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Our researchers at The Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland offer the latest experimental treatments to lung cancer patients. Working across disciplines opens up new possibilities for better ways to treat lung cancer. Lung cancer patients at Johns Hopkins receive not only experienced, specialized care but also benefit from the pioneering lung cancer research that has resulted in new treatments and therapies. Read more below about groundbreaking lung cancer research at Johns Hopkins.
Justin Hanes, Ph.D., a chemical and biomedical engineer at Johns Hopkins Kimmel Cancer Center and Hopkins’ Whiting School of Engineering in Baltimore who specializes in nanotechnology for cancer treatment, explains that a nanoparticle is to a soccer ball what a soccer ball is to the planet earth. Suffice it to say that we’re talking very small.
As small as nanoparticles are, part of their value in cancer medicine is that they are bigger than other things. Nanoparticles are much larger than small molecules—agents commonly used to treat cancer. Hanes says hundreds of thousands of small molecules can fit into one nanoparticle. As a result, they can be loaded up like a Trojan horse and sent out to deliver their cargo to tumors.
Hanes is a member of Hopkins’ Center of Cancer Nanotechnology Excellence, which aims to use nanotechnology to improve cancer treatment. He is excited about the prospects of nanotechnology to improve the delivery of anticancer drugs and combat toxicities.
“Right now, we use systemic cancer therapies, which are incredibly useful, but typically a very small percentage of the chemotherapy ends up in the tumor,” explains Hanes. “The rest of it poisons normal cells throughout the body.”
He uses nanotechnology in an attempt to reverse that ratio so that anticancer drugs go directly to tumors with very little injury to normal cells: “Think of a tumor as a weed in a prized rose garden. What we do now is spray the entire rose garden with weed killer. But, we can only spray so much poison or we risk killing the roses.”
The project he is working on with Johns Hopkins lung cancer experts is a nano-based treatment that seeks out and targets cancer cells. “Like a pre-addressed envelope, we are developing methods to direct them to where we want them to go,” says Hanes.
Hanes directs the Center for Nanomedicine where he and his colleagues are working with investigators from Hopkins’ Institute for NanoBioTechnology on anticancer-drug filled nanoparticles that can be inhaled into the lung. His team created the first nanoparticle system that can penetrate the mucus lining the lung airways. In the past, inhaled forms of nanotherapy have failed largely because the lungs’ natural mucus barrier, in place to keep out bacteria and other infectious invaders, swept the drugs away before they could go to work. When Hanes and team discovered that the mucus lining was more like a net than a blanket, they constructed nanoparticles small enough and slippery enough to get through the holes in the sticky mucus “net.”
Hanes’ particles are comprised of two parts made of molecules routinely used in existing medications. An inner core traps therapeutic agents inside while a dense outer coating allows a particle to slip through mucus nearly as easily as if it were moving through water. The nanoparticles cause no immune or inflammatory response so drugs travel freely through the lungs, including areas scientists believed were impenetrable, releasing their anticancer cargo over an extended period of time.
Hanes’ nano-based approached could be applied to cancers of any mucus-lined organ, including the colon and cervix. He said such treatments could be ready for clinical trials in as little as five years and cost about the same as traditional chemotherapy.
Johns Hopkins Kimmel Cancer Center Deputy Director Stephen Baylin, M.D., could be called Mr. Epigenetics. The title is bestowed for Baylin’s work linking biochemical alterations in the DNA environment to the initiation and growth of cancer. These non-mutational alterations are categorized as epi—in addition to—genetic.
The work of Baylin and his colleagues resulted in some of the first uses of epigenetic abnormalities as cancer biomarkers for diagnosis and to predict how a cancer would respond to treatment. Now engineer Jeff Wang, Ph.D., with Hopkins’ Center for Cancer Nanotechnology Excellence is helping move these trailblazing therapeutic discoveries forward more rapidly.
In 2008, Kimmel Cancer Center-led lung cancer research found epigenetic alterations to any or all of four specific genes caused cancers to be more aggressive. Depending upon the combination of altered genes, the recurrence rates of the lung cancers studied increased two- to 25-fold. Based on these findings, clinician-scientists initiated a clinical study of epigenetic therapy for patients with advanced and heavily treated lung cancer, and a small percentage of patients experienced very robust and long lasting responses.
With funding from Stand Up to Cancer, the team are hoping to develop these findings into a personalized treatment approach for lung cancer, and Wang’s work in developing a nano-based assay to test for alterations in these and other genes is central to it.
SU2C support allowed the researchers to do an unusual thing—to go back and find out what happened to the patients they thought they didn’t help. They reviewed the records of patients who were participating in a clinical trial of epigenetic therapy because their lung cancers had not responded to standard therapy. Specifically, the team was interested in some 40 patients who were taken off of the epigenetic treatment trial because their tumors continued to grow. What they found surprised them all.
While many patients seemed to progress while on therapy, many, including those who had received just two or three treatments, had unprecedented, long-lasting responses. The team poured over every scan and every clinical report and even re-biopsied some tumors and could come up with only two explanations: Either the epigenetic therapy sensitized their cancers to subsequent treatment with standard drugs or their improvement was a direct response to the targeted therapy.
Targeted therapies do not work like the old cytotoxic chemotherapies which do not discriminate between cancer cells and normal cells. Instead, they specifically seek out and reprogram the malfunctioning mechanism within cancer cells causing the tumors. As a result, Baylin says, targeted therapies shrink tumors more slowly over time as they make their repairs and genes are returned to normal function.
Jerry Morton, a 61 year-old retired firefighter, was building a sandbox for his grandson two years ago when he was diagnosed with lung cancer. The cancer had already spread throughout his lungs and to his liver. “I didn’t expect to live long enough to complete it,” says Morton. “Today, that sandbox is finished.” Morton’s tumors melted away on the epigenetic treatment. When he developed a new, small tumor, his doctors again tried epigenetic therapy, and Morton, once again, benefitted.
“The team has evidence that the status of epigenetic alterations in these four genes, assayed in the blood by sensitive technologies that Dr. Wang is working to perfect, may predict the good responses in patients like Mr. Morton,” says Baylin. "It is a perfect illustration” he says “of the value of collaborative research and translational, personalized cancer medicine.”
With such promising results, Baylin and team are now planning another trial for newly diagnosed patients. If findings continue to show that the epigenetic-targeted therapy works, Wang figures prominently in the wide clinical application. What the team does in their basic science laboratory to screen for the epigenetic alterations would be difficult to routinely do in a clinical lab, so they asked for help from engineers.
Wang, who works in the Institute for Nanobiotechnology, is using nanotechnology, engineering at a molecular level, to develop a broad-based test that could be used routinely in any clinical laboratory to predict which patients would benefit from the targeted therapy.
“This facet is critically important in taking these therapies beyond our own walls. Without the nano-tech approach, testing for the alterations might be too cumbersome for a clinical lab,” says Baylin. If ongoing trials confirm the earlier findings, Wang’s test can help ensure that the Johns Hopkins-based discovery becomes available to lung cancer patients everywhere.
In applying cancer gene discoveries to treatment, investigators are focusing on the pathways through which altered cancer genes work because the genes themselves can often be elusive to therapy. Many of the gene mutations driving cancers are in tumor suppressor genes. The loss of these genes removes important brakes on cell growth, but it’s difficult to attack a target that’s already missing.
Sometimes, however, tumor suppressor genes become ineffective without being mutated. The causes of this are known as epigenetic alterations. Biochemical changes to the environment of the DNA, rather than directly to it, can silence key genes. Investigators have found that using drugs to block this biochemical activity provides an opportunity to reverse the changes and reset the DNA to its pre-cancer environment.
Johns Hopkins Kimmel Cancer Center researcher Stephen Baylin, M.D., is a leading experts on epigenetics, cited more frequently than any other researcher in the field. His epigenetic work in lung cancer earned Baylin recognition from the National Cancer Institute for the most outstanding research in its SPORE (specialized programs of research excellence) program, an endeavor aimed at rapidly moving laboratory discoveries to patient care.
Baylin began his epigenetics work in the 1980s when he noticed regions of genes with increased methylation, a biochemical process that seemed to occur only in cancer cells. This chemical change, he found, was like an off switch to tumor suppressor genes. With support from the Commonwealth Fund, Ludwig Foundation, Hodson Trust, and the National Institutes of Health, he and his team began to look for ways to apply these observations to cancer patients.
Early laboratory studies in lung cancer and leukemia at the Kimmel Cancer Center in Baltimore and elsewhere led recently to clinical trials of the first demethylating agent, 5-azacytidine. Promising results in a leukemia and a pre-leukemia condition known as myelodysplastic syndrome (MDS) resulted in U.S. Food and Drug Administration approval of the drug for MDS. Now, they are working to prove the effectiveness of the drug in other cancers.
Their research has led them to other changes working in concert with methylation, specifically something known as the chromatin structure.
Chromatin is a complex combination of DNA and proteins, mainly histones. Its job is to compress DNA to make it fit inside cells, providing a mechanism for controlling gene expression and DNA replication. Changes in the structure of chromatin are controlled by the histones. A loose chromatin allows for normal gene expression. But, add methylation to the equation and histones hold DNA together tightly interfering with the normal expression of genes, including tumor suppressor genes. It keeps genes in a constant state of non-expression.
Prior to this discovery, most investigators studying cancer genes looked at gene silencing as a linear process across the DNA, as if genes were flat, one-dimensional objects. Research did not take into account the way genes are packaged.
For a key set of tumor suppressor genes, this packaging can cause cells to behave in a primitive, embryonic cell-like fashion. Unlike true embryonic cells which receive and respond to signals to stop making cells, cancer cells maintain their ability to replicate, renew, and divide. The cells never receive the command to stop dividing partly because abnormal DNA methylation has silenced the key growth-limiting signals.
“Chromatin is held in a tight, compressed form, particularly when associated with DNA methylation,” says Baylin. “These tighter coils and loops touch and interact with many gene sites, folding it into a structure that shuts off tumor suppressor genes.”
When the researchers removed DNA methylation from the genes, using a combination of 5-azacytidine and a drug known as a histone deacetylase (HDAC) inhibitor for its ability to block histones, the coils loosened, and some gene expression was restored.
What prompts the cancer-promoting changes in chromatin structure is unknown. Baylin suspects some of it is due to continued environmental assaults to the cells, such as chronic inflammation. As cells try to renew and repair over and over, something breaks, epigenetic alterations accumulate, and some cells become locked in this primitive state. As a result, these cells learn to live outside the context of their normal environment and begin to expand autonomously beyond the limits of normal cell control mechanisms.
With funding from Stand Up To Cancer, Baylin and his team have now moved their laboratory discoveries to the clinic in studies with lung, breast, and colon cancer patients. Learning from the earlier clinical trials in leukemia, the new patient studies combine the DNA demethylating agent 5-azacytidine with histone-specific HDAC inhibitors to target both abnormal methylation of genes and the alterations to DNA packaging that help give cancer cells their edge.
It is a novel concept. Rather than attacking and destroying replicating cells as standard chemotherapy drugs do, this therapy actually aims to reprogram cells to behave more like normal cells. Clinical responses in lung cancer patients that have lasted long after treatment has ended indicate that it’s working. It’s too early in the breast and colon cancer trials to evaluate, but Baylin and his team are optimistic that they will see favorable results in these cancers as well.
Using drugs that specifically target the abnormal mechanisms, allows the investigators to give patients lower doses and still maintain effectiveness. They believe the lower doses allow them to hit the epigenetic target without interfering with the activity of other non-target genes. As a result collateral damage to normal cells has been low, with relatively mild and few side effects, including fatigue, minor decreases in blood counts, and irritation at the injection site.
It is a striking contrast to high-dose studies of the drug in the 1970s and 1980s when it was all but abandoned because it was too toxic.
“We reduced the dose and added an HDAC inhibitor and are working to prove in clinical trials what we already suspect; that the combination of the two drugs is safe and works better than either individually,” says Baylin.
Despite the success of the trials, Baylin says there are still challenges to overcome: “We’re going back to the laboratory to learn how to personalize it. We need to develop a molecular fingerprint that will tell us which patients it will help and who it will not.”
The revival of 5-azacytidine may be indicative of a change in the cancer culture. “Clinical trials have been set up to find the highest tolerable dose, but this won’t work for this particular drug and other therapies designed for personalized medicine,” says Baylin.
Unlike the cancer therapies the world has become accustomed to that indiscriminately kill cells—cancer and normal ones—this new generation of targeted therapies doesn’t directly kill cells, Baylin : “Instead, we hope they will reprogram cancer cells to kill themselves.”
Scientists from several institutions, led by researchers at the Kimmel Cancer Center, completed a comprehensive map of the genetic mutations linked to a lethal type of lung cancer, known as small cell lung cancer (SCLC). Small cell lung cancers are very aggressive. Most are found late, when the cancer has spread, and typically survival is less than a year after diagnosis. Our genomic studies may help identify genetic pathways responsible for the disease and provide new avenues for developing drugs to treat it.
Among the genetic alterations identified by the investigators was an increase in the number of copies (amplification) of a gene called SOX2. Normal cells should contain just two copies of the gene (one copy from each parent), which is involved in embryo development. In cancer, researchers suspect that amplification causes an overproduction of SOX2 proteins that, in turn, reignites and sustains cell growth associated with tumor formation. SOX2 is an important clue in finding new ways to treat small cell lung cancer. Cancer experts may be able to link a patient’s outcome to this gene and develop a drug to target it or other genes it regulates.
Lung cancer is most commonly thought of as a smoker’s disease, but about 15 percent of cases occur in people who never smoked, and researchers are finding there is more than just the smoking component that sets them apart. Researchers at the Johns Hopkins Kimmel Cancer Center in Baltimore say it is becoming increasingly clear that the genetic, cellular, and molecular nature of lung cancer in people who have never smoked is different from smoking-related lung cancers. There is good evidence that the treatment and prevention strategies should be different as well.
Kimmel Cancer Center lung cancer experts were part of a scientific committee that published a guide on the biology, diagnosis, and treatment of lung cancer in people who have never smoked.
They reviewed data from several hundred studies published by experts in public health, population science, molecular biology, pathology, and oncology to identify the distinct characteristics of lung cancer in people who have smoked less than 100 cigarettes in their lifetimes. The team found lung cancers in people who never smoked more often had mutations of the EFGR gene than those of smokers. As a result, never-smokers benefitted most from drugs that block or inhibit EGFR signaling. Other gene alterations more prevalent among never smokers also were identified, and a genome-wide study of this population could reveal still more. The group’s guide calls for lung cancer clinical trial participants to be classified by smoking status so scientists can better evaluate the success of therapies among smokers and never smokers.
The first clinical reports of checkpoint inhibitors in melanoma were exciting and peaked interest, but excitement was tempered because the few successes in immune therapy over the last three decades had also been primarily in melanoma and kidney cancer.
There had been documented cases of these cancers occasionally going into spontaneous remission, so experts long maintained that, by nature, these types of cancers had a way of engaging the immune system. No other type of cancer was considered to be responsive to immune interventions. The new therapy was greeted with guarded optimism.
That all changed in 2012, when a group from the Johns Hopkins Kimmel Cancer Center published the results of anti-PD-1 therapy in lung cancer patients.
Lung cancer had never before responded to an immune therapy, and the remarkable activity of anti-PD-1 in a small number of lung cancer patients proved what researcher Drew Pardoll and other cancer immunologists long believed—if understood, the immune system could be used to fight any cancer.
Although lung cancers had not responded to other past immune therapy attempts, this discovery provided new evidence that it had the potential to work and was the reason the Kimmel Cancer Center team included lung cancer patients in the first anti-PD-1 trial. Two immune checkpoint blockers were approved by the U.S. Food and Drug Administration in January 2016 for use against lung cancer, kidney cancer and melanoma, and show promise in more than ten additional types of cancer.
Ultimately, they envision boosting the effectiveness of the therapy by combining it with other anti-cancer agents, including cancer vaccines.
Read a press release from the team’s 2012 publication in the New England Journal of Medicine demonstrating that immune therapy showed success in patients with non-small cell lung cancer, melanoma and kidney cancer.
Read a press release from the team’s 2015 publication in the New England Journal of Medicine demonstrating immunotherapy increased the lifespan of patients with squamous non-small cell lung cancer.
Read Promise & Progress magazine and learn more about immunotherapy at Johns Hopkins.