Ronald P. DeMatteo MD

GIST is the most common human sarcoma, and approximately 85% of these tumors are attributable to a mutation in either KIT or PDGFRA genes. Imatinib mesylate is a tyrosine kinase inhibitor (TKI) that targets both of these genes and is effective in nearly 80% of patients with GIST. The advent of tyrosine kinase inhibitors has increased the median survival from 1 year to over 5 years. Despite this success, imatinib and the other tyrosine kinase inhibitors are not curative even in patients who respond, and many GISTs develop resistance to these drugs, necessitating further therapeutic approaches.

We have recently developed the first patient-derived xenograft of PDGFRA D842V-mutant GIST, the most common PDGFRA mutation that is also resistant to
imatinib and most other TKIs.

 

Gastrointestinal stromal tumor (GIST) is a rare type of cancer that affects approximately 40,000 patients with an annual incidence of 5,000 cases in the US. It arises from the “pacemaker” cells of the gastrointestinal tract and is mainly characterized by activating mutations in KIT or PDGFRA receptor tyrosine kinases. Despite the initial clinical success of imatinib that targets mutant KIT/PDGFRA, nearly all advanced GIST patients develop imatinib-resistance and eventually die of their disease. It is critical to gain a better understanding of the pathogenesis of GIST to dissect the molecular underpinning of aggressive and metastatic behaviors and to develop novel treatment strategies that enhance first-line imatinib therapy and target and/or prevent imatinib-resistance.

 

As a result of the generous GCRF funding, we were able in the past year to complete an ambitious project on defining genomic biomarkers to better assess risk of malignancy in GIST and guide the patient’s selection for adjuvant therapy (Dermawan J et al, Clinical Cancer Research, 29:3974-85, 2023). This study was triggered by the many existing limitations of the current risk stratification schemes in GIST. To mention a few, the conventional guidelines for risk assessment were defined in the pre-imatinib era and rely solely on clinicopathologic metrics: tumor site, tumor size, and mitotic activity. These risk models have performed inconsistently in differentiating potentially aggressive from indolent clinical behavior, offering limited guidance on adjuvant therapy. Additional significant limitations of the current prognostication include the lack of integrated molecular biomarkers and not accounting for the imatinib sensitivity of the primary GIST genotype. In our recent study, we specifically investigate means of extracting additional information from large-scale genomic landscape signatures, focusing on selecting and validating prognostic biomarkers of tumor progression.

 

 

 

 

 

 

 

 

 

 

The GIST Cancer Research Fund graciously supports the research efforts of Margaret von Mehren, MD and Lori Rink, PhD, who manage a lab devoted to GIST research. With your support, Dr. von Mehren, Dr. Rink and their team continue to focus on advancing our understanding of GIST in pursuit of novel therapies.

The primary goal of Dr. von Mehren’s work is the testing and evaluation of new therapies for soft tissue sarcomas. There are approximately 7,000 new Margaret von Mehren, MD cases of soft tissue sarcomas diagnosed annually with only 50 percent of patients surviving their disease, and with the limitations of current therapies, a far lower rate of survival if the sarcoma recurs. Dr. von Mehren has a particular interest in novel therapies for Gastrointestinal Stromal Tumors (GIST), the most common sarcoma of the intestinal tract. GIST is characterized by the presence of a growth factor, named KIT, found on the surface of the tumor cells. The gene for KIT, or in rare cases PDGFRA, BRAF, or SDH, undergoes mutations that activate the protein, causing tumor cells with these mutated genes to continuously grow and divide.

Perhaps because of its rarity, GIST has not received the same level of attention and research funding as other more common cancers. As a result, research in this field has attracted fewer investigators, and progress has been less rapid than needed. In addition, few hospitals and cancer centers have been able to develop the multidisciplinary treatment and research programs necessary to develop new therapies for GIST. Philanthropic support provides needed start-up funds for promising new research and support for educational programs, as well as building new patient care and research facilities. Our hope is to make a difference for current and future GIST patients. A single donor can make a world of difference for GIST research. A gift of any amount would have an immediate significant impact on developing better care for GIST patients at The University of Miami, Sylvester Comprehensive Cancer Center and throughout the world. Any gift is 100% directed to GIST Cancer Research.

Dr. Jon Trent, MD, PhD, and staff for GIST Cancer Research at the University of Miami, Sylvester Comprehensive Cancer Center has been exploring the use of a new medicine for GIST called Procaspase Activating Compound (PAC)-1. PAC-1 is designed to make other drugs more effective. During the past 10 years, Sylvester Comprehensive Cancer Center’s Sarcoma Program has developed into the largest sarcoma center in the southeastern United States.

Not only do Fox Chase physicians have extensive experience in diagnosing and treating sarcomas, but they head panels of experts tasked with writing and updating sarcoma treatment guidelines that are used both nationally and globally. They also work with other world-renowned experts to conduct clinical trials, both for early and advanced stage sarcomas.

“When we see a patient with sarcoma, we think about how to best treat them as a team,” said Margaret von Mehren, MD, Chief of the Division of Sarcoma Oncology at Fox Chase. “Our program includes specialists in sarcoma medical oncology, surgical oncology, orthopedic surgical oncology, radiation oncology, radiology and pathology who review tumor biopsies and imaging to determine the best possible treatment for each case.”

“I started with just a little website,” Tania says. “I went on local radio. I went to our local paper and told them my story.” In 2001, she held her first walkathon and raised $23,000. In 2018, the foundation has raised more than $10 million dollars and every penny has gone to GIST Cancer Research.

United States Senator, Charles “Chuck” Schumer graciously acknowledged the GIST Cancer Research Fund with a proclamation for the importance of the numerous contributions that the GIST Cancer Research Fund and the Walk For A Cure has made to find a cure for GIST Cancer.

 

 

 

 

 

 

Michael Heinrich, M.D., and Christopher Corless, M.D., Ph.D.

Understanding mechanisms of resistance

Recently, two new drugs (avapritinib, ripretinib) have become approved for treatment of advanced GIST. These drugs provide new therapy options, but already we have seen clinical resistance to these new drugs. In order to continue to improve treatments, we need to understand the ways by which GIST cells can overcome these new “wonder drugs”. We have established new technologies and cell lines to determine the mechanisms of resistance to these agents. Using our improved technologies, we can “fast forward” our experiments to more rapidly discover new resistance mutations. In addition to determining resistance mechanisms for these two new agents, we will also study resistance mechanisms to new drugs that will be tested in clinical studies in 2023-2024: CGT9486, THE-630, IDRX42, NB003, and the combination of CGT9486 + sunitinib. We have already completed pilot experiments with THE-630, IDRX42, NB003, and CGT9486

The 2024 GIST Education Conference and Luncheon will be held on October 24, 2024 at The OHSU Knight Cancer Institute in Portland, Oregon.  Speakers to be announced. An official invitation will be posted later this year. The 2023 GIST Education Conference can be viewed below:

Click Here To View Presentation

 

A look behind the scenes in the lab of Dr. Michael Heinrich and Dr. Chris Corless at the Oregon Health & Science Center/Knight Cancer Institute. Here is an overview of the current research being performed to find a cure for GIST Cancer.

GIST is a rare form of cancer that most doctors misdiagnose or are not familiar with the appropriate treatment. If you or a loved-one is diagnosed with GIST, getting in touch with a physician who specializes in GIST Cancer is of utmost importance. These doctors and researchers deal with this disease on a daily basis and can help guide you to the right treatment.

In addition to the GIST Cancer Research Team of physicians, researchers and nurses, the following link will put you in touch with domestic and international GIST Cancer specialists.

In 2012, The GIST Cancer Research Fund and Robert and Tania Stutman were honored by Memorial Sloan Kettering Cancer Center for GCRF’s generous donations given for GIST Cancer Research. Their names were etched into MSKCC’s donor wall for posterity. For almost twenty years, The GIST Cancer Research Fund has been tirelessly fighting to raise funds to eradicate this deadly disease with no staff, corporate headquarters or overhead. Since 2002, the foundation has raised more than $10 million and MSK has been the beneficiary of $1.6 million. Events including walkathons, 1,000-mile Cycling for a Cure bike rides, golf outings and galas now span the nation. (Other GCRF beneficiaries include Fox Chase, Brigham and Women’s Hospital in Boston, Oregon Health Sciences University Cancer Institute, and MD Anderson Cancer Center in Houston.) At MSK, the GCRF supports the work of Dr. Antonescu and Dr. Ping Chi.

Robert and Tania Stutman join the generous philantropists including Susan G. Komen, who donate to MSKCC. The GCRF has raised $10 million dollars for GIST Cancer Research and has given 100% of these fund to finding a cure for GIST Cancer. As Tania Stutman said, ‘I’m not only battling for my life, I’m fighting for the lives of others.’”

Walt Frazier is a two-time NBA champion with the New York Knicks, a seven-time NBA All-Star and a member of the Basketball Hall of Fame. His retired No. 10 Knicks jersey is hanging in the rafters in Madison Square Garden. The NBA veteran is also known to be the GCRF's very own spokesperson. Walt has attended the GCRF New York Walk For A Cure for 18 years. His loyalty and commitment to GIST Cancer Research is relentless and he always finds the time to "be there" for the GIST Cancer Research Fund in good times and bad. Thank you Walt for all you have done and know that we hold a special place for you in our hearts!