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Chemotalk NewsletterChemotalk Newsletter, Vol. 97 May 1, 2016 Good May to you all. Here goes: PROGRAMMED DEATH: A CAT AND MOUSE GAME By Craig R. Hildreth, MD The world of cancer care has been shaken up by the news that patients with hard-to-treat tumors benefit from a new type of immunotherapy, called checkpoint inhibition. A key receptor, called programmed death 1 (PD-1), is charged with suppressing the ability of activated T cells and other immune cells to destroy cancer cells, all in the name of preventing damage to normal tissue via autoimmunity. When PD-1 receptors on T cells bind with PD-L1 and PD-L2, complimentary receptors expressed on tumor cells, the immune response (call it the assassination of the cell) is checked and the tumor lives on. The anti PD-1 monoclonal antibodies nivolumab and pembrolizumab keep PD-L1 from turning off T cells, which has produced durable responses in several tumor types including MELANOMA, LUNG CANCER and RENAL CELL CARCINOMA and represents a new hope for many. Oncologists are excited to relay this news to patients, but is there a way to explain this without putting everyone in the room to sleep? Well, I like to use analogies to make seemingly complicated mechanisms easier to understand and the PD-1/PD-L1 relationship has inspired several colorful examples, to wit: ³Think of T cells as killers that use photographs to identify individual bad guys. Their weakness is that they will not act if the intended victim shakes their hand first. The bad guys used to be born without arms, but over time they evolved to grow arms and hands, thus avoiding elimination. The antibodies are boxing gloves that cover the hands of the T cells. Goodbye, bad guys.² ³Think of T cells as cats specially trained to eliminate mice wherever they hide. Their only weakness is if they smell catnip they will roll over and purr like idiots instead of doing their job. The mice then develop special glands that secrete catnip, thus pacifying the kitties. Solution: plug up the cats¹ noses with nivolumab or pembrolizumab. Sayonara, Mr. Mouse. ³Think of T cells as a fire sprinkler system designed to activate when a metal plug is heated to its melting point, releasing water from a pipe. The fire then emits a toxin that coats the fusible metal, keeping it below its melting point. By fitting a protective shield around the plug we block the toxic molecules and allow the plug to melt in a fire. The shield is the monoclonal antibody against PD-1 and thus the fire is successfully extinguished.² * * * FINE-PARTICLE POLLUTION LINKED TO WIDER NUMBER OF CANCERS Researchers have long known that long-term exposure to fine-particle air pollution is linked to high rates of LUNG CANCER and heart disease, but a new study shows it is also associated with sharply higher mortality rates from cancers of the BREAST, the UPPER DIGESTIVE TRACT and other organs. Between 1998 and 2011, scientists followed more than 66,000 Hong Kong residents, who were at least 65 years old at the time of enrollment, and their exposure to particulate matter with a diameter of 2.5 micrometers or less. Such pollution typically forms when gases are emitted from cars, trucks, power plants and other industrial sources. Using fixed-site monitors and satellites, the researchers measured the concentration of particle pollution. They found that every increased exposure of 10 micrograms per cubic meter was associated with a 22 percent higher risk of dying from any cancer. For some cancers, the greater mortality risk was much more: 42 percent for the upper digestive tract and 80 percent for breast cancer. ³The implications for other similar cities around the world are that (particulate pollution) must be reduced as much and as fast as possible,² said G. Neil Thomas, a researcher at the University of Birmingham in England and one of the co-authors of the study. John Groopman, an environmental-health expert at Johns Hopkins Bloomberg School of Public Health and who was not involved in the study, agreed that the results of the study could be extrapolated to similar urban areas in high-functioning economies, such as Singapore, New York and Los Angeles. ³We really need the research to understand what it is about the nature of these particles that is contributing to this.² Besides Thomas, the other main co-author was Thuan Quoc Thach, a scientific officer of the University of Hong Kong¹s School of Public Health. The study was published in the journal Cancer Epidemiology, Biomarkers & Prevention. The researchers said that the association between the fine particulate matter and cancer could be the result of damage to the body¹s DNA-repair function, changes in the immune response or inflammation that triggers the growth of new blood vessels fueling the spread of tumors. Particulate matter is a complicated mixture of extremely small particles and liquid droplets, according to the Environmental Protection Agency. Once inhaled, the particles can cause lung, heart and other problems. A separate study by the Bloomberg School showed that even small amounts of air pollution appear to raise the risk of a condition in pregnant women linked to premature births. Researchers, in a study conducted in Boston, found that fine particles from car exhaust and other industrial sources can end up in the placentas of pregnant women. The greater the maternal exposure to pollution, the more likely that the women would have a condition called intrauterine inflammation, a leading cause of premature birth. The scientists said the study, reported online in Environmental Health Perspectives, suggested that EPA air-pollution standards may not be stringent enough to protect developing fetuses. ³We found biological effects in women exposed to air pollution levels below the EPA standard,² said lead author Rebecca Massa Nachman, who is a postdoctoral fellow at the Bloomberg School. * * * ORAL CANER DRUGS PRICE INCREASE: RISING COST OF CANCER TREATMENT HURTING PATIENTS, STUDY FINDS Many people are complaining about the rise of drug costs in the country. Cancer patients are also suffering because of the increase in the price of oral cancer drugs. "The cost of certain oral medications for cancer treatment have increased multiple-fold since 2000, according to a study published in the Journal of the American Medical Association," ABC News reports. The study also found that new drugs are getting even more expensive compared to drugs that are already on the market. These oral cancer drugs that are increasing in price cause less stress and discomfort to patients compared to chemotherapy treatments for cancer. The study findings show that the cost of oral cancer drugs has increased from an average of $1,869 a month in 2000 to a shocking $11,325 a month in 2014. "The major trend here is that these products are just getting more expensive over time," study author Stacie Dusetzina said in a statement. She also noted that this increase in drug cost is making it almost impossible for cancer patients to get access to these beneficial oral cancer drugs. No one is quite sure why oral cancer drugs continue to rise in cost. However, some analysts believe that drug manufacturers are charging more for the oral cancer drugs because many cancer patients prefer this treatment compared to chemotherapy. * * * STUDY PINPOINTS MECHANISM THAT ALLOWS CELLS WITH FAULTY DNA TO REPRODUCE Researchers open doors to new strategies for combating cancer Researchers have figured out how some cells do an end-run on replication quality control -- opening the door to developing new cancer-quashing treatments. When it comes to replicating their DNA so they can propagate, normal cells are perfectionists. Cancer cells, on the other hand, have no problem tolerating mistakes while copying their DNA. In fact, messed-up DNA is a big part of what lets them keep changing and eluding the body's efforts to fight them. Now, University of Minnesota researchers have figured out how some cells do an end-run on replication quality control -- opening the door to developing new cancer-quashing treatments. Yee-Mon Thu and Anja-Katrin Bielinsky together with colleagues in the University's Department of Biochemistry, Molecular Biology and Biophysics and Informatics Institute described their discovery of the mechanism behind the ability to overcome barriers to faulty DNA replication in the scientific journal Cell Reports. Bielinsky is co-director of the Genetic Mechanisms of Cancer program in the Masonic Cancer Center. "We think we found the pathway that enables cancer cells to get away with doing a poor job of replicating their DNA," said Thu. The study started as a quest to understand how cells proceed to divide despite DNA errors. The team's tool of choice was to globally analyze changes in protein regulation that are triggered by faulty DNA replication. Because these events can be modeled in yeast mutants, which are easier to manipulate than cancer cells, the researchers utilized yeast to home in on the crucial players. Then they conducted further experiments that allowed them to identify the specific mechanism that lets faulty cells survive. Along the way, the team developed specific upgrades to their tool that will come in handy to other scientists. Since the key proteins are highly conserved between yeast and human cells, the researchers suspect the mechanism they discovered is also what lets cancer cells get away with replication errors. They're now using their new tool to look at the protein make-up of cancer cells and see whether their suspicion is correct. If it is, the finding could lead to the development of new anti-cancer therapies. Bielinsky credits the University's strong proteomics and bioinformatics programs with the success of this study. "We have a fantastic history of proteomics research -- it's a real strength," she says. "Also, the University has made big investments in bioinformatics in recent years. Those have really paid off for researchers like myself." * * * Until next month, y'all... And if you have any thoughts of how this newsletter could be improved, please email me directly, at Elaine@elainejesmer.com. Elaine Jesmer
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