Aggressive lung cancer’s aggressiveness may be its Achilles’ heel

Using an existing drug, the scientists were able to halt the progression of small cell lung cancer tumors in genetically engineered mice. This was a notable achievement because small cell lung cancer (SCLC) is known for spreading quickly throughout the body. The finding raises the hope that the drug, which is being tested in people … Continue reading “Aggressive lung cancer’s aggressiveness may be its Achilles’ heel”

Using an existing drug, the scientists were able to halt the progression of small cell lung cancer tumors in genetically engineered mice. This was a notable achievement because small cell lung cancer (SCLC) is known for spreading quickly throughout the body. The finding raises the hope that the drug, which is being tested in people overseas for several types of cancers in clinical trials, might prove to be an effective way to control or prevent small cell tumor growth — possibly keeping the cancer as harmless tiny lesions.

Even if the drug does not prove effective for that purpose, the researchers have identified a tantalizing target in the battle against a particularly deadly form of cancer. They believe their approach could lend itself to the development of new drugs that would target the cancer progression while sparing healthy cells.

Small Cell Lung Cancer

Small cell lung cancer makes up approximately 15 percent of all lung cancer cases. However, it spreads much more quickly than non-small cell lung cancer, and once it has spread, it is extremely difficult to treat. Five-year survival for people whose small cell lung cancer has metastasized (spread) is only about 2 percent.

Notably, small cell lung cancer is seen almost exclusively in smokers. UVA’s Kwon Park, PhD, of the Department of Microbiology, Immunology and Cancer Biology, was seeking to better understand why that is when he and his team discovered the potential way to undercut tumor development.

Park was investigating whether a mutation in the gene MYCL was what is known as an oncogene — a gene that drives tumor development. His team determined that the gene did, in fact, have an important role to play. Amplifying its effect spurred tumor growth in genetically engineered mice, while blocking it suppressed tumor growth. Unfortunately, there is no known drug that could be used to target the gene in people.

So Park took another approach. He looked at what the gene was doing, to see if it would be possible to target the results of the gene’s activity, rather the gene itself. “It turns out that this master oncogene regulates these protein assembly machines called ribosomes,” he said. “For a cell to divide faster, you need everything faster. Not just DNA but also the proteins. By making more machinery at a faster speed, [the oncogene] actually promotes tumorigenesis.”

Maybe there’s no way to get at the oncogene, Park thought, but perhaps there’s a way to stop the amped-up protein production it causes. Through a stroke of luck, there was a drug available to do just that. And it worked: Tumor growth was inhibited significantly.

It’s important to note that the drug used in what Park called his “proof-of-concept pharmaceutical experiment” is not yet available to patients. It’s being evaluated for other forms of cancer in Australia and Canada, but it’s not being tested in patients in the U.S., so much work would need to be done to determine if it would be safe and effective for this purpose. Regardless, the research has identified a potential back-door way to block a critical aspect of the tumor-production process in small cell lung cancer.

Park noted that the finding could potentially lead to a preventative strategy involving food and nutrition, so that people could modify their diets to reduce their chances of developing the disease.

Leukemia blood testing has ‘massive potential’

Dr Suzanne Johnson says that cancerous acute lymphoblastic leukemia cells produce and release special structures that can be traced in the blood.

The discovery could have major implications on the diagnosis, monitoring, drug delivery and treatment of childhood leukemia.

Dr Johnson publishes the research, which was led by Professor of Paediatric Oncology Vaskar Saha, in the leading journal Blood. This research received funding from the European Union’s Seventh Framework Programme for research, technological development, and demonstration (Grant agreement no. 278514 — IntReALL); a program grant from Cancer Research UK; and a Bloodwise project grant. V.S. is the recipient of an India Alliance Margdarshi Fellowship

Until recently, the ‘Extracellular Vesicles’, as they are known, were thought to be worthless debris. Dr Johnson investigated their presence in the plasma from bone marrow biopsies and discovered their ability to circulate in the blood using mice.

Though there is an 85 to 90% success rate in treatment, children must endure repeat bone marrow biopsies to assess the progress of treatment.

But the researchers hope this discovery might reduce the frequency of the painful procedures, which can also cause bruising, bleeding and infection.

Vesicles, which contain the protein actin and have identifiable characteristics of their parent cell, are typified by branching structures beautifully shown in images produced by the team.

Dr Johnson said: “Our discovery of Extracellular Vesicles could be a game changer in terms of the way we care for children with lymphoblastic leukemia.

“Our research has shown that cancerous Leukemia cells have the ability to package parts of themselves and then send these structure — vesicles — to anywhere in the body though the blood.

“That opens up a world of possibilities in terms of monitoring the progress of the disease and making diagnosis quickly and efficiently. They are also internalised by other cells and act as an effective route for cell communication.

“Now the challenge is to investigate whether other cancers produce and release these structures as well.”

Further down the road, the discovery could have implications on the way drugs are delivered to patients, explains to Dr Johnson, if we can find a way to combine them with the vesicles.

And the team also hope that the vesicles might provide individualised information about the tumours, eventually helping doctors to deliver personalised care.

She added: “What is amazing is that Vesicles were previously dismissed as mere debris from the cancerous cell, but we now realise this absolutely not the case. They are far more interesting than that!”

New standard helps ensure accurate clinical measurements of HER2 breast cancer gene

Scientists at the Molecular Characterization Laboratory (MCL) at the Frederick National Lab, which is sponsored by the National Cancer Institute, evaluated the usefulness of the NIST HER2 Standard Reference Material (SRM 2373) for ensuring the accuracy of measurements of HER2 gene copy numbers. Excessive copies of the HER2 gene indicate heightened risk for an aggressive form of breast cancer.

The trial run “clearly demonstrated the value of SRM 2373” for both evaluating assay performance and “increasing confidence in reporting HER2 amplification for clinical applications,” Frederick National Lab and NIST researchers report in the new issue of the Journal of Molecular Diagnostics.

“The gene is a biomarker for treatment selection. Diagnostic sequencing tests like HER2 assays make it possible to select the best treatment for individual patients based on the genetic makeup of their tumors,” said MCL Director Mickey Williams.

Normal cells have two copies of HER2, but about 20 to 25 percent of breast cancers have multiple copies of the gene, resulting in overproduction of the HER2-encoded protein. This gene amplification stimulates tumors to be particularly fast growing in this subset of breast cancer patients — about 40,000 women in the United States annually.

Fortunately, these patients can be treated with a monoclonal antibody called trastuzumab (brand name Herceptin) that targets and inhibits the growth of tumor cells with higher-than-normal levels of the HER2 protein. The combination of more traditional chemotherapy drugs plus trastuzumab has been found to increase long-term survival rates significantly.

The treatment also can have adverse side effects, so it’s important to screen for those patients who would benefit from it by testing them. However, the two primary tests used prior to the ongoing transition to genomic screening — one relying on fluorescent probes and the other on tissue staining — have been prone to error. An estimated 20 percent of tests were estimated to yield inaccurate results, either false positives or false negatives.

In fact, NIST had originally set out to develop measurement tools to improve the accuracy of those diagnostic tests. But with the rapid emergence of next-generation genome sequencing, NIST chose, instead, to focus on developing measurement references that support the more sensitive and more specific detection capabilities of the new technologies.

SRM 2373 consists of DNA extracted from five breast-cancer cell lines, each with a different average number of copies of the HER2 genes, relative to a selected set of unvarying reference genes. Across the five-vial set, NIST-certified ratios of HER2 copies to the reference genes range from just over one to about 18.

“The collaboration with the Frederick National Lab is very valuable for NIST to ensure that the reference materials we develop are relevant and timely to meet the needs of the clinical and research communities in the rapidly changing field of molecular diagnosis of cancer,” said NIST biochemist Kenneth Cole.

The HER2 reference material is the latest addition to a growing list of measurement tools that NIST has developed to help advance genomics-inspired precision medicine. NIST also is working with Frederick National Lab researchers and industry to improve detection and reliable measurement of cell-free circulating tumor DNA, sometimes called liquid biopsies. Circulating tumor DNA has been detected in many cancers and might be used to monitor patients’ therapeutic progress and whether tumors mutate to become resistant to treatments.

NIST recently signed a three-year Cooperative Research and Development Agreement with SeraCare Life Sciences to collaborate on an interlaboratory study comparing measurements of the company’s circulating tumor DNA reference material.

In 2015, NIST and its partners in the Genome in a Bottle Consortium issued NIST Reference Material (RM) 8398 Human DNA for Whole-Genome Variant Assessment, for which about 77 percent of the genome is characterized with high levels of confidence. The Food and Drug Administration used the genome reference material as its “truth set” for its just-completed PrecisionFDA Consistency Challenge, intended to advance quality standards for whole human genome sequencing.

In May 2016, NIST issued a “Peptide Mixture for Proteomics” (RM 8321), which contains 440 synthetic peptides, or segments of proteins. Proteomics is the identification and study of proteins, which are encoded by genes and are, ultimately, the body’s “doers,” acting alone or in groups to drive processes involved in health and disease.