Now, a research team led by scientists at the Dana-Farber Cancer Institute and the Broad Institute of Harvard and MIT has unearthed one of the key players behind such drug resistance. Published in the Nov. 25 issue of the journal Nature, the researchers pinpoint a novel cancer gene, called “COT” (also known as MAP3K8), and uncover the signals it uses to drive melanoma. The research underscores the gene as a new potential drug target, and also lays the foundation for a generalized approach to identify the molecular underpinnings of drug resistance in many forms of cancer. “In melanoma, as well as several other cancers, there is a critical need to understand resistance mechanisms, which will enable us to be smarter up front in designing drugs that can yield more lasting clinical responses,” said senior author Levi Garraway, a medical oncologist and assistant professor at Dana-Farber and Harvard Medical School, and a senior associate member of the Broad Institute. “Our work provides an unbiased method for approaching this problem not only for melanoma, but for any tumor type.”More than half of all melanoma tumors carry changes (called “mutations”) in a critical gene called B-RAF. These changes not only alter the cells’ genetic makeup, but also render them dependent on certain growth signals. Recent tests of drugs that selectively exploit this dependency, known as RAF inhibitors, revealed that tumors are indeed susceptible to these inhibitors — at least initially. However, most tumors quickly evolve ways to resist the drug’s effects.To explore the basis of this drug resistance, Garraway and his colleagues applied a systematic approach involving hundreds of different proteins called kinases. They chose this class of proteins because of its critical roles in both normal and cancerous cell growth. Garraway’s team screened most of the known kinases in humans — roughly 600 in total — to pinpoint ones that enable drug-sensitive cells to become drug-resistant.The approach was made possible by a resource created by scientists at the Broad Institute and the Center for Cancer Systems Biology at Dana-Farber, including Jesse Boehm, William Hahn, David Hill, and Marc Vidal. The resource enables hundreds of proteins to be individually synthesized (or “expressed”) in cells and studied in parallelFrom this work, the researchers identified several intriguing proteins, but one in particular stood out: COT. Remarkably, the function of this protein had not been previously implicated in human cancers. Despite the novelty of the result, it was not entirely surprising, since COT is known to trigger the same types of signals within cells as B-RAF. (These signals act together in a cascade known as the MAP kinase pathway.)While their initial findings were noteworthy, Garraway and his co-workers sought additional proof of the role of COT in melanoma drug resistance. They analyzed human cancer cells, searching for ones that exhibit B-RAF mutations as well as elevated COT levels. The scientists successfully identified such “double positive” cells and further showed that the cells are indeed resistant to the effects of the RAF inhibitor.“These were enticing results, but the gold standard for showing that something is truly relevant is to examine samples from melanoma patients,” said Garraway.Such samples can be hard to come by. They must be collected fresh from patients both before and after drug treatment. Moreover, these pre- and post-treatment samples should be isolated not just from the same patient but also from the same tumor.Garraway and his colleagues were fortunate to obtain three such samples for analysis, thanks to their clinical collaborators led by Keith Flaherty and Jennifer Wargo at Massachusetts General Hospital. In two out of three cases, COT gene levels became elevated following RAF inhibitor treatment or the development of drug resistance. In other cases, high levels of COT protein were evident in tissue from patients whose tumors returned or relapsed, following drug treatment. “Although we need to extend these results to larger numbers of samples, this is tantalizing clinical evidence that COT plays a role in at least some relapsing melanomas,” added Garraway.One of the critical applications of this work is to identify drugs that can be used to overcome RAF inhibitor resistance. The findings of the Nature paper suggest that a combination of therapies directed against the MAP kinase pathway — the pathway in which both B-RAF and COT are known to act — could prove effective.“We have no doubt that other resistance mechanisms are also going to be important in B-RAF mutant melanoma,” said Garraway, “but by taking a systematic approach, we should be able to find them.” The past year has brought to light both the promise and the frustration of developing new drugs to treat melanoma, the most deadly form of skin cancer. Early clinical tests of a candidate drug aimed at a crucial cancer-causing gene revealed impressive results in patients whose cancers resisted all currently available treatments. Unfortunately, those effects proved short-lived, as the tumors invariably returned a few months later, able to withstand the same drug to which they first succumbed. Adding to the disappointment, the reasons behind these relapses were unclear.
Editor’s note: CIDRAP News learned on Jun 10 that some of the Canadian indigenous groups that have been hit by serious cases of H1N1 influenza are not Inuit, but rather are among the groups known in Canada as First Nations or aboriginals. In particular, a Canwest News Service report referred to hundreds of cases and 20 hospitalizations at St. Theresa Point, a First Nation in northern Manitoba. Jun 9, 2009 (CIDRAP News) – An official from the World Health Organization (WHO) said today that health experts are closely monitoring novel H1N1 influenza infections in Canada’s Inuit populations, following reports that the communities are seeing more than their share of severe cases.Keiji Fukuda, MD, told reporters at a press briefing, “We can say now that we know a larger number than expected of young Inuit people developed serious illnesses and had to get hospitalized.”He added that the WHO doesn’t know if the trend is linked to socioeconomic factors, genetic factors, or chronic underlying diseases, and commented that Inuit groups were hit hard in some earlier pandemics. Fukuda is the WHO’s assistant director-general for health security and the environment.Yesterday, Joel Kettner, MD, Manitoba’s chief medical officer, told reporters that 26 people were being treated in intensive care units for suspected novel influenza infections, which is unusual for an influenza outbreak, the Canadian Broadcasting Corporation (CBC) reported. He said more than half of the patients are of aboriginal descent, with an average age of 35.Manitoba’s health department said in a statement yesterday that 15 extra ventilators have arrived at the province’s ICUs and that the Winnipeg Regional Health Authority is helping the departments prioritize patients and was considering deferring non-urgent surgical procedures that would normally require use of the units.As of yesterday, Manitoba said it had confirmed 40 novel flu cases in 6 of its 11 health regions.Meanwhile, health officials in Canada’s Nunavut territory today said the number of confirmed novel flu cases has jumped from 25 to 53, with six patients in the hospital, the CBC reported. Nunavut’s population is primarily Inuit.Donald R. Olson, MPH, research director for the International Society for Disease Surveillance, based in New York City, told CIDRAP News that the severe cases in Canada’s Inuit populations are puzzling. However, he added that among remote populations, the 1918 pandemic influenza was more severe and didn’t follow the age patterns seen in the rest of the world.”Inuit groups didn’t show the same apparent sparing of the elderly, so possibly the older proportion of the population had not been exposed” to previous viruses related to the pandemic strain, he said.The medical literature tells of “flu orphans” from remote Alaskan villages who survived the 1918-19 pandemic, though their parents and grandparents died, presumably because they had not been exposed to earlier H1-like viruses.In 2006 at a state summit in Alaska, former US Health and Human Services Secretary Mike Leavitt described the impact of the 1918 pandemic virus on Alaska’s native populations. “The Alaska native population in Nome was decimated—176 of the 300 Alaska Natives in the region died,” he said in comments posted on the HHS pandemic flu Web site. “The pandemic swept through communities, killing whole villages.”Preexisting health conditions may also have contributed to the severity of the 1918 pandemic in Inuit populations, which also had high tuberculosis rates in the early 20th century, Olson said.Officials don’t know if higher rates of chronic illnesses in today’s Inuit populations are playing a role in the high number of severe cases. However, Health Canada reports that when compared to the rest of the nation, First Nations and Inuit people have 1.5 times the rate of heart disease, 3 to 5 times the rate of type 2 diabetes, and 8 to 10 times the rate of tuberculosis infection.Yesterday, an Australian health expert from Darwin warned that the country’s indigenous populations might be at greater risk for novel H1N1 infections.Besides citing lack of exposure to similar virus and underlying conditions as possible risk factors, experts have also theorized that remote populations might have a genetic predisposition that makes them more susceptible to the virus, Olson said. But he expressed doubt that the factor is playing a role in Canada’s current outbreak.The signals coming out of Canada are worrying, he said. “The less developed world may have a terrible experience with this, though there is a lot of coughing and sneezing in the rest of the world,” Olson said.Danuta Skowronski, MD, a physician and epidemiologist at the University of British Columbia, told CIDRAP News that over the past few years, circulation of seasonal H1N1 viruses in North America has been patchy, and people in remote communities are likely to have had less exposure to the viruses than have people living in urban settings.There’s still much that researchers don’t know about possible cross-protection against the novel H1N1 virus from exposure to previous H1N1 strains, she said. Though researchers have identified antibody markers and determined that seasonal vaccination offers little protection, they still haven’t gauged the cell-mediated response—which can offer protection during severe infections—afforded by exposure to previous H1N1 strains, Skowronski added.Public health officials will also be looking for environmental factors that might be contributing to the infections in the First Nations and Inuit groups, she said. For example, large numbers of people living in one household may have greater exposure to the virus. “This all needs to be assessed, because we’re picking up possible signals of concern,” Skowronski said.See also:Jun 8 Manitoba press releaseHealth Canada disease and health condition statisticsAhmed R, Oldstone MBA, Palese P. Protective immunity and susceptibility to infectious diseases: lessons from the 1918 influenza pandemic. Nature Immunol 2007 Nov;18(11):1188-93 [Abstract]
Four University of Wisconsin rowers have secured invitations to attend the 2017 USRowing Men’s U23 Selection Camp, a precursor to representing the U.S. in the 2017 World Rowing Under 23 Championship. Wisconsin rowers, senior Sebastian Amberger, senior Andrew Griffin, senior Sam Weeks and junior Erik Kernozek are among the 29 athletes invited to the national team camp. The Men’s U23 Selection Camp will be held in Oklahoma City, Oklahoma, this summer. The group of invited rowers will compete for making boat placement to represent the U.S. at the World Rowing Under 23 Championships in July in Plovdiv, Bulgaria. The training camp will be coached by Dave O’Neill of the University of Texas and Brian De Regt of Oakland Strokes. They will evaluate the rowers and winnow down the group to comprise just an eight and a four.Rowing in a league of their own, Wisconsin women compete at elite levelsOn an international stage in Rotterdam, Netherlands, rowers from around the world gathered to compete in the 2016 World Under 23 Rowing Read…Wisconsin’s Sam Weeks attended the national team selection camp in 2016 and is determined to take his upcoming experience as far as he can. “I’m looking forward to the opportunity to get a second shot at selection camp,” Weeks said. “Being cut on the final day of camp last year, I’m hoping to use my experience to take the next step this summer and make one of the boats.”As a senior, with his NCAA eligibility coming to a close and years of rowing for one of the top men’s rowing teams in the country, Weeks has both the ideal mindset and skillset to accomplish his goals. “This is likely the best I will be at rowing since my collegiate eligibility runs out once this season is over, so I will be in the best possible position to perform at my highest ability,” Weeks said.College basketball’s top performers throughout historyCentral Michigan’s Marcus Keene recorded the first 50-point game in NCAA Division I play in the last four years a Read…Along with Wisconsin rowers being frequently invited to U23 selection camp on consecutive years, UW’s rowing team also provides the most athletes chosen for the prestigious camp compared to other schools each year. In 2016, six Badgers were invited to the Men’s U23 National Team Selection camp: John Laing Wise IV, Sam Weeks, Sebastian Amberger, Andrew Griffin, James Lueken and James Roen. An invitation to selection camp is based upon “coach recommendations, physical and physiological characteristics (e.g. height, weight,), past performance in international and domestic competition, and the athlete’s ability to match the style and technique of the crew as determined by the designated coach,” according to USRowing. Cornell University and Yale are each sending three rowers, followed by Harvard and Princeton, who will each send two. The men’s rowing program at Wisconsin has great strength in producing athletes who are highly competitive at the top level of collegiate rowing. “Coach Clark has always told us he runs the Wisconsin system like a national team program,” Weeks said. “We race a lot and are constantly being tested and scored, but this gives every rower countless opportunities to show improvement and move up in the rankings.” While other colleges with rowing traditions use a strategy of creating a winning team by further developing rowers who proved themselves on the high school stage, Wisconsin largely draws from “walk-ons” with no prior rowing experience. UW cultivates top rowers from scratch in the realm of collegiate rowing, and for some, on the national and international arena.Wisconsin’s Erik Kernozek walked on to the men’s rowing team at Wisconsin his freshman year and now has the revered opportunity to make the national team. “The top end of collegiate rowing right now is extremely saturated with internationally recruited oarsmen,” Kernozek said. “I’m proud to be a part of a team that develops walk-on, home-grown athletes like myself to the United States national team selection camp level.”Men’s hockey: Here are all the Badgers currently playing in the 2017 NHL PlayoffsWith the NHL Playoffs beginning last weekend, it can be hard to know who to root for. Maybe your team Read…Weeks came into NCAA Division I collegiate rowing with some high school rowing experience, but showed dramatic improvement while rowing for the Badgers. “The system here allowed me to develop from being the slowest recruit in my class to being invited to the U23 camp,” Weeks said. “What is even more impressive is that two of the other three guys invited from Wisconsin are walk-ons and had never rowed a stroke before college, which really validates how quickly and well the system can develop elite American oarsmen.” Beyond the athletic development that makes a top collegiate rower, the dedication and commitment needed for such achievements has also had profound positive mental effects on the athletes. “Rowing has forced my mentality to change from being afraid of work and pain, to the love of results,” Kernozek said. “Because of rowing, when I approach obstacles in my life, rather than thinking about where I would rather be in the moment, I always look forward to where I know I will be if I put in the work.” The Wisconsin rowers selected for the Men’s U23 Selection Camp are optimistic about their upcoming experience and the prudence of their efforts. “Ending my rowing career by representing the United States at the World Championships would be a very nice way to go out,” Weeks said. “Regardless of the final outcome, I want to end the camp with no regrets about my effort.”