Rare and poorly understood, sarcomas are a broad group of cancers that start in the bone or soft tissue. While some sarcomas are effectively treated, many are more stubborn and difficult to eradicate.
With limited knowledge of their underlying biology, scientists are unable to develop targeted treatments for these tumors. This lack of understanding prevents scientists from zeroing in on specific faulty molecular pathways or genes and dismantling the tumor.
Researchers made a seminal discovery in one type of sarcoma, gastrointestinal stromal tumor or GIST, in 1998. They determined that most GISTs contain mutations in the KIT gene, making KIT kinase inhibitors a viable treatment for the many GIST patients either not eligible for surgery or in need of subsequent therapy. At the same time, the kinase inhibitor, imatinib, was emerging as a “miracle drug” for patients with chronic myeloid leukemia, compounding the excitement. GIST researchers realized that KIT kinase inhibitors (or KIT inhibitors) such as imatinib could also help their patients. This discovery illustrates how understanding tumor biology can fuel monumental gains in treatment options.
Although KIT inhibitors transformed GIST treatment, adding years to patients’ lives, they did not represent a cure and most tumors develop resistance. It’s been 25 years since the initial GIST treatment breakthrough and another one is overdue.
To whom should we turn for help? With razor-sharp expertise in GIST biology and a steadfast dedication to treating sarcoma patients, Matthew Hemming, MD, PhD, is up for the task.
The search for new therapeutic targets
Dr. Hemming and his colleagues used CRISPR to systematically knock out genes in GIST cell lines, searching for ones essential to the cells’ survival. They found that GIST cells uniquely depend upon the gene regulatory complexes MOZ and Menin-MLL to live. After combing the literature, they identified several small molecules capable of inhibiting these complexes. Their experiments showed these drugs shrink tumors, both in GIST cell lines and patient-derived xenograft (PDX) models—human GIST tumor cells implanted into immunodeficient mice.
“Drugs are already in clinical trials for both these types of inhibitors—but not for GIST. We are hopeful that our research will mature into a clinical trial for GIST patients,” Dr. Hemming says.
Matching patients to treatments
Identifying therapeutic targets to pursue is only part of the battle. It is also crucial to properly match patients to treatments. Scientists now recognize that each cancer is nuanced, possessing a unique combination of genetic features that may not overlap with other cancers—even those of the same type. Therefore, when two people have the same cancer diagnosis, they may respond differently to identical treatment.
With GIST, many patients undergo surgery, but not all need subsequent—or adjuvant—therapy. Follow-up therapy using imatinib is considered in patients whose tumor is completely resected but at high risk for recurrence. To make this assessment, GIST experts evaluate tumor size, location and mitotic rate—or how fast the cells divide.
“These are archaic metrics that could have been defined 300 years ago. Wedon’t have an intelligent, thoughtful explanation for what biological factors drive a tumor’s risk of recurrence. So, we looked for biomarkers that can predict high- or low-risk of tumor recurrence, and how these factors were influencing GIST biology,” Dr. Hemming says.
He and his colleagues applied the latest biomedical technologies to previously collected clinical samples. Their study unveiled the programs driving gene expression in GIST that were predictive of recurrence risk. The team discovered that expression of the genes HAND1 and BARX1 were reliable biomarkers for high-risk and low-risk of recurrence, respectively—and these markers were superior to the traditional measures.
“In the future, when we evaluate patient samples, we will record traditional risk factors in addition to whether the tumors express HAND1 or BARX1. This additional information will likely tell us more [than traditional data alone] about the risk of recurrence. Then we can more accurately decide, for example, that if a patient’s tumor expresses HAND1, they may benefit from adjuvant therapy while if their tumor expresses BARX1, they may not,” Dr. Hemming says.
Since his arrival at UMass Chan in August 2022, Dr. Hemming hasn’t stopped moving. His determination to offer better treatments to patients with GIST and other sarcomas is palpable.
“My goal is to plant a flag here at UMass Chan, setting up our lab to conduct world-class sarcoma research and make novel discoveries. We will then use these tools to help build a clinical trial program, offering new therapies to sarcoma patients,” Dr. Hemming says.
With Dr. Hemming on duty, sarcoma patients are in good hands.
