Low doses of the anti-cancer drug imatinib can spur the bone marrow to produce more innate immune cells to fight against bacterial infections, Emory and Winship Cancer Institute researchers have found.
The findings suggest imatinib, known commercially as Gleevec, or related drugs could help doctors treat a wide variety of infections, including those that are resistant to antibiotics, or in patients who have weakened immune systems. The research was performed in mice and on human bone marrow cellsÂ in vitro, but provides information on how to dose imatinib for new clinical applications.
â€œWe think that low doses of imatinib are mimicking â€˜emergency hematopoiesis,â€™ a normal early response to infection,â€ says senior author Daniel Kalman, PhD, associate professor of pathology and laboratory medicine at Emory University School of Medicine.
Imatinib, is an example of a â€œtargeted therapyâ€ against certain types of cancer. It blocks tyrosine kinase enzymes, which are dysregulated in cancers such as chronic myelogenous leukemia and gastrointestinal stromal tumors.
Imatinib also inhibits normal forms of these enzymes that are found in healthy cells. Several pathogens â€“ both bacteria and viruses â€“ exploit these enzymes as they transit into, through, or out of human cells. Researchers have previously found that imatinib or related drugs can inhibit infection of cells by pathogens that are very different from each other, includingÂ tuberculosis bacteriaÂ andÂ Ebola virus. Read more
MicroRNAs have emerged as important master regulators in cells, since each one can shut down several target genes. Riding on top of the master regulators is Drosha, the RNA-cutting enzyme that initiates microRNA processing in the nucleus. Drosha and its relative Dicer have been attracting attention in cancer biology, because they are thought to beÂ behind a phenomenon where cancerous cells can â€œinfectâ€ their healthy neighbors via tiny membrane-clothed packets called exosomes.
At Emory, pharmacologist Zixu Mao and colleagues recently published in Molecular Cell their findings that Drosha is regulated by stress (experimentally: heat or peroxide) through p38 MAP kinase.
Everything is connected, especially in the brain. A protein called BAI1 involved in limiting the growth of brain tumors is also critical for spatial learning and memory, researchers have discovered.
Mice missing BAI1 have trouble learning and remembering where they have been. Because of the loss of BAI1, their neurons have changes in how they respond to electrical stimulation, and subtle alterations in parts of the cell needed for information processing.
Erwin Van Meir, PhD, and his colleagues at Winship Cancer Institute of Emory University have been studying BAI1 (brain-specific angiogenesis inhibitor 1) for several years. Part of the BAI1 protein can stop the growth of new blood vessels, which growing cancers need. Normally highly active in the brain, the BAI1 gene is lost or silenced in brain tumors, suggesting that it acts as a tumor suppressor.
The researchers were surprised to find that the brains of mice lacking the BAI1 gene looked normal anatomically. They didnâ€™t develop tumors any faster than normal, and they didnâ€™t have any alterations in their blood vessels, which the researchers had anticipated based on BAI1â€™s role in regulating blood vessel growth. What they did have was problems with spatial memory.
A recent publication from Bill Kaiserâ€™s and Ed Mocarskiâ€™s labs in Cell Host & Microbe touches on a concept that needs explaining: oncolytic viruses.
Viruses have been subverting the machinery of healthy cells for millions of years, and many viruses tend to infect particular tissues or cell types. So they areÂ a natural starting point for researchers to engineer oncolytic viruses, which preferentially infect and kill cancer cells.
Emory dermatologist Jack Arbiser has been investigating (andÂ recently patented) inhibitors of the enzyme Nox4 as potential anti-cancer drugs.
Nox4 has emerged as a potentialÂ therapeutic targetÂ in ataxia-telangiectasia, a rare multifaceted genetic disorder that leads to neurological problems, a weakened immune system and an increased risk of cancer. Ataxia-telangiectasia (or A-T) is caused by a defect in ATM, a sensor responsible for managing cellsâ€™ responses to DNA damage and other kinds of stress.
In a February PNAS paper, researchers at the National Cancer Institute led by William Bonner reportÂ that a Nox4 inhibitor can dial back oxidative stress and DNA damage in ataxia-telangiectasia cells, and can reduce cancer rates in a mouse model of the disease. Nox4 wasÂ activated in cells and tissue samples obtained from A-T patients.
The Nox4 inhibitor the NCI team used, fulvene-5, was originally identified by Arbiser in a 2009 Journal of Clinical Investigation paper as a possibleÂ treatment for hemangiomas, a common tumor in infants that emerges from blood vessels.
It arises from what scientists previously described as “junk DNA” or “the dark matter of the genome,” but this gene is definitely not junk. The gene Gas5 acts as a brake on steroid hormone receptors, making it a key player in diseases such as hormone-sensitive prostate and breast cancer.
Emory researchers have obtained a detailed picture of how the Gas5 RNA interacts with steroid hormone receptors. Their findings show how the Gas5 RNA takes the place of DNA, and give hints as to how it evolved.
Scientists used to think that much of the genome was “fly-over country”: not encoding any protein and not even accessed much by the cell’s gene-reading machinery. Recent studies have revealed that a large part of the genome is copied into lincRNAs (long intergenic noncoding RNAs), of which Gas5 is an example. Read more
PeopleÂ interested in drug discoveryÂ may have heard of “Lipinski’s rule of five,” a rough-and-ready set of rules for determining whether a chemical structure is going to be viable as a orally administered drug or not. TheyÂ basically say that if a compound is too big, too greasy or too complicated, it’s not going to get into the body and make it to the cells you want to affect. These guidelinesÂ have been the topic of much debate among medicinal chemists and pharmacologists.
The namesakeÂ forÂ this set of rules, Chris Lipinski, will be speakingÂ at Winship Cancer Institute Wednesday afternoonÂ (4:30 pm, Nov 5, C5012) onÂ “The Rule of 5, Public Chemistry-Biology Databases and Their Impact on Chemical Biology and Drug Discovery.” Lipinski spent most of his career at Pfizer (while there,Â he published the “rule of 5 paper“) and now is a consultant at Melior Discovery.
Doctors are using a â€œdivide and conquerâ€ strategy against lung cancer, and in some corners of the battlefield, itâ€™s working. A few mutations â€“ genetic alterations in the tumor that donâ€™t come from the patientâ€™s normal cells — have been found for which drugs are effective in pushing back against the cancer.
However, most lung tumors do not have one of these mutations, and response rates to conventional chemotherapy in patients with advanced lung cancer are poor. Generally, only around 20 percent of patients show a clinical response, in that the cancer retreats noticeably for some time.
Johann Brandes and colleagues at Winship Cancer Institute have been looking for biomarkers that can predict whether an advanced lung tumor is going to respond to one of the most common chemotherapy drug combinations, carboplatin and taxol.
â€œThe availability of a predictive test is desirable since it would allow patients who are unlikely to benefit from this treatment combination to be spared from side effects and to be selected for other, possibly more effective treatments,â€ Brandes says.
Brandesâ€™ teamâ€™s data comes from looking at patients with advanced lung cancer at the Atlanta VAMC from 1999 to 2010. In a 2013 paper in Clinical Cancer Research, the team looked at a protein called CHFR. It controls whether cells can reign in their cycles of cell division while being bombarded with chemotherapy.
In this group being treated with carboplatin and taxol, patients who had tumors that measured low in this protein lived almost four months longer, on average, than those who had tumors that were high (9.9 vs 6.2 months).
His team takes a similar approach in a new paper published in PLOS One. Postdoc Seth Brodie is the first author of the PLOS One paper; he is also co-first author of the CHFR paper along with Rathi Pillai. Read more
The Spectropen, a hand-held device developed by Emory and Georgia Tech scientists, was designed to help surgeons see the margins of tumors during surgery.
Some of the first results from procedures undertaken with the aid of the Spectropen in human cancer patients were recently published by the journal PLOS One.Â A related paper discussing image-guided removal of pulmonary nodules was just published in Annals of Thoracic Surgery.
To test the Spectropen, biomedical engineer Shuming Nie and his colleagues have been collaborating with thoracic surgeon Sunil Singhal at the University of Pennsylvania.
As described in the PLOS One paper, five patients with cancer in their lungs or chest participated in a pilot study at Penn. They received an injection of the fluorescent dye indocyanine green (ICG) before surgery.
ICG is already FDA-approved for in vivo diagnostics and now used to assess cardiac and liver function. ICG accumulates in tumors more than normal tissue because tumors have leaky blood vessels and membranes. The Spectropen shines light close to the infrared range on the tumor, causing it to glow because of the fluorescent dye.
[This technique resembles the 5-aminolevulinic acid imaging technique for brain tumor surgery being tested by Costas Hadjipanayis, described in Emory Medicine.]
In one case from the PLOS One article, the imaging procedure had some tangible benefits, allowing the surgeons to detect the spread of cancerous cells when other modes of imaging did not. Read more
Jing Chen and colleagues at Winship Cancer Institute recently published a paper in Molecular Cell.Â Most of the paper deals with a metabolic enzyme, 6PGD (6-phosphogluconate dehydrogenase), and how it is more active in cancer cells.
Rheum palmatum/Chinese rhubarb/da-huang
Tucked in at the end is a note that an inhibitor of 6GPD with an odd name, physcion, has anticancer activity in Chen’sÂ teamâ€™s hands. Physcion, also known as parietin, is an orange-yellow pigment extractableÂ fromÂ lichens and Chinese rhubarb that has been employed as an anti-mildew agent.