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High Blood Glucose May Sensitize Pancreatic Cancer To Chemotherapy
Pancreatic cancer is one of the most difficult cancers to treat, being highly resistant to chemotherapy.
However, there are no effective alternative therapies to chemotherapy, so chemo remains the best available treatment.
Although there are fewer than roughly 60,000 new cases of pancreatic cancer diagnosed annually in the U.S., about 95 percent of people with it die from it, mainly because it often goes undetected in early stages.
Approved multi-agent chemotherapy regimens offer a marginal advance over single-agent treatments, and resistance to these "cocktails" virtually always develops. Multi-agent chemo offers a median survival benefit of roughly four months over a single-agent. Overall, median survival of patients with metastatic pancreatic cancer in the modern era is just eight to 11 months, and the five-year survival rate is around 3 percent.
Physicians hope that adjuncts, or added chemical formulations, may be discovered in the future to improve the effectiveness of chemotherapy against this disease and improve survival outcomes.
In a new study, published June 28 by the prestigious science journal Nature Communications, researchers from University Hospitals Seidman Cancer Center and the Case Comprehensive Cancer Center report that a hyperglycemic state – that is, one where the blood glucose level is raised – made pancreatic cancer more sensitive to chemotherapy in a mouse model. (Pancreatic cancer is more formally known as Pancreatic Ductal Adenocarcinoma and shortened as PDAC). Results were replicated in cell culture and a cohort of patients with metastatic PDAC.
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Subscribe for FREE These findings present a potentially new method of making chemotherapy more effective against pancreatic cancer, according to the paper's senior author Jordan Winter, MD, Director Surgical Services, University Hospitals Seidman Cancer Center, John and Peggy Garson Family Endowed Chair in Pancreatic Cancer research and Jerome A. And Joy Weinberger Family Master Clinician in Surgical Oncology."Sensitization of tumors to chemotherapy using forced hyperglycemia offers a completely novel therapeutic strategy. Our findings reveal an approach that would have relatively low-cost and could be easily tested in patients with pancreatic cancer," said Dr. Winter. Over the past three decades, pancreatic cancer researchers have yet to find new effective targeted therapies. However, if relatively simple interventions can be administered that can greatly enhance the effect of conventional drugs, then patients stand to benefit. Importantly, this advance would potentially bypass the usual cost and time required to develop new therapeutics. This could save over a decade of time and more than $1 billion, based on drug development data.
In the study, the researchers validated a prior clinical study by the same authors that showed patients with localized pancreatic cancer and elevated glucose levels were more responsive to chemotherapy. For the current study, the researchers examined the impact of glycemic status on another group of patients treated for metastatic pancreatic cancer.
About 33 percent of the patients had elevated glucose levels (at least one glucose reading above 200 mg/dL). There were no appreciated demographic differences between normal (99 mg/dL or lower) and high glucose patients. A greater proportion of patients in the high glucose group had a documented diagnosis of diabetes.
The median overall survival among all patients who completed at least two cycles of chemotherapy was approximately 9.8 months in all the patients, on par with historical clinical trial data. Further analysis showed, however, that patients in the high glucose level group had a a nearly 40% lower risk of dying, despite a higher level of a cancer antigen (CA19-9, which is a measure of disease burden), as compared to patients in the normal glucose group.
"Notably, no associated survival difference was observed based on glucose levels in an independent cohort of metastatic patients who did not receive treatment, suggesting that the interaction with glycemic status may be present only for patients who receive chemotherapy," said lead author Ali Vaziri-Gohar, PhD, of the Case Comprehensive Cancer Center at Case Western Reserve University at the time of the study and now with the Stritch School of Medicine, Loyola University Chicago.
Paired with prior cell culture and clinical data, these clinical data indicated that a high-glucose state could sensitize PDAC to conventional chemotherapy.
The researchers followed up on these findings with a series of well-controlled studies in various mouse PDAC models of hyperglycemia. First, they induced hyperglycemia pharmacologically with a drug called streptozotocin (STZ). In another group of experiments, they induced hyperglycemia through diet, allowing mice to drink highly sweetened water at will.
In experiments with grafted PDAC tumors on hyperglycemic mice, the researchers found greater sensitivity to single-agent chemotherapy in the two independent models of mice with hyperglycemia. As observed previously with patients in the absence of chemotherapy, no significant differences in growth rates were observed with hyperglycemia compared to mice with normal blood sugar levels in the absence of chemotherapy exposure. The researchers also tested a multiple agent chemotherapy to replicate what a patient might receive today and validated that hyperglycemia alters the metabolic state within tumors to sensitize it to treatment.
"We show that the effectiveness of diverse chemotherapies was markedly improved under high glucose conditions, as compared to low glucose conditions. In some instances, the mice appeared to be cured of their cancer, while mice receiving the same chemotherapy under normal glycemic conditions had relatively little benefit" said Dr. Winter. How can this observation be translated to patients? In the clinical setting, tumors can be theoretically 'primed' for chemotherapy by inducing a forced hyperglycemic state, just as we did in mice. In theory, glucose levels can even be modified more precisely through intravenous dextrose infusions (combined with rigorous inpatient glucose monitoring) at the time of chemotherapy administration." The next step is to implement a clinical trial. Dr. Winter notes that "our patients need better treatment options urgently. Therefore, we are already getting to work designing a trial to treat patients safely with intentionally elevated blood sugars, and will determine if this strategy can improve patient outcomes."
Reference: Vaziri-Gohar A, Hue JJ, Abbas A, et al. Increased glucose availability sensitizes pancreatic cancer to chemotherapy. Nat Commun. 2023;14(1):3823. Doi: 10.1038/s41467-023-38921-8
This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.
Study Finds High Blood Glucose Levels Sensitizes Pancreatic Cancer Cells To Chemotherapy
Pancreatic cancer is one of the most difficult cancers to treat, being highly resistant to chemotherapy.
However, there are no effective alternative therapies to chemotherapy, so chemo remains the best available treatment.
Although there are fewer than roughly 60,000 new cases of pancreatic cancer diagnosed annually in the U.S., about 95% of people with it die from it, mainly because it often goes undetected in early stages.
Approved multi-agent chemotherapy regimens offer a marginal advance over single-agent treatments, and resistance to these "cocktails" virtually always develops. Multi-agent chemo offers a median survival benefit of roughly four months over a single-agent. Overall, median survival of patients with metastatic pancreatic cancer in the modern era is just eight to 11 months, and the five-year survival rate is around 3%.
Physicians hope that adjuncts, or added chemical formulations, may be discovered in the future to improve the effectiveness of chemotherapy against this disease and improve survival outcomes.
In a new study in Nature Communications, researchers from University Hospitals Seidman Cancer Center and the Case Comprehensive Cancer Center report that a hyperglycemic state—that is, one where the blood glucose level is raised—made pancreatic cancer more sensitive to chemotherapy in a mouse model. (Pancreatic cancer is more formally known as Pancreatic Ductal Adenocarcinoma and shortened as PDAC). Results were replicated in cell culture and a cohort of patients with metastatic PDAC.
These findings present a potentially new method of making chemotherapy more effective against pancreatic cancer, according to the paper's senior author Jordan Winter, MD, Director Surgical Services, University Hospitals Seidman Cancer Center, John and Peggy Garson Family Endowed Chair in Pancreatic Cancer research and Jerome A. And Joy Weinberger Family Master Clinician in Surgical Oncology.
"Sensitization of tumors to chemotherapy using forced hyperglycemia offers a completely novel therapeutic strategy. Our findings reveal an approach that would have relatively low-cost and could be easily tested in patients with pancreatic cancer," said Dr. Winter. Over the past three decades, pancreatic cancer researchers have yet to find new effective targeted therapies.
However, if relatively simple interventions can be administered that can greatly enhance the effect of conventional drugs, then patients stand to benefit. Importantly, this advance would potentially bypass the usual cost and time required to develop new therapeutics. This could save over a decade of time and more than $1 billion, based on drug development data.
In the study, the researchers validated a prior clinical study by the same authors that showed patients with localized pancreatic cancer and elevated glucose levels were more responsive to chemotherapy. For the current study, the researchers examined the impact of glycemic status on another group of patients treated for metastatic pancreatic cancer.
About 33% of the patients had elevated glucose levels (at least one glucose reading above 200 mg/dL). There were no appreciated demographic differences between normal (99 mg/dL or lower) and high glucose patients. A greater proportion of patients in the high glucose group had a documented diagnosis of diabetes.
The median overall survival among all patients who completed at least two cycles of chemotherapy was approximately 9.8 months in all the patients, on par with historical clinical trial data. Further analysis showed, however, that patients in the high glucose level group had a nearly 40% lower risk of dying, despite a higher level of a cancer antigen (CA19-9, which is a measure of disease burden), as compared to patients in the normal glucose group.
"Notably, no associated survival difference was observed based on glucose levels in an independent cohort of metastatic patients who did not receive treatment, suggesting that the interaction with glycemic status may be present only for patients who receive chemotherapy," said lead author Ali Vaziri-Gohar, Ph.D., of the Case Comprehensive Cancer Center at Case Western Reserve University at the time of the study and now with the Stritch School of Medicine, Loyola University Chicago,
Paired with prior cell culture and clinical data, these clinical data indicated that a high-glucose state could sensitize PDAC to conventional chemotherapy.
The researchers followed up on these findings with a series of well-controlled studies in various mouse PDAC models of hyperglycemia. First, they induced hyperglycemia pharmacologically with a drug called streptozotocin (STZ). In another group of experiments, they induced hyperglycemia through diet, allowing mice to drink highly sweetened water at will.
In experiments with grafted PDAC tumors on hyperglycemic mice, the researchers found greater sensitivity to single-agent chemotherapy in the two independent models of mice with hyperglycemia. As observed previously with patients in the absence of chemotherapy, no significant differences in growth rates were observed with hyperglycemia compared to mice with normal blood sugar levels in the absence of chemotherapy exposure.
The researchers also tested a multiple agent chemotherapy to replicate what a patient might receive today and validated that hyperglycemia alters the metabolic state within tumors to sensitize it to treatment.
"We show that the effectiveness of diverse chemotherapies was markedly improved under high glucose conditions, as compared to low glucose conditions. In some instances, the mice appeared to be cured of their cancer, while mice receiving the same chemotherapy under normal glycemic conditions had relatively little benefit," said Dr. Winter.
How can this observation be translated to patients? In the clinical setting, tumors can be theoretically 'primed' for chemotherapy by inducing a forced hyperglycemic state, just as we did in mice. In theory, glucose levels can even be modified more precisely through intravenous dextrose infusions (combined with rigorous inpatient glucose monitoring) at the time of chemotherapy administration. The next step is to implement a clinical trial.
Dr. Winter notes that "our patients need better treatment options urgently. Therefore, we are already getting to work designing a trial to treat patients safely with intentionally elevated blood sugars, and will determine if this strategy can improve patient outcomes."
More information: Ali Vaziri-Gohar et al, Increased glucose availability sensitizes pancreatic cancer to chemotherapy, Nature Communications (2023). DOI: 10.1038/s41467-023-38921-8
Citation: Study finds high blood glucose levels sensitizes pancreatic cancer cells to chemotherapy (2023, July 26) retrieved 27 July 2023 from https://medicalxpress.Com/news/2023-07-high-blood-glucose-sensitizes-pancreatic.Html
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Steve McQueen's Cancer Likely Resulted From His Service In The US Marine Corps
Steve McQueen was one of the most popular actors of the 20th century. Known for portraying the tough guy in such films as The Great Escape (1963), The Getaway (1972) and The Sand Pebbles (1966), he was a mainstay of the big screen. In 1980, McQueen passed after a short battle with cancer, a diagnosis that likely relates back to his service with the US Marine Corps.
Steve McQueen's cancer diagnosis The Great Escape, 1963. (Photo Credit: ash595 / Metro-Goldwyn-Mayer / United Artists / MovieStillsDB)In 1979, a year after he developed a tenacious cough, Steve McQueen was diagnosed with pleural mesothelioma, a type of cancer associated with exposure to asbestos. The fiber is known to cause a variety of ailments, including asbestosis, lung cancer and, as aforementioned, mesothelioma. Prior to this being proven, it was frequently used as an insulator and fire retardant.
By early 1980, it was found that McQueen's cancer had metastasized, with him telling the National Enquirer that his diagnosis was "terminal." With traditional treatments no longer feasible, the actor sought out alternative medicine. This, however, failed to help, and his condition continued to worsen, with tumors developing in his abdomen, as well as his neck.
On November 7, 1980, McQueen suffered a fatal heart attack in his sleep. He was just 50 years old. The medical incident occurred just 12 hours after he'd undergone surgery to remove the cancerous tumors.
Service in the US Marine Corps Bullitt, 1968. (Photo Credit: Zayne / Warner Bros. / MovieStillsDB)In 1947, a 17-year-old Steve McQueen received permission from his mother to enlist in the US Marine Corps. After attending boot camp at Marine Corps Recruit Depot, Parris Island, he earned the rank of private first class and was assigned to an armored unit.
Despite it being his choice to enlist, McQueen struggled to follow the strict rules that came with military service. He was demoted seven times, and was even once sentenced to 41 days in the brig after going AWOL to spend time with his girlfriend. This had an impact on the future actor, who changed his ways and went on to see great success while in the Marines.
Among the most notable incidents to occur while McQueen was with the Marine Corps was his rescue of five comrades during an exercise in the Arctic. He pulled the group to safety just before their tank fell through the ice. Following this, he was assigned to the honor guard that was responsible for guarding Harry S. Truman's presidential yacht.
McQueen was honorably discharged in 1950. Speaking about his service later in life, he said, "The Marines made a man out of me. I learned how to get along with others, and I had a platform to jump off of."
Did Steve McQueen's service cause him to develop cancer? The Magnificent Seven, 1960. (Photo Credit: movienutt / United Artists / MovieStillsDB)Steve McQueen initially believed his cancer was caused by exposure to asbestos on the sets of his movies – in particular, sound stage insulation and the protective suits he wore while performing stunts. While this definitely contributed to his diagnosis, it's more likely that the direct cause was his service in the US Marine Corps.
According to Mesothelioma.Com, those who served in all branches of the military had contact with asbestos via engine and boiler rooms, sleeping quarters, navigational and storage rooms, galleys and mess halls. It was also used to produce gaskets, valves and cables. In McQueen's case, he was likely exposed to it while stationed aboard a troop ship, upon which he was tasked with moving insulation from pipes.
More from us: Famous Marines: 9 Celebrities Who Served In the US Marine Corps
The US military used asbestos until the 1980s in the construction of ships, barracks, tanks, various buildings, trucks and tanks. Marines, in particular, were exposed to the fiber through the vehicles, ships and aircraft that transported them to the battlefield.
Clare Fitzgerald Clare Fitzgerald is a Writer and Editor with eight years of experience in the online content sphere. Graduating with a Bachelor of Arts from King's University College at Western University, her portfolio includes coverage of digital media, current affairs, history and true crime.
Among her accomplishments are being the Founder of the true crime blog, Stories of the Unsolved, which garners between 400,000 and 500,000 views annually, and a contributor for John Lordan's Seriously Mysterious podcast. Prior to its hiatus, she also served as the Head of Content for UK YouTube publication, TenEighty Magazine.
In her spare time, Clare likes to play Pokemon GO and re-watch Heartland over and over (and over) again. She'll also rave about her three Maltese dogs whenever she gets the chance.
Writing PortfolioStories of the Unsolved
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