says.
Dr. Halmos feels lucky to be working in this era of molecular revolution and in a field where patient need and research potential are equally profound. “I have had, by now, a number of patients who have gone many, many years with advanced lung cancer, going from one oral targeted agent to the next,” he says. “This is going to become more and more of a reality.”
This article originally appeared in the 2014 Annual Report of Columbia University College of Physicians & Surgeons.