Immune and Molecular Therapy of Gastrointestinal Stromal Tumor/ DeMatteo Lab 2023
Ronald P. DeMatteo MD
Background: 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. Our lab has recently focused on discovering alternative approaches that may increase the efficacy of these tyrosine kinase inhibitors with combination therapy.
Current Focus & Future Directions: We have been using our immunocompetent, genetically engineered Kit V558Δ/+ mouse model which develops a cecal GIST with similar histology, Kit signaling, response to tyrosine kinase inhibitors, and immune response as seen in human GIST. We recently published work on Kit ligand, the natural ligand for the Kit receptor and showed that tumor cells as well as endothelia and smooth muscle cells produce Kit ligand in our mouse model, even after imatinib therapy.
Kit ligand remains an important therapeutic target. In addition, we also recently published details of an in vivo model that was developed to study a particular PDGFRA mutation and the mechanism of tumor persistence following treatment with avapritinib, a drug used after patients develop resistance to imatinib. We found that resistance to avapritinib can be caused by upregulation of myosin light-chain kinase (MYLK) inhibition and suggest that concomitant MYLK inhibition may enable the use of a lower dose of avapritinib to avoid cognitive side effects.
In addition to the above mechanisms, we are also studying various immune targets to block or activate in conjunction with imatinib to enhance imatinib’s anti-tumoral effect. These targets include ICOS, CD40, and VISTA. We are also utilizing recently acquired scRNAseq data of human GIST samples in order to categorize different immune cell populations and their gene expression to correlate to treatment response.
Summary: Our lab continues to search for new therapies to enhance the activity of tyrosine kinase inhibition in the treatment of GIST. We will be working to better understand TAMs in order to recruit and activate these immune cells to enhance the immune response to GIST. We will then be using combination therapy focusing on CD40 with the goal of activating the immune system to work in tandem with imatinib. We are so grateful for your continued support as we work toward these goals of combating human GIST.
DeMatteo Laboratory Personnel:
Ronald P. DeMatteo MD is John Rhea Barton Professor and Chair of Surgery at the University of Pennsylvania. His laboratory has been funded by the NIH since 2001. His laboratory attracts trainees from throughout the country. He will supervise all aspects of the proposal. All of the work in the lab is now focused on GIST.
Ferdi Rossi PhD is a molecular biologist. He has worked with Peter Besmer for over 10 years and now works in our lab. He has multiple projects in GIST.
Shan Zeng PhD is a molecular biologist and is primarily studying the role of gamma delta T cells in GIST.
Drew Tieniber MD is a postdoctoral fellow from the University of Pennsylvania and is using bioinformatics to study the CD8 T cell response to GIST.
Hyunjee Kwak MD is a postdoctoral fellow from the University of California San Francisco – East Bay, and is studying VISTA blockade and CD40 agonism in enhancing imatinib’s anti-tumoral effect.
Katherine Tardy MD is a postdoctoral fellow from Lankenau Medical Center and is studying ICOS blockade to enhance imatinib’s anti-tumoral effect.
Alina Mangold MD is a postdoctoral fellow from Germany and is studying the role of regulatory T cells in the GIST tumor microenviroment and immune response.
Juan Esteban Perez MD is a postdoctoral fellow from the University of Pennsylvania and is working to classify the subtypes of Tumor Associated Macrophages (TAMs) and their role in GIST.
Kevin Do is a research technician currently investigating alternative tyrosine kinase inhibitors.
Understanding the molecular determinants of GIST pathogenesis and novel therapeutics development in GIST
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. Previous studies have focused on understanding and targeting the ICC/GIST lineage-specific transcriptional factor, ETV1, in preclinical models and in an investigator initiated “phase Ib/II study of binimetinib in combination with imatinib in patients with untreated advanced GIST” to directly evaluate the safety and clinical efficacy of this novel combination therapy in advanced GIST. The phase Ib portion of the study has been completed and has demonstrated the safety and defined the recommended phase II doses of the combination therapy in GIST patients. In a small expansion cohort of patients with SDH-deficient GIST, the combination therapy has shown promising efficacy (Chi P et al., CCR 2022). The phase II study has completed accrual and met the primary endpoint with best RECIST objective response rate (ORR) of 68.3% (two-sided 95% CI, 51.9-81.9%; one-sided 90% CI, 57.2-100%) (Chi P, et al., JCO 2022).
Antonescu Research Lab Synopsis: Proposal for 2023-2024 Funding
Current risk stratification schemes in gastrointestinal stromal tumor (GIST) have been 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. We will focus on two areas using genomic platforms:
(1) identifying molecular biomarkers of primary and secondary resistance to imatinib/TKI beyond secondary KIT mutations; and
(2) investigating alternative mechanisms of imatinib failure in GIST such as the presence of KIT amplifications.
DR. JON TRENT'S IMPACT REPORT
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. With more than 20 dedicated, multidisciplinary, board-certified sarcoma doctors on staff, Sylvester serves approximately 900 new patients per year.
Download the pdf of Dr. Trent's Impact Report August 2022 for Gastrointestinal Stromal Tumor Research.
Impact 2022 Sarcoma_GIST
Dr. Meg von Mehren & Fox Chase Cancer Team Report
Dr. Meg von Mehren, GCRF's GIST Cancer Advisor and researcher at The Fox Chase Cancer Center, Philadelphia, PA, gives an update on how GCRF has helped their research.
Why Second Opinions Matter for Sarcoma
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.”
WALK FOR A CURE
Our smallest supporter at the 16th Annual GCRF Walk For A Cure in San Jose, CA
The GIST Cancer Research Doctors,
joined by Walt Frazier,
at the 22th Annual GCRF Walk For A Cure
in New York, New York
(L to R-back row) Dr. Jonathan A. Fletcher, MD, Brigham and Women's Hospital, Boston, MA,
Walt Frazier, NBA champion, NY Knicks, NBA All-Star and Basketball Hall of Famer,
Dr. Michael C. Heinrich, M.D.,
Oregon Health & Science University, Knight Cancer Institute and
Dr. Jon Trent, MD, PhD, University of Miami,
Sylvester Comprehensive Cancer Center
(L to R-front row) Lori Rink, PhD and
Dr. Margaret von Mehren, MD, Fox Chase Cancer Center, Philadelphia, PA,
Ping Chi, MD, PhD and
Dr. Cristina R. Antonescu, MD, Memorial Sloan Kettering Cancer Center, New York City
and Dr. Ronald P. DeMatteo, MD, FACS,
Penn Medicine, Philadelphia, PA.
Tania’s Story and the Formation of the GIST Cancer Research Fund
“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.
IN MEMORY OF
January 14, 1957 - February 19, 2018
HONOR MY LIFE BY LIVING YOURS!
A Message of Hope
GCRF received a special letter from the spouse of a GIST Cancer patient giving us all hope.
GIST Cancer Research Fund Proposal for 2023-2024
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
Developing strategies to optimize the treatment of PDGFRA-mutant GIST
Avapritinib is a recently approved drug for treatment of GIST with PDGFRA exon 18 mutations, particularly the imatinib-resistant PDGFRA D842V mutation. It is widely believed that all PDGFRA exon 18 mutant GIST are resistant to imatinib, but have developed evidence that this is not true. We are developing cell lines and prediction models that will help clinicians chose between imatinib and avapritinib for initial treatment of advanced GIST with PDGFRA exon 18 mutations. In addition, we are developing models and strategies to overcome avapritinib resistance as current there are no effective therapy.
Analysis of Succinate Dehydrogenase (SDH) Subunit Mutations in a human cell model
Mutation of various SDH subunits is seen in some cases of wild-type GIST, especially GIST arising in children or younger adults. These mutations can be sporadic or inherited as part of the Carney-Stratakis Syndrome. Recently, we have developed the first human cell lines that are deficient in SDHA, the most common type of mutation in SDH-deficient GIST. We are using these cell lines to assist in the diagnosis and genetic counseling of patients with potential inherited forms of GIST. In addition, we will use these cell lines to screen for novel treatments for SDH-deficient GIST. In collaboration with UCSD, we discovered that SDH-deficient cells are uniquely sensitive to an existing mild oral chemotherapy agent (temozolomide). As part of a consortium, we recently completed a phase 2 study of temozolomide for treatment of SDH-deficient GIST. We will continue to develop our cell line bank and study new therapeutic approaches We are now testing the efficacy of the combination of temozolomide and a DR5 agonist antibody (INBRX-109) for treatment of patients with advanced/metastatic SDH-deficient GIST.
2023 GIST Education Conference and Luncheon, OHSU Knight Cancer Institute
The 2023 GIST Education Conference and Luncheon was held on October 12, 2023 at The OHSU Knight Cancer Institute in Portland, Oregon. Speakers at the conference were: Christopher Corless, M.D., Ph.D., Executive Director and Chief Medical Officer, OHSU Knight Diagnostic Laboratories Professor and Vice Chair for Research, Department of Pathology, OHSU School of Medicine, Michael Heinrich, M.D., Professor of Medicine and Cell/Developmental Biology OHSU School of Medicine, Tracy Havnaer, R.N., B.S.N., Clinical Research Nurse, OHSU Knight Cancer Institute, Joseph S. Bubalo, PharmD, Oncology Clinical Pharmacy Specialist and Tania and Robert Stutman, GIST Cancer Research Fund.
A Message From Dr. Jonathan Fletcher
Dr. Jonathan Fletcher, GCRF's GIST Cancer Advisor and researcher at Brigham and Women's Hospital in Boston, Massachusetts and members of the Fletcher Lab give a message of hope as well as updates on their GIST Cancer research. Thank you Dr. Fletcher and Lab members for all that you have contributed to the fight for a cure of GIST Cancer.
Dr. Michael Heinrich, OHSU, Portland, Oregon, explains how GCRF helps in the research of GIST Cancer.
Dr. Michael Heindrick's GIST Research Update 2023
Dr. Michael C. Heinrich, one of GCRF's GIST Cancer Advisors and researcher at The OHSU Knight Cancer Institute in Portland, Oregon, gives an update of his work and progress of finding a cure for GIST.
Welcome to the Heinrich-Corless Research Lab
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.
“Thank you to Tania, Robert and everyone with the GIST Cancer Research Fund for your loyal support of the OHSU Knight Cancer Institute in our mission to end cancer as we know it. I am inspired and humbled by your commitment to us. Thank you again.”
Brian Druker, M.D., Director, OHSU Knight Cancer Institute
The best cancer care starts with the best cancer information. With nearly 50,000 members in 170 countries who are leaders in advancing cancer care, the American Society of Clinical Oncology (ASCO) is the voice of the world’s cancer physicians. ASCO’s patient information website Cancer.Net brings the expertise and resources of ASCO to people living with cancer and those who care for and care about them. This website provides a wealth of information on gastrointestinal stromal tumor (GIST) cancer. Click the button below for more information on this GIST Cancer website.
GIST - A Rare Orphan Cancer
Gastrointestinal Stromal Tumor or GIST is a rare, orphan cancer which starts in a type of tissue called the stromal or the body’s connective tissue (fat, muscle, blood vessels, deep skin tissues, nerves, bones or cartilage). GIST is a silent cancer often spreading before the patient has symptoms. Each year, approximately 5,000 adults in the United States alone are diagnosed with GIST Cancer. According to the American Cancer Society, many doctors misdiagnose GIST as another type of GI cancer. The lifesaving treatment for GIST is delayed and the GIST Cancer destroys lives. The overall five year survival rate of people diagnosed with a malignant tumor has been estimated to be 76%.
Looking For A GIST Cancer Doctor?
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.
Memorial Sloan Kettering Cancer Center Honors The GCRF On Its Donor Wall in New York City
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.’”
GIST Cancer Bracelets, Ribbons and T-Shirts Available for Sale!
GCRF has GIST Cancer Bracelets, Ribbons and T-Shirts available for sale. By wearing and displaying them, you are spreading a message and awareness to find a cure for this rare cancer.
Click on the button below to buy today!
Walt "Clyde" Frazier, GCRF's Distinguished Spokesperson
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!
Thank You Team Turano!
The amazing Team Turano, headed by Karen and Angelo Turano and family,
held their 7th Annual Fundraiser for GCRF 7th Annual GCRF Fundraiser
on September 22, 2023 at the Hanover Manor, East Hanover, NJ.
It was a tremendous success with over 200 prizes, a 50/50 raffle of $3,000 and delicious food. Thank you to Team Turano for all of your hard work and dedication to GCRF and raising funds and awareness to find a cure for GIST Cancer.
In Memory of My Aunt, Stephanie Kalenda
Stephanie (Teta) Kalenda had GIST cancer. Like so many patients, she fought a valiant fight against this disease and yet lost her life. Her niece, Jamela, decided to start a small fundraiser beginning on July 12, GIST Awareness Day in memory of her Teta, who would have been 64 years old. She was looking for 64 donations. While she didn't make the goal, she still raised over $1700. for GIST Cancer Research. This young woman is making a difference in the fight for a cure of GIST Cancer. She made a stand and took action so that one day, there will be cure of this terrible disease.
One behalf of all of us at GCRF, thank you Jamela! Your Teta will always be remembered and loved.