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Comprehensive study of esophageal cancer reveals several molecular subtypes, provides new insight into increasingly prevalent disease

The Cancer Genome Atlas Research Network recommends clinical trials organizers and drug manufacturers focus on newly discovered molecular subtypes

GRAND RAPIDS, Mich. (Jan. 4, 2017) – A comprehensive analysis of 559 esophageal and gastric cancer samples, collected from patients around the world, suggests the two main types of esophageal cancer differ markedly in their molecular characteristics and should be considered separate diseases.

The study, published today in Nature from The Cancer Genome Atlas (TCGA) Research Network, includes two key takeaways. First, upper esophageal cancers more closely resemble cancers of the head and neck, while tumors further down in the esophagus are virtually indistinguishable from a subtype of stomach cancer. Second, cancer clinical trials should group patients according to molecular subtype—in general, grouping lower esophageal tumors with stomach cancers, while evaluating upper esophageal cancers separately.

“These findings add several layers of depth and sophistication to our current understanding of esophageal cancer genomics,” said Adam Bass, M.D., co-leader of TCGA’s esophageal cancer study and physician-scientist at Dana-Farber Cancer Institute. “Our hope is this work settles several long-standing uncertainties in the esophageal cancer field and will serve as the definitive reference manual for researchers and drug developers seeking more effective clinical trials and new treatment approaches.”

tcga-banner-pngPhysicians have known for decades that esophageal cancers, when looked at under the microscope, fall into one of two categories—adenocarcinomas, which resemble stomach or colorectal cancers, and squamous cell carcinomas, which are similar to some lung, skin, and head and neck cancers. What remained unknown was the extent to which adenocarcinomas and squamous esophageal cancers differ molecularly and the relationship between esophageal adenocarcinoma and stomach adenocarcinoma.

“We have shown that these clinical subtypes differ profoundly at the molecular level,” said Peter W. Laird, Ph.D., a principal investigator in the international TCGA Research Network and a professor at Van Andel Research Institute. “These findings suggest that whether the tumor originates in the esophagus or the stomach is less relevant than the molecular characteristics of the individual tumors.”

Esophageal cancer represents just 1 percent of new cancer diagnoses in the U.S. However, it kills 4-in-5 patients within five years of diagnosis, and current treatment approaches often fail to help. Additionally, cases of esophageal adenocarcinoma have skyrocketed over the last four decades, increasing seven-fold since the mid-1970s. Within the field, there has been great uncertainty regarding the relationship between this growing burden of esophageal adenocarcinoma and adenocarcinomas that occur in the stomach.

Results from this new report argue against the need to continue to debate the demarcations of esophageal and gastric adenocarcinoma and instead view gastroesophageal adenocarcinoma as a more singular entity, analogous to colorectal cancer. Specifically, this study revealed that esophageal adenocarcinomas have striking molecular similarity to a class of stomach cancers called chromosomally unstable tumors, the hallmark of which are significant structural chromosomal aberrations.

Oncologists say this nuanced view of the disease, including the detailed molecular taxonomy of esophageal adenocarcinomas, will likely change their approach to studies and treatment.

“It is clear from the TCGA data that esophageal squamous and esophageal adenocarcinomas are completely different diseases and should never be included in the same therapeutic trial,” said Yelena Y. Janjigian, M.D., a gastrointestinal oncologist from Memorial Sloan Kettering Cancer Center who contributed samples to the study and served as a co-author. “In esophageal adenocarcinoma, it is likely a combination of pathways and therapeutic strategies that will be successful. The therapeutic significance of these alterations will be explored in follow-up studies.”

Members of the TCGA Research Network team say these studies represent the work of dedicated collaborators, who seek to maximize results in search of new ways to battle cancer.

“Studies from TCGA transcend the work of any one institution or individual,” said Ilya Shmulevich, Ph.D., a principal investigator in the international TCGA Research Network and a professor at the Institute for Systems Biology. “These are massive undertakings that are possible only through contributions from hundreds of specialists and scientists around the world—people dedicate years of their lives to these projects in the hope of finding new treatments for people who are very sick.”

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Peter W. Laird, Ph.D.
Professor, Center for Epigenetics

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Diabetes drug slows experimental Parkinson’s disease progression, human trials to begin next year

New data published today shows drug preserves critical brain function in laboratory models of Parkinson’s

GRAND RAPIDS, Mich. (Dec. 7, 2016)—A new investigational drug originally developed for type 2 diabetes is being readied for human clinical trials in search of the world’s first treatment to impede the progression of Parkinson’s disease following publication of research findings today in the journal Science Translational Medicine.

“We hope this will be a watershed moment for millions of people living with Parkinson’s disease,” says Patrik Brundin, M.D., Ph.D., director of Van Andel Research Institute’s Center for Neurodegenerative Science, chairman of The Cure Parkinson’s Trust’s Linked Clinical Trials Committee, and the study’s senior author. “All of our research in Parkinson’s models suggests this drug could potentially slow the disease’s progression in people as well.”

Dopamine-producing brain cells after treatment with MSDC-0160. Photo courtesy of the Patrik Brundin Laboratory, Van Andel Research Institute.

Until now, Parkinson’s treatments have focused on symptom management. If successful in human trials, MSDC-0160 would be the world’s first therapy to treat the underlying disease and slow its progression—potentially improving quality of life and preventing the occurrence of falls and cognitive decline. It may also reduce or delay the need for medications that can have debilitating side effects, says Brundin.

Parkinson’s disease afflicts between 7-10 million people worldwide, including an estimated 1 million Americans, and these numbers are expected to increase dramatically as the average human lifespan increases.  There is currently no cure, and first-line treatment has remained relatively unchanged since the introduction of levodopa in the 1960s.

Tom Isaacs, a co-founder of The Cure Parkinson’s Trust who has lived with Parkinson’s for 22 years, says MSDC-0160 represents one of the most promising treatment the Trust’s international consortium has seen to date.

“Our scientific team has evaluated more than 120 potential treatments for Parkinson’s disease, and MSDC-0160 offers the genuine prospect of being a breakthrough that could make a significant and permanent impact on people’s lives in the near future,” says Isaacs. “We are working tirelessly to move this drug into human trials as quickly as possible in our pursuit of a cure.”

MSDC-0160 was developed by Kalamazoo, Michigan-based Metabolic Solutions Development Company (MSDC) to treat type 2 diabetes. In 2012, Brundin recognized it as an exciting drug candidate because of its mode of action, proven safety in people, local availability and the start-up company’s interest in collaborating on drug repurposing initiatives. After four years of work, the effects of the drug in the laboratory exceeded Brundin’s expectations.

The novelty of MSDC-0160 stems from a recently revived revelation that Parkinson’s may originate, at least partially, in the body’s energy metabolism. The new drug appears to regulate mitochondrial function in brain cells and restore the cells’ ability to convert basic nutrients into energy. Consequently, the cells’ ability to handle potentially harmful proteins is normalized, which leads to reduced inflammation and less nerve cell death.

“Parkinson’s disease and diabetes may have vastly different symptoms with unrelated patient outcomes; however, we’re discovering they share many underlying mechanisms at the molecular level and respond similarly to a new class of insulin sensitizers like MSDC-0160,” says Jerry Colca, Ph.D., co-founder, president and chief scientific officer of MSDC.

While Brundin says he is eager to see MSDC-0160 launched into a clinical trial in Parkinson’s disease, he’s equally excited about the possibility of testing the drug in Lewy body dementia and other cognitive decline conditions, such as Alzheimer’s disease.

“This is an immensely promising avenue for drug discovery,” says Brundin. “Whatever the outcome of the upcoming trial for Parkinson’s, we now have a new road to follow in search of better treatments that cut to the root of this and other insidious diseases.”

The Cure Parkinson’s Trust and Van Andel Research Institute are currently working with MSDC to address regulatory issues and obtain funding to organize the clinical trial, which Brundin hopes can begin sometime in 2017.

Funding for the research was provided by Van Andel Research Institute, The Cure Parkinson’s Trust, the Campbell Foundation, and the Spica Foundation.

The paper’s authors include Anamitra Ghosh, Trevor Tyson, Sonia George, Erin N. Hildebrandt, Jennifer A. Steiner, Zachary Madaj, Emily Schulz, Emily Machiela, Martha L. Escobar Galvis, Jeremy M. Van Raamsdonk and Patrik Brundin, all of Van Andel Research Institute; William G. McDonald and Jerry R. Colca, both of Metabolic Solutions Development Company; and Jeffrey H. Kordower, of Rush University Medical Center and Van Andel Research Institute.

 

 

 

 

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Patrik Brundin, M.D., Ph.D.
VARI Associate Director of Research
Professor and Director of the Center for Neurodegenerative Science
Jay Van Andel Endowed Chair in Parkinson’s Research

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