Nav: Home

Potential new therapy takes aim at a lethal esophageal cancer's glutamine addiction

May 20, 2019

Researchers at the Medical University of South Carolina (MUSC) have found a way to target drug-resistant esophageal cancer cells by exploiting the different energy needs of cancerous versus healthy cells. This breakthrough is now opening the doorway to new treatments for an otherwise lethal cancer. The findings of the National Institutes of Health (NIH)-funded study are reported in Nature Communications.

Only about 20 percent of patients diagnosed with esophageal squamous cell carcinoma (ESCC) are still alive five years later, according to the American Cancer Society. Unfortunately, this disease is usually found at a late or advanced stage, meaning that, for many patients with ESCC, the cancer has already spread to other parts of their bodies. The severity of the disease is compounded by its high rate of recurrence.

"[It's] an aggressive, lethal cancer," says Shuo Qie, M.D., Ph.D., a postdoctoral fellow at MUSC Hollings Cancer Center and first author on the article.

"[S]urgery is the only and the best choice. But some patients, especially patients with metastasis, need chemotherapy or other additional treatments."

For the study, Qie aimed to further characterize and ideally address the cancer-driving pathway previously discovered by J. Alan Diehl, Ph.D., his mentor and the senior author on the article. Diehl is the SmartState Endowed Chair in Lipidomics and Pathobiology and Associate Director of Basic Science at MUSC Hollngs Cancer Center.

This pathway, the Cyclin D1 axis, is an intersection at which several cancer-promoting changes occur. The protein Fbxo4, which usually prevents cancer by controlling cyclin D1 degradation, no longer exerts its protective effects. This allow cells to spiral out of control.

Qie discovered that the axis activates a metabolic switch that causes ESCC cells to depend much more on glutamine than glucose. Healthy cells break down both glucose and glutamine for their energy needs, but ESCC cells are virtually addicted to glutamine.

"The cancer cells have to have glutamine. You can bathe them in glucose and they're still going to die without glutamine," explains Diehl.

These findings point to a vulnerability in these cancer cells and suggest a new therapeutic possibility--the use of glutaminase inhibitors. Glutaminase is an enzyme required for the cellular digestion of glutamine. Inhibiting it effectively blocks the cell's ability to process glutamine.

The MUSC researchers tested the efficacy of a combination regimen that included a glutaminase inhibitor (Telaglenastat; Calithera, San Francisco, CA) and metformin in cancer cell lines and mice.

They found that the combination regimen effectively treated tumors with the molecular signature that Diehl had previously described.

Importantly, the treatment was effective even against tumors that had developed resistance to CDK4/6 inhibitors. Indeed, the resistant cancer cells were even more vulnerable to this treatment than non-resistant ones.

"It's quite remarkable that the tumor cells that we have that are resistant to CDK4/6 inhibitors are actually five-, six-fold more sensitive to this combination therapy than they were before they developed resistance," says Diehl.

The promising findings for this combination regimen in both cellular and animal models suggest that it could have therapeutic potential for patients diagnosed with this traditionally dangerous and difficult cancer. Having moved this treatment from concept to reality in the laboratory, Qie and Diehl hope to move forward with clinical trials for their combination treatment and are currently seeking funding to do so.

The MUSC researchers' curiosity about a biological pathway has led to a potential new therapeutic approach for patients with ESCC.

"You'll hear the term 'an Achilles heel,'" explains Diehl.

"Can you find the Achilles heel that's in the cancer but not in the normal cell? And that's what Qie has done. Just from trying to understand the biology of the pathway, he and I have identified a unique therapeutic opportunity."
-end-
The content of the article summarized by this release is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

About MUSC

Founded in 1824 in Charleston, MUSC is the oldest medical school in the South, as well as the state's only integrated, academic health sciences center with a unique charge to serve the state through education, research and patient care. Each year, MUSC educates and trains more than 3,000 students and 700 residents in six colleges: Dental Medicine, Graduate Studies, Health Professions, Medicine, Nursing and Pharmacy. The state's leader in obtaining biomedical research funds, in fiscal year 2018, MUSC set a new high, bringing in more than $276.5 million. For information on academic programs, visit http://musc.edu.

As the clinical health system of the Medical University of South Carolina, MUSC Health is dedicated to delivering the highest quality patient care available, while training generations of competent, compassionate health care providers to serve the people of South Carolina and beyond. Comprising some 1,600 beds, more than 100 outreach sites, the MUSC College of Medicine, the physicians' practice plan, and nearly 275 telehealth locations, MUSC Health owns and operates eight hospitals situated in Charleston, Chester, Florence, Lancaster and Marion counties. In 2018, for the fourth consecutive year, U.S. News & World Report named MUSC Health the number one hospital in South Carolina. To learn more about clinical patient services, visit http://muschealth.org.

MUSC and its affiliates have collective annual budgets of $3 billion. The more than 17,000 MUSC team members include world-class faculty, physicians, specialty providers and scientists who deliver groundbreaking education, research, technology and patient care.

About Hollings Cancer Center

The Hollings Cancer Center at the Medical University of South Carolina is a National Cancer Institute-designated cancer center and the largest academic-based cancer research program in South Carolina. The cancer center comprises more than 100 faculty cancer scientists and 20 academic departments. It has an annual research funding portfolio of more than $40 million and a dedication to reducing the cancer burden in South Carolina. Hollings offers state-of-the-art diagnostic capabilities, therapies and surgical techniques within multidisciplinary clinics that include surgeons, medical oncologists, radiation therapists, radiologists, pathologists, psychologists and other specialists equipped for the full range of cancer care, including more than 200 clinical trials. For more information, visit http://www.hollingscancercenter.org

Medical University of South Carolina

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

Teaching For Better Humans 2.0
More than test scores or good grades–what do kids need for the future? This hour, TED speakers explore how to help children grow into better humans, both during and after this time of crisis. Guests include educators Richard Culatta and Liz Kleinrock, psychologist Thomas Curran, and writer Jacqueline Woodson.
Now Playing: Science for the People

#556 The Power of Friendship
It's 2020 and times are tough. Maybe some of us are learning about social distancing the hard way. Maybe we just are all a little anxious. No matter what, we could probably use a friend. But what is a friend, exactly? And why do we need them so much? This week host Bethany Brookshire speaks with Lydia Denworth, author of the new book "Friendship: The Evolution, Biology, and Extraordinary Power of Life's Fundamental Bond". This episode is hosted by Bethany Brookshire, science writer from Science News.
Now Playing: Radiolab

Dispatch 3: Shared Immunity
More than a million people have caught Covid-19, and tens of thousands have died. But thousands more have survived and recovered. A week or so ago (aka, what feels like ten years in corona time) producer Molly Webster learned that many of those survivors possess a kind of superpower: antibodies trained to fight the virus. Not only that, they might be able to pass this power on to the people who are sick with corona, and still in the fight. Today we have the story of an experimental treatment that's popping up all over the country: convalescent plasma transfusion, a century-old procedure that some say may become one of our best weapons against this devastating, new disease.   If you have recovered from Covid-19 and want to donate plasma, national and local donation registries are gearing up to collect blood.  To sign up with the American Red Cross, a national organization that works in local communities, head here.  To find out more about the The National COVID-19 Convalescent Plasma Project, which we spoke about in our episode, including information on clinical trials or plasma donation projects in your community, go here.  And if you are in the greater New York City area, and want to donate convalescent plasma, head over to the New York Blood Center to sign up. Or, register with specific NYC hospitals here.   If you are sick with Covid-19, and are interested in participating in a clinical trial, or are looking for a plasma donor match, check in with your local hospital, university, or blood center for more; you can also find more information on trials at The National COVID-19 Convalescent Plasma Project. And lastly, Tatiana Prowell's tweet that tipped us off is here. This episode was reported by Molly Webster and produced by Pat Walters. Special thanks to Drs. Evan Bloch and Tim Byun, as well as the Albert Einstein College of Medicine.  Support Radiolab today at Radiolab.org/donate.