Two studies seek to go beyond GIST in cancer of the intestinal tract

Gastrointestinal stromal tumors (GISTs) are cancers that start in specialized nerve cells found in the digestive system, from the esophagus and stomach to the intestines and rectum.

They are rare, but because they often develop slowly or initially cause no symptoms, GISTs can be problematic to detect and treatment options are limited to a handful of targeted drug therapies or surgery. It is estimated that 5,000 new cases of GIST are diagnosed in the United States each year. The 5-year relative survival rate is 93% for localized tumors; 55% if the GIST has metastasized and spread to other tissues.

“One of the main barriers to treating GIST is the mistaken belief that this disease is easily curable,” said Jason Sicklick, MD, professor of surgery in the Division of Surgical Oncology in the University of Medicine School of Medicine. California to San Diego and GIST specialist. But in reality, we know this is not the case. Even patients with tumors that may be sensitive to certain drugs rarely have complete responses to treatment. There is more to be discovered in biology. “

Jason Sicklick, MD, is Professor of Surgery in the Division of Surgical Oncology at UC San Diego School of Medicine.

In a pair of new studies, both published in the journal Clinical Cancer Research, two teams of scientists led by lead author Sicklick describe advances that may help predict how well GIST responds to therapy and possibly lead to new treatments.

In an article published online August 23, 2021, researchers present the first methods to create a patient-derived tumor model of a rare inherited subset of GIST cases that are poorly understood and difficult to treat.

In a previous article, published on July 29, 2021, Sicklick and colleagues analyzed where GIST tumors appear in the stomach (the most common site) and their underlying mutations, suggesting the location may be an early clue. the type of mutation to guide optimal treatment.

Modeling of Gastrointestinal Succinate Dehydrogenase Deficient Stromal Tumors Derived from Patients to Predict Therapeutic Response

GISTs with mutations in succinate dehydrogenase (mSDH), a type of enzyme complex involved in key cellular functions, are relatively rare, comprising less than 10 percent of GISTs. But unlike other GISTs which occur sporadically, mSDH GIST patients are usually adolescents and young adults, the tumor often metastasizes and they tend to be resistant to standard drugs, such as tyrosine kinase inhibitors, which suppress enzymatic activity.

To compound the challenge, there is no widely applicable human model for SDH mutant tumors, including GISTs, which have limited molecular understanding and drug development.

In their paper, Sicklick and his team identified the molecular and metabolic characteristics of the patent-derived GIST mSDH and confirmed that the models reflected the known characteristics of parental tumors with loss of function in the SDH protein complex.

They then found that temozolomide, a drug used to treat certain types of brain tumors, damaged the DNA inside mSDH GIST cells and caused apoptosis or programmed cell death. Turning to SDH mutant GIST patients, they report that those treated with temozolomide demonstrated a 40 percent response rate and a 100 percent disease control rate, suggesting that the drug may be a promising therapy for patients. with GIST mSDH.

“The limited availability of patient-derived SDH-deficient GIST models has hampered our in-depth understanding of disease and drug screening. Our study helped establish successful patient-derived GIST mSDH cells that can recapitulate key molecular characteristics of parent tumors, ”said co-lead author Shruti Bhargava, PhD, postdoctoral researcher in Sicklick’s lab.

“Another challenge in the field is the limited treatment options for these patients. We demonstrate that temozolomide is a promising therapy for GIST patients deficient in SDH. We are currently using these patient-derived models to better understand the disease and to find other treatment options for GIST patients with SDH deficiency.

Location of gastrointestinal stromal tumor (GIST) in stomach predicts tumor mutation profile and drug sensitivity

GISTs can occur anywhere in the gastrointestinal tract, but most often they appear in areas of the stomach, caused by various mutations. Sicklick and colleagues hypothesized that the anatomical location of gastric GISTs was associated with unique genomic profiles and distinct mutations.

The researchers examined 2,418 patients with primary gastric GIST, both with mutations in the gene that produces the receptor tyrosine kinase (KIT) enzyme and those without the KIT mutation. In addition, they analyzed data from an international cohort of 236 patients.

They found that gastric GIST patients with non-KIT mutations, including SDH mutations, typically had tumors in the distal or lower region of the stomach, while patients with KIT mutations suffered extensively from tumors in the stomach. proximal or upper part of the stomach.

“Knowing a patient’s GIST genomic profile is very important in guiding treatment, but the sad reality is that most people don’t have genetic testing and many start a single treatment,” said the first author. Ashwyn K. Sharma, MD, researcher and general surgery resident at UC San Diego Health.

“In our study, we showed that the origin of a GIST offers clues about the type of genomic profile of this tumor and how it may respond to the treatments we offer. We finally discovered that the anatomical location of a tumor can be a very simple and cost-effective way to tailor our therapies to our patients. “

August 2021 paper

Co-authors include: Mayra Yebra, Shruti Bhargava, Avi Kumar, Adam M. Burgoyne, Chih-Min Tang, Hyunho Yoon, Sudeep Banerjee, Joseph Aguilera, Thekla Cordes, Sangkyu Noh, Rowan Ustoy, Sam Li, Sunil J Advani, Razelle Kurzrock, Scott M. Lippman, Paul T. Fanta, Olivier Harismendy, and Christian Metallo, all at UC San Diego; Vipul Sheth, Stanford University; and Christopher L. Corless and Michael C. Heinrich, OHSU Knight Cancer Institute.

Funding for this research comes, in part, from the Food and Drug Administration (R01 FD006334), the National Institutes of Health (grants R01 CA226803, R37 CA215081, R01 CA188652 and R01CA234245), GIST Research Fund, SDH Research Fund, Pedal the Cause, Kristen Ann Carr Fund and NSF CAREER Award (# 1454425).

July 2021 paper

Co-authors include: Ashwyn K. Sharma, Jorge de la Torre, Beiqun Zhao, Sudeep Banerjee, Christina Cui, Vi Nguyen, Maha Alkhuziem, Chih-Min Tang, Hyunho Yoon, Alexa De la Fuente, Shumei Kato, Hitendra Patel, Christopher L. Corless, Santiago Horgan, Adam M. Burgoyne, Paul Fanta, and Jill P. Mesirov, all at UC San Diego; Thomas L. Sutton, Michael C. Heinrich and Skye C. Mayo, OHSU Knight Cancer Institute; Nikki S. IJzerman, Erasmus University Medical Center; Tahsin M. Khan, Andrew M. Blakely and Jeremy L. Davis, National Cancer Institute; Petur Snaebjornsson, Hester van Boven, Annemarie Bruining, Winan J. vanhoudt and Neeltje Steeghs, Dutch Cancer Institute.

Funding for this research came, in part, from the Surgical Society of the Alimentary Tract Mentored Fellowship, National Institutes of Health (grants T32 CA121938 Cancer Therapeutics Training Fellowship, U24 CA248457, U01 CA184898, R01 CA226803), the Lighting the Path Forward for GIST Cancer Research, GIST Cancer Research Fund, the David Foundation, VA Merit Award Grant (2I01BX000338-05), NIH R01 CA226803 (JKS) and the Food and Drug Administration (R01 FD006334).

Disclosures: Sicklick Receives Research Funding From Amgen Pharmaceuticals and Foundation Medicine; fees for Deciphera consultants; lecturer fees from Deciphera, Foundation Medicine, La-Hoffman Roche, Merck, MJH Life Sciences, QED Therapeutics, and he has shares in Personalis. Kurzrock owns shares and other interests in IDbyDNA, CureMatch, Inc. and Soluventis; advisory or advisory role of Gaido, Loxo, X-Biotech, Actuate Therapeutics, Roche, NeoMed, Soluventi and Pfizer; honoraria for the La Hoffman-Roche lecturer; Research funding (Incyte, Genentech, Merck Serono, Pfizer, Sequenom, Foundation Medicine, Guardant Health, Grifols, Konica Minolta, DeBiopharm, Boerhringer Ingelheim and OmniSeq [all institutional]) and is a member of the board of directors of CureMatch, Inc and CureMetrix Inc.

Burgoyne serves as a consultant with fees from Genentech, Deciphera, Exelixis and Eisai. Sicklick receives research funding from Novartis Pharmaceuticals, Amgen Pharmaceuticals and Foundation Medicine, consultant fees from Grand Rounds, Loxo and Deciphera, and speaker fees from Roche.