Nav: Home

'Collateral' lethality may offer new therapeutic approach for cancers of the pancreas, stomach and colon

January 18, 2017

Cancer cells often delete genes that normally suppress tumor formation. These deletions also may extend to neighboring genes, an event known as "collateral lethality," which may create new options for development of therapies for several cancers.

Scientists at The University of Texas MD Anderson Cancer Center have discovered that during early cancer development when a common tumor suppressor known as SMAD4 is deleted, a nearby metabolic enzyme gene called malic enzyme 2 (ME2) also is eradicated, suggesting the possibility of malic enzyme inhibitors as a novel therapy approach. Study findings were published in the Jan. 18 online issue of Nature.

"In an effort to expand therapeutic strategies beyond oncogenic targets to those not directly linked to cancer development, we have identified collateral lethal vulnerability in pancreatic cancers that can be targeted pharmacologically in certain patient populations," said Prasenjit Dey, Ph.D., postdoctoral fellow in Cancer Biology and co-author of the Nature article. "Genomic data across several cancers further suggest this therapeutic strategy may aid many cancer patients, including those with stomach and colon cancers."

Collateral lethality occurs when tumor suppressor genes are deleted, a nearly universal occurrence in cancer. Correspondingly, a large number of genes with no direct role in tumor progression also are deleted as a result of their proximity to tumor suppressor genes.

SMAD4 is deleted in one-third of pancreatic cancers. The research team found that when the SMAD4 gene is eradicated in mice, it also results in depletion of ME2 levels. The genetic depletion of ME3, a sister gene to ME2, sets off a complex chain of events that ultimately regulates an amino acid group called branched chain amino acid (BCAA), which are crucial to cancer's ability to thrive. Thus, if a therapy could be developed that inhibits ME3, it might prevent ME2-deleted tumor growth.

"Our work suggests a mechanism for cell lethality involving the regulation of BCAAs as crucial elements in pancreatic cancer by regulating ME3," said Ronald DePinho, M.D., professor of Cancer Biology, senior author of the Nature paper and president of MD Anderson. "We propose that highly specific ME3 inhibitors could provide an effective therapy for many cancer patients, but more research must be done."
-end-
MD Anderson research team participants included Wen-Ting Liao, Ph.D., Zangdao Lan, M.D., Alina Chen, and Y. Alan Wang, Ph.D., Cancer Biology; Florian Muller, Ph.D., and Nikunj Santani, M.D., Cancer Systems Imaging; Chia Chin Wu, Ph.D., Tony Gutschner, Ph.D., Edward Chang, M.D., Giannicola Genovese, M.D.; Andrea Viale, M.D., Ph.D.; and Giulio Draetta, M.D., Ph.D., Genomic Medicine, and Huamin Wang, M.D., Ph.D., Pathology; Haoqiang Ying, M.D., Ph.D., Molecular and Cellular Oncology; Anirban Maitra, M.B.B.S., Translational Molecular Pathology; and Yaan Kang, M.D., Ph.D., and Jason Fleming, M.D., Surgical Oncology. Rice University, Houston, also participated in the study.

The study was funded by the National Institutes of Health (P30 CA16672 and NCI P01 CA117969); the Cancer Prevention and Research Institute of Texas (RP140612); the Department of Defense (W81XWH-14-1-0429); the MD Anderson Bridge Fund; the St. Louis Ovarian Cancer Awareness Research Grant; and Odyssey Fellowships at MD Anderson.

University of Texas M. D. Anderson Cancer Center

Related Cancer Articles:

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.
Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.
Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.
Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.
More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.
New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.
American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.
Oncotarget: Cancer pioneer employs physics to approach cancer in last research article
In the cover article of Tuesday's issue of Oncotarget, James Frost, MD, PhD, Kenneth Pienta, MD, and the late Donald Coffey, Ph.D., use a theory of physical and biophysical symmetry to derive a new conceptualization of cancer.
Health indicators for newborns of breast cancer survivors may vary by cancer type
In a study published in the International Journal of Cancer, researchers from the UNC Lineberger Comprehensive Cancer Center analyzed health indicators for children born to young breast cancer survivors in North Carolina.
Few women with history of breast cancer and ovarian cancer take a recommended genetic test
More than 80 percent of women living with a history of breast or ovarian cancer at high-risk of having a gene mutation have never taken the test that can detect it.
More Cancer News and Cancer Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Clint Smith
The killing of George Floyd by a police officer has sparked massive protests nationwide. This hour, writer and scholar Clint Smith reflects on this moment, through conversation, letters, and poetry.
Now Playing: Science for the People

#562 Superbug to Bedside
By now we're all good and scared about antibiotic resistance, one of the many things coming to get us all. But there's good news, sort of. News antibiotics are coming out! How do they get tested? What does that kind of a trial look like and how does it happen? Host Bethany Brookeshire talks with Matt McCarthy, author of "Superbugs: The Race to Stop an Epidemic", about the ins and outs of testing a new antibiotic in the hospital.
Now Playing: Radiolab

Graham
If former Minneapolis police officer Derek Chauvin's case for the death of George Floyd goes to trial, there will be this one, controversial legal principle looming over the proceedings: The reasonable officer. In this episode, we explore the origin of the reasonable officer standard, with the case that sent two Charlotte lawyers on a quest for true objectivity, and changed the face of policing in the US. This episode was produced by Matt Kielty with help from Kelly Prime and Annie McEwen. Support Radiolab today at Radiolab.org/donate.