Cause of drug resistance in a drug resistance in intestinal tumors identified

October 16, 2019

BOSTON - Most cases of gastrointestinal stromal tumor (GIST), a type of soft-tissue cancer (sarcoma), are caused by mutations in genes that can be effectively targeted with drugs that inhibit the activity of rogue cancer-promoting enzymes.

But an estimated 10% to 20% of GISTs have no identifiable or targetable mutations. Now, investigators in a Boston-area cancer research collaboration have clarified mechanisms that allow these hard-to-treat cancers to develop, and in lab experiments have identified strategies that could lead to effective new therapies.

The research, a joint effort of investigators at Massachusetts General Hospital (MGH), the Broad Institute of MIT and Harvard, Dana-Farber Cancer Institute (DFCI) and the Ludwig Center at Harvard Medical School (HMS), is published in the journal Nature.

Importantly, the investigators show how "epigenetic" changes - changes in how the code of genes is read by tumor cells that are not caused by genetic mutations - can lead to the development of GISTs and other cancers, and how it may be possible to short-circuit the cancer-causing machinery.

"Your genome consists of about 6 feet of DNA wrapped very carefully to fit into microscopic cells. One of the tricks that the cell uses to compact all of this DNA is to tie it up into little loops," says senior co-author Bradley E. Bernstein, MD, PhD, of MGH, Broad Institute and the Ludwig Center at Harvard.

He likens the process to shoelaces, in which each carefully tied loop is separated by a knot. The "knot" in the cells is called an "insulator" in scientific parlance. He and his colleagues found that one of these insulators normally keeps a cancer-causing gene, FGF4, from coming into contact with a stretch of DNA with a powerful switch that turns on an unrelated gene. In normal cells, the cancer-causing gene and the switch are in separate loops and never come into contact with one another. However, in some forms of GIST, the insulator is not functional, the loops merge into one, and the on-switch mistakenly activates the cancer-causing FGF4 gene.

The investigators were studying a form of GIST that lacks typical cancer-causing mutations but has instead lost the function of an enzyme complex called SDH, which normally is key to energy generation in the cell. How SDH deficiency contributed to this malignancy was a mystery, but an interesting clue was that a process called DNA methylation, which adds small chemical 'tags' to the DNA, was abnormally revved up in SDH-deficient tumors. The team found that the excess methylation destroyed many insulators in these tumors, leading to abnormal contacts between on-switches and oncogenes. In addition to the disrupted insulator that activated the FGF4 oncogene, they identified a second disrupted insulator near a normal gene called KIT - the gene that is abnormally activated by a mutation in most other GISTs.

To validate their findings, the investigators then transplanted a human GIST tumor into a mouse to create an experimental model or 'mouse avatar'. They showed that their model "faithfully maintains the epigenetics of the parental tumor" including the supercharged DNA methylation and defective insulators.

Finally, the investigators showed that growth of the model tumors could be suppressed with a class of drugs known as fibroblast growth factor receptor (FGFR) inhibitors, either alone or in combination with an enzyme-inhibiting targeted therapy called sunitinib (Sutent®), a drug FDA-approved for treatment of GIST.

"Although some targeted therapies can help SDH-deficient GIST patients, the children and young adults who typically get this form of GIST generally develop resistance rapidly to the standard targeted drugs. The insights from our collaborative research can open new avenues for testing combinations of new therapies in this subset of GIST and other cancers," said George Demetri MD, senior co-author from the Dana-Farber Cancer Institute and the Ludwig Center at Harvard. Bernstein adds that "the FDA approved the first FGFR-inhibitor drug for treatment of metastatic bladder cancer earlier this year, and it may be possible to re-purpose this or similar drugs in development to treat SDH-deficient GIST."
Co-lead authors of the Nature paper are Bernstein; George D. Demetri, MD, DFCI and Ludwig Center at Harvard and HMS; Yotam Drier, PhD, MGH and Broad; and William A. Flavahan, PhD from MGH and Broad. Additional co-authors are: Sarah F. Johnstone. MD, PhD, MGH; Matthew L. Hemming, MD, PhD, DFCI; Daniel R. Tarjan [PhD], MGH and Broad; Esmat Hegazi, BS, MGH and Broad; Sarah Shareef, BS, MGH and Broad; Nauman Javed, BS, MGH/Broad; Chandrajit P. Raut, MD, MSc, Brigham and Women's Hospital and DFCI; Benjamin K. Eschle, BA, DFCI; Prafulla C. Gokhale, PhD, DFCI; Jason L. Hornick, MD, PhD, Brigham and Women's Hospital and DFCI; and Ewa T. Sicinska, MD, DFCI.

The study was supported in part by The National Cancer Institute, the NIH Common Fund, the Ludwig Center at Harvard, the American Cancer Society, the MGH Research Institute, the Broad Institute of MIT and Harvard, and the Pan Mass Challenge.

About the Massachusetts General Hospital

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $1 billion and comprises more than 8,500 researchers working across more than 30 institutes, centers and departments. In August 2019 the MGH was once again named #2 in the nation by U.S. News & World Report in its list of "America's Best Hospitals."

Massachusetts General Hospital

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

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.

Read More: Cancer News and Cancer Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to