Corporate Banner
Satellite Banner
RNAi
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

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 2,500+ scientific posters on ePosters
  • More than 3,700+ 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 TechnologyNetworks.com 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

Long-sought Discovery Fills in Missing Details of Cell 'Switchboard'
A biomedical breakthrough reveals never-before-seen details of the human body’s cellular switchboard that regulates sensory and hormonal responses.
Monday, July 27, 2015
Existing Drug May Treat Deadliest Childhood Brain Tumor
For the first time, scientists have identified an existing drug that slows the growth of the deadliest childhood brain tumor.
Friday, May 08, 2015
Foreign Antibodies Mobilize Immune System to Fight Cancer
A mouse’s T cells can be primed to attack and eliminate a malignant tumor by injecting antibodies from another mouse with resistance to the tumor, as well as by activating certain signaling cells, a study has found.
Thursday, May 07, 2015
Tumor Suppressor Also Inhibits Key Property Of Stem Cells
The retinoblastoma protein inhibits cancer by controlling cell division. Now, researchers have shown that it also binds to and inhibits genes necessary for pluripotency.
Friday, November 14, 2014
Protein Complex May Play Role in Preventing Many Forms of Cancer, Study Shows
Researchers at the Stanford University School of Medicine have identified a group of proteins that are mutated in about one-fifth of all human cancers.
Tuesday, May 07, 2013
For Stanford Scientists, RNAi Gene Therapy Takes two Steps Forward, one Step Back
If RNAi is going to be viable as a therapy for organ-wide diseases such as hepatitis B or C, it will have to stick around.
Thursday, May 25, 2006
Scientific News
Liquid Biopsies: Utilization of Circulating Biomarkers for Minimally Invasive Diagnostics Development
Market Trends in Biofluid-based Liquid Biopsies: Deploying Circulating Biomarkers in the Clinic. Enal Razvi, Ph.D., Managing Director, Select Biosciences, Inc.
Self-Assembling, Biomimetic Membranes May Aid Water Filtration
A synthetic membrane that self assembles and is easily produced may lead to better gas separation, water purification, drug delivery and DNA recognition, according to an international team of researchers.
Error Correction Mechanism in Cell Division
Cell biologists have reported an advance in understanding the workings of an error correction mechanism that helps cells detect and correct mistakes in cell division early enough to prevent chromosome mis-segregation and aneuploidy, that is, having too many or too few chromosomes.
Researchers Resurrect Ancient Viruses
Researchers at Massachusetts Eye and Ear and Schepens Eye Research Institute have reconstructed an ancient virus that is highly effective at delivering gene therapies to the liver, muscle, and retina.
Cell Aging Slowed by Putting Brakes on Noisy Transcription
Experiments in yeast hint at ways to extend life of some human cells.
Crucial for Stem Cell Survival Protein Identified Using Editing Tool CRISPR
A team of University of Wisconsin-Madison engineers has identified a protein that is integral to the survival and self-renewal processes of human pluripotent stem cells (hPSC).
Long Telomeres Associated with Increased Lung Cancer Risk
Genetic predisposition for long telomeres predicts increased lung adenocarcinoma risk.
First Artificial Ribosome Designed
Researchers at the University of Illinois at Chicago and Northwestern University have engineered a tethered ribosome that works nearly as well as the authentic cellular component, or organelle, that produces all the proteins and enzymes within the cell.
Identifying a Key Growth Factor in Cell Proliferation
Researchers discover that aspartate is a limiter of cell proliferation.
A Gene-Sequence Swap Using CRISPR to Cure Haemophilia
For the first time chromosomal defects responsible for hemophilia have been corrected in patient-specific iPSCs using CRISPR-Cas9 nucleases
SELECTBIO

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
2,500+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,700+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FREE!