Gastrointestinal stromal tumors (GISTs) are uncommon cancers that start in special cells in the wall of the gastrointestinal (GI) tract, also known as the digestive tract. Unfortunately, GISTs are the most common type of sarcoma with approximately 5,000 to 6,000 new patient cases annually in the United States. GISTs cannot be cured by drugs alone, and there is a high rate of drug resistance. Now researchers at the University of California, San Diego (UCSD), School of Medicine and Moores Cancer Center report that cell-to-cell communication drives gastrointestinal tumor progression.
Their study, “Cancer-associated fibroblast secretion of PDGFC promotes gastrointestinal stromal tumor growth and metastasis,” was published in the journal Oncogene. Researchers identified new therapeutic targets that could lead to new treatment options for patients.
“Targeted therapies for GIST are modestly effective, but GIST cannot be cured with single agent tyrosine kinase inhibitors,” the researchers wrote. “In this study, we sought to identify new therapeutic targets in GIST by investigating the tumor microenvironment.”
The researchers examined the tumor microenvironment of GIST, and were able to observe previously unrecognized cellular targets for GIST therapy that could result in improved disease control and cure rates. Certain GIST cancer-associated fibroblasts (CAFs), a cell population within GISTs, were discovered to communicate with GIST cells. This crosstalk between CAFs and GIST cells results in more aggressive tumor biology.
“However, when CAFs are present, they produce platelet-derived growth factor (PDGFC), a signal that can activate PDGFRA and overcome drug inhibition,” explained first author Hyunho Yoon, PhD, a research associate with UCSD School of Medicine.
Half of metastatic GIST patients will develop drug resistance within 20 months of starting first-line therapy. Once the first line of treatment for GIST loses effectiveness, response rates to subsequent therapies also decline. These findings suggest targeting CAFs may be more effective and offer those who face drug resistance hope.
The researchers are exploring drug combinations for CAF-targeted therapies.
“Our findings represent a paradigm shift for the sarcoma field, which has mainly focused on therapies directly aimed at killing tumor cells. These new findings suggest that non-cancerous mesenchymal cells within stromal tumors are critical for tumor growth and metastasis, as well as for improving treatment efficacy. Together, our work has novel therapeutic implications for clinical management of GIST and immediate potential for translation into a clinical trial,” concluded the researchers.