Corporate Banner
Satellite Banner
Scientific Communities
Become a Member | Sign in
Home>News>This Article

Antibody Hinders Growth of Gleevec-Resistant Gastrointestinal Tumors in Lab Test

Published: Thursday, February 07, 2013
Last Updated: Thursday, February 07, 2013
Bookmark and Share
An antibody that binds to a molecule on the surface of a rare but deadly tumor of the gastrointestinal tract inhibits the growth of the cancer cells in mice.

The effect remains even when the cancer cells have become resistant to other treatments, and the findings may one day provide a glimmer of hope for people with the cancer, known as gastrointestinal stromal tumor, or GIST. The scientists hope to move into human clinical trials of the antibody within two years.

The antibody’s target is a receptor called KIT, which is often mutated in patients with the cancer. When mutated, KIT sends a continuous stream of messages into the cell urging it to grow uncontrollably. The Stanford researchers found that the antibody reduces the amount of KIT on the surface of the cancer cells and stimulates immune cells called macrophages to kill the rogue cells.

Currently, people with GIST are often treated first with surgery and then with the drug imatinib, marketed as Gleevec — a small molecule that also targets KIT. The treatment, which was approved for GIST in 2002, has been remarkably successful: It has increased the average survival time of many people with advanced disease from about 18 months to about five years. It was the first targeted small molecule inhibitor that proved effective against a solid tumor, but its effect is temporary.

“Gleevec, or imatinib, marked a paradigm shift in our understanding about cancer treatment and sparked much additional research into these inhibitors,” said Matt van de Rijn, MD, PhD, professor of pathology. “However, a new mutation almost always occurs over time in KIT that renders the tumor insensitive to the drug. We’ve found that treatment of these resistant cells with an antibody targeting KIT slows the growth of human GIST cells in cell culture and in animals, and increases their chances of being removed by the immune system.”

The researchers believe it may be possible that the anti-KIT antibody treatment could be used as an alternative to, or even in combination with, imatinib or other small-molecule or antibody-based therapies to provide better control of the cancer.

“We’re moving from an era in which, historically, patients are often treated with a single agent or class of agents into a time when tumors might be treated with more than one approach from the moment of diagnosis,” said van de Rijn.

He is a co-senior author of the study, which will be published online Feb. 4 in the Proceedings of the National Academy of Sciences. Irving Weissman, MD, director of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine, is the other co-senior author. Former graduate student Badreddin Edris, PhD, postdoctoral scholar Stephen Willingham, PhD, and graduate student Kipp Weiskopf share first authorship of the paper. Weissman is also a member of Stanford’s Cancer Institute.

About 3,000 to 6,000 people per year are diagnosed with GIST in the United States. Seventy to 80 percent of these cancers have what’s called an activating mutation in the cell surface receptor called KIT. This mutation causes the receptor to bombard the cells with the signal to proliferate and drives tumor growth. Although imantinib binds to KIT and inactivates its signaling — resulting in the temporary control of the disease in about 80 percent of cases — the receptor will nearly always develop a new mutation that renders it resistant to the small molecule.

Researchers in the van de Rijn and Weissman labs used cancer cell lines isolated from three patients with GIST for their study: Two were from patients whose tumors had become resistant to imatinib, and one was from a patient whose tumor was still sensitive to the treatment. They also used a cancer cell line from a patient with an unrelated cancer, called a leiomyosarcoma, as a control.

When they treated the cancer cells in a laboratory dish with the anti-KIT antibody, called SR1, the researchers found that the GIST tumor cells grew significantly more slowly than did the control cancer cells, regardless of their sensitivity or resistance to imatinib. When they investigated more closely, they found that the tumor cells exposed to the anti-KIT antibody expressed less KIT on their surface than did untreated cells. Furthermore, all three of the antibody-treated GIST cell lines were significantly more likely to be enveloped and destroyed by a type of immune cell called a macrophage than were untreated or control cancer cells.

To confirm their findings, the researchers genetically engineered the three GIST tumor cell lines to express proteins that emit colored light under certain conditions. This allowed them to track the growth and location of the cells in living laboratory animals over time. They injected the engineered cells into the abdominal cavities of mice, waited two weeks for the cancer cells to become established and then treated the animals with the anti-KIT antibody.

“Although the tumors from the imatinib-resistant cell lines continued to grow, their growth rate was reduced by about 10-fold when compared to that observed in untreated animals,” said van de Rijn.

The researchers are now planning to investigate whether a combination treatment of anti-KIT plus imatinib, or anti-KIT plus an antibody that targets a cell-surface molecule called CD47 previously identified in Weissman’s laboratory, will further inhibit tumor growth. (Anti-CD47 treatment has been shown to block a “don’t eat me” signal expressed by many types of cancer cells that protects them against macrophages.)

Coupling anti-CD47 with another treatment such as anti-KIT that appears to enhance the engulfment of the cancer cells by macrophages may provide a synergistic effect against the tumor, the researchers believe. A similar approach was shown to cure aggressive non-Hodgkin’s lymphoma in mice in Weissman’s lab in 2010.

Other Stanford researchers involved in the study include postdoctoral scholar Anne Volkmer, MD; instructor Jens-Peter Volkmer, MD; technician Kelli Montgomery; research assistant Humberto Contreras-Trujillo; former medical student Agnieszka Czechowicz, MD, PhD; and associate professor of pathology Robert West, MD, PhD.

Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,600+ scientific posters on ePosters
  • More Than 3,800+ scientific videos on LabTube
  • 35 community eNewsletters

Sign In

Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Drug Disarms Deadly C. difficile Bacteria Without Destroying Healthy Gut Flora
A drug that blocks the intestinal pathogen without killing resident, beneficial microbes may prove superior to antibiotics, currently the front-line treatment for the infection.
Friday, September 25, 2015
Virus Re-Engineered to Deliver Targeted Therapies
Researchers stripped a virus of its infectious machinery and turned its benign core into a delivery vehicle that can target sick cells while leaving healthy tissue alone.
Thursday, September 24, 2015
Combination Drug Therapy Shrinks Pancreatic Tumors In Mice
Two drugs that affect the structure and function of DNA have been found to block the growth of pancreatic tumor cells in mice, researchers hope the drugs can soon be tested in humans with the disease.
Thursday, September 24, 2015
Delivering Missing Protein Heals Damaged Hearts in Animals
Researchers have discovered that a particular protein, Fstl1, plays a key role in regenerating dead heart-muscle cells.
Tuesday, September 22, 2015
Key Mechanism in Gene Expression Discovered
RNA polymerase II makes life possible by expressing genes. Now, a team of Stanford biologists, chemists and applied physicists has observed it at work in real time.
Thursday, September 17, 2015
Drug Prevents Type 1 Diabetes In Mice
A compound that blocks the synthesis of hyaluronan, a substance generally found in in all body tissue, protected mice from getting Type 1 diabetes. The compound is already approved in Europe and Asia for the treatment of gallbladder disease.
Wednesday, September 16, 2015
New Method for Producing Vital Cancer Drug
Stanford scientists produced a common cancer drug – previously only available from an endangered plant – in a common laboratory plant.
Tuesday, September 15, 2015
Scientists Home In On Origin Of Human, Chimpanzee Facial Differences
A study of species-specific regulation of gene expression in chimps and humans has identified regions important in human facial development and variation.
Monday, September 14, 2015
X-ray Laser Experiment Could Help in Designing Drugs for Brain Disorders
Scientists found that when two protein structures in the brain join up, they act as an amplifier for a slight increase in calcium concentration, triggering a gunshot-like release of neurotransmitters from one neuron to another.
Monday, August 24, 2015
Researchers Develop qPCR Prognosis Test for NSCLC Patients
A nine-gene molecular prognostic index (MPI) for patients with early-stage non-small cell lung cancer (NSCLC) was able to provide accurate survival stratification and could potentially inform the use of adjuvant therapy in patients struggling with the disease.
Thursday, August 20, 2015
Scientists Genetically Modify Yeast to Produce Opioids
The technique could improve access to medicines in impoverished nations, and later be used to develop treatments for other diseases.
Monday, August 17, 2015
Identifying Defective Heart Genes
A new technique could eventually enable doctors to diagnose genetic heart diseases by rapidly scanning more than 85 genes known to cause cardiac anomalies.
Thursday, August 13, 2015
Elusive Liver Stem Cell Identified in Mice by Researchers
Researchers have found a previously unknown population of cells in mice that function as liver stem cells. The finding could aid drug testing and increase understanding of liver biology and disease.
Friday, August 07, 2015
Rescuing Genetic Material from Formaldehyde Treated Tissue Samples
Formaldehyde is excellent for preserving cellular structures, but it makes it difficult to pull genetic information from tissue samples. Eric Kool and colleagues have developed a catalyst that saves RNA, which could lead to better patient outcomes.
Tuesday, August 04, 2015
Women’s Immune System Genes Operate Differently from Men’s
A new technology reveals that immune system genes switch on and off differently in women and men, and the source of that variation is not primarily in the DNA.
Friday, July 31, 2015
Scientific News
13 Ways to Stop an Unseen Force from Disrupting Weighing
Download a free Mettler Toledo paper to discover how to halt static’s negative effects before the next weigh-in.
Flinders Ig Nobel Winner Cracks Global Anaesthetic
One of the world’s most in-demand anaesthetics can now be produced on the spot, thanks to the thermos-flask sized device that recently won Flinders University inventor Professor Colin Raston an Ig Nobel prize.
Resurrected Proteins Double Their Natural Activity
Researchers demonstrate method for reviving denatured proteins.
Genes That Protect African Children From Developing Malaria Identified
Variations in DNA at a specific location on the genome that protect African children from developing severe malaria, in some cases nearly halving a child’s chance of developing the life-threatening disease, have been identified in the largest genetic association study of malaria to date.
Messing With The Monsoon
Manmade aerosols can alter rainfall in the world’s most populous region.
Potential Target for Treatment of Autism
Grant of $2.4 million will support further research.
Scientists Decode Structure at Root of Muscular Disease
Researchers at Rice University and Baylor College of Medicine have unlocked the structural details of a protein seen as key to treating a neuromuscular disease.
Sniffing Out Cancer
Scientists have been exploring new ways to “smell” signs of cancer by analyzing what’s in patients’ breath.
New Test Detects All Viruses
A new test detects virtually any virus that infects people and animals, according to research at Washington University School of Medicine in St. Louis, where the technology was developed.
Inroads Against Leukemia
Potential for halting disease in molecule isolated from sea sponges.
Scroll Up
Scroll Down
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,600+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,800+ scientific videos