Q&A: DR. JASON SICKLICK

Dr. Jason Sicklick recently received notice of award for his NCI-supported U01 cooperative project titled, “National Succinate Dehydrogenase-deficient GIST Translational Research and Clinical Trial Consortium." The study is advancing translational gastrointestinal stromal tumor research in collaboration with the physicians and scientists at the NIH and 10 other academic institutions, as well as a patient advocacy group (Life Raft Group) and an industry partner (Inhibrx, Inc.). For this month’s Q&A, we talked to Dr. Sicklick about his research on gastrointestinal stromal tumors and the importance of this new study.

Q: What sets gastrointestinal stromal tumors apart from other cancers?
A: A gastrointestinal stromal tumor is a rare cancer that occurs throughout the gastrointestinal tract. These tumors can be quite variable in terms of clinical characteristics. For example, gastrointestinal stromal tumors can be sporadic or inherited, can vary greatly in growth and invasiveness capacity from indolent to aggressive, and can occur across the age spectrum from childhood to late adulthood.

Q: What distinguishes the gastrointestinal stromal tumor research being done at UC San Diego?
A: Our gastrointestinal stromal tumor program is unique from other research programs in that we focus on studying the rarer subsets of this disease, like SDH-deficient gastrointestinal stromal tumor, where we have only a limited understanding of the underlying biology or how best to treat these tumors. In 2016, we were the first group to study so-called quadruple negative gastrointestinal stromal tumor (i.e., no known “driver” mutations). This emphasis was important because we identified ETV6-NTRK3 and FGFR gene fusions in gastrointestinal stromal tumors that are now targetable with newer drugs. This seminal finding is now incorporated into the National Comprehensive Cancer Network (NCCN) guidelines for managing gastrointestinal stromal tumors.

Q: What is the value of having a National Succinate Dehydrogenase-deficient Gastrointestinal Stromal Tumor Translational Research and Clinical Trial Consortium?
A: This consortium creates a large, formal alliance of SDH-def gastrointestinal stromal tumor clinicians and researchers that consists of both intramural investigators with the NIH and extramural investigators from medical centers throughout the US, an alliance that has worked out well in many clinical applications in the past. These SDH-def gastrointestinal stromal tumor investigators and clinicians have demonstrated expertise in adult and pediatric medical oncology, surgical oncology, basic and translational science. Together with patient advocates and an industry partner, our goals are to: (1) evaluate the safety and efficacy of TMZ with INBRX-109 (a potent DR5 agonist) among patients with progressive SDH-def gastrointestinal stromal tumor in a Phase I/II clinical trial; (2) create a centralized biobank of well-annotated SDH-def gastrointestinal stromal tumor samples for later study; (3) develop a network of research laboratories to develop improved preclinical models to investigate diverse SDH-deficient gastrointestinal stromal tumor biology; and (4) develop new clinical tools to predict SDH-def gastrointestinal stromal tumor prognosis. This will represent a major step forward in understanding the underlying biology of SDH-def gastrointestinal stromal tumor, in developing new ways to predict the eventual course of these tumors, and in creating novel ways to treat them, and it will unite the field in each of these endeavors, as well.

Q: Why are SDH-def gastrointestinal stromal tumors so hard to treat?
A: It has been challenging to treat SDH-deficient gastrointestinal stromal tumors in the past because we lacked human models to study this cancer and identify therapeutic targets. Moreover, we still do not fully understand why some patients with a SDH-deficient gastrointestinal stromal tumor have very indolent biology while about 1-in-4 patients will die from their cancer within 10 years after diagnosis.

Q: How do you hope this trial will add to existing therapies for SDH-def gastrointestinal stromal tumor?
A: Our hope is that the clinical trial of temozolomide with INBRX-109 that we propose will be the first FDA- approved therapy approved specifically for SDH-deficient gastrointestinal stromal tumor. While we are still early in the trial, our previous trial of single agent temozolomide showed that even this drug therapy can be used to effectively treat a subset of SDH-deficient gastrointestinal stromal tumor patients. This is a first for the field, but we need to do much better than this. We have found clear evidence that temozolomide and INBRX-109 have two independent mechanisms of efficacy, and that exploiting both of these will target a key weakness of SDH-def gastrointestinal stromal tumor. We thus hope that a combination of two drugs with entirely different but related mechanisms of action will be more effective than either drug alone.