People usually associate the most terrible cancers with their ability to grow aggressively, but neuroendocrine tumors are dangerous for exactly the opposite reason: They grow so slowly that they can go undetected before it’s too late to intervene.
The incidence of digestive neuroendocrine tumors has increased 600 percent in the past 30 years, largely because doctors find them unexpectedly when looking for other problems on tests like CT scans. The challenge of finding optimal treatments is compounded by the fact that their slow growth has been next to impossible to replicate in the laboratory.
With this in mind, scientists at the Morgridge Institute for Research and the Carbone Cancer Center at the University of Wisconsin-Madison are finding promising new ways to model this disease in the laboratory and measure the effectiveness of various treatments. In a study published April 14, 2021 in the journal Cancers, the research team describes the creation of 3D cancer organoids that mimic the slow-growing neuroendocrine cancers found in the human body.
Armed with this clinically relevant model, the team then used optical metabolic imaging to measure changes in the cancer in response to different treatment combinations. The hope is that the team has created a platform to develop more effective drugs faster.
“The majority of patients with neuroendocrine tumors are diagnosed when they are in the later stages of cancer,” said Amani Gillette, lead author of the paper and a researcher in the laboratory of Morgridge researcher Melissa Skala. “Unfortunately, with the three or four chemotherapy options available, the tumors are very difficult to treat when surgery is not possible. These chemotherapies also tend to be heavy hitters with lots of side effects. Therefore, better medicines are urgently needed. “
The project was created with Dr. Dustin Deming, a UW Madison oncologist who specializes in gastrointestinal cancer, including colon and esophageal cancer. Deming had begun seeing an increasing number of patients with gastroenteropancreatic neuroendocrine tumors (GEP-NET) and was motivated to address the need for more specific treatment.
The Deming Lab used samples from seven patients to develop 3D organoids that, in the right media conditions, stayed alive and grew at rates similar to humans. After the organoids showed stable growth, the Skala Lab used a label-free, non-destructive optical metabolic imaging method to test a novel treatment that combined a standard drug with a promising experimental drug.
Gillette, also a graduate student in biomedical engineering at UW-Madison, says the combination therapy was more effective than standard treatment on five of the seven patient samples and provided a good proof of concept of their model. While the initial results are promising, Gillette says it will be important to expand the study with additional patient samples to identify the most promising drug candidates.
The gold standard for measuring the effectiveness of cancer treatment is to look at the change in size of the tumor being treated. But because neuroendocrine tumors grow so slowly, Gillette says changes in tumor size are almost undetectable. Their imaging technology measures the metabolic activity in individual cells of the tumor. This is a more accurate way to tell if medication is causing a response.
“The advantage of looking at an optical metabolic imaging signal, more like the diameter of the tumor or the number of cells, is that you get a lot of information about the heterogeneity of individual cells,” says Gillette. “Individual cells can react differently to treatments. This is important in chemotherapy because all cells must respond to treatment. If not, the tumors will come back and likely come back worse. “
This paper is part of a special edition from Cancers that contains several unique studies mapping cancer metabolism. The work is supported by the National Institutes of Health, the National Science Foundation, and Stand Up to Cancer.