Biobanks of three-dimensional organoid cultures from colorectal cancer patients provided a substrate for genetic analysis and multidrug testing, showing promise for personalized treatment options in colorectal cancer.
Researchers at the Hubrecht Institute and the Cancer Genomics and University Medical Center, in the Netherlands, recently published their findings in Cell.
“This is the first time that a collection of cancer organoids, or a living biobank, has been derived from patient tumors. We believe that these organoids are an important new tool in the arsenal of cancer biologists and may ultimately improve our ability to develop more effective cancer treatments,” said geneticist Mathew Garnett at the Wellcome Trust Sanger Institute in a press release.
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Previous studies using genetic sequencing have revealed numerous mutations in the pathogenesis of colorectal cancer, such as P53, WNT, RAS-MAPK, DNA mismatch repair, and TGF-Beta. However, incorporating the identified genetic mutations of an individual patient’s tumor into predictable outcomes and treatment response has been limited.
Combining a previously established culture medium, including basement membrane extract, with nicotinamide, prostaglandin E2, p38 inhibitor, and Alk inhibitor, researchers were able to create a colon tissue organoid resembling the original epithelium of normal and cancerous colon in structure, ability to grow, and cell variety.
Tumor samples and adjacent normal tissue biopsies from 20 untreated colorectal cancer patients were obtained, which successfully produced 19 normal organoid cultures and 22 cancerous organoid cultures.
Genetic analysis of DNA extracted from tumor organoids revealed mutations commonly seen in colorectal cancer. “But now we’ve shown that when we look at the mutation pattern that they are faithful representations of the original tumor. Meaning that the genetic landscape is basically maintained, so that you can use them as a sort of reflection of the tumor itself,” said Marc van de Wetering of the Hubrecht Institute in the Netherlands.
Likewise, the researchers compared RNA expression of the normal and tumor organoids. The data was used to classify the results into subtypes based on the gene signatures and for analysis of individual gene expression in the organdies.
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Finally, the researchers tested the organoids against 83 drugs in clinical trials and in clinical use, including first-line treatments such as oxaliplatin and 5-FU and cetuximab. The investigators detected several gene-drug associations, including nutlin-3a resistance and mutations in TP53. Cetuximab and afatinib resistance was also observed with organoids demonstrating KRAS mutations. Furthermore, one organoid with a mutation of RNF43 was noted to be responsive to porcupine inhibitor.
The researchers concluded they were able to establish a colorectal organoid biobank as a realistic technology for testing drug response for individual patients and noted a possibility of using it as a bridge between genetic research and clinical trials.
The researchers noted, “We perceive patient-derived organoids to be used to directly test drug sensitivity of the tumor in a personalized treatment approach. For this, we envision organoids to be tested against a limited number of clinically approved drugs within weeks after derivation.”
Thoughts for the future include clinical trials “where we look at the sensitivity of the organoids for a certain drug and then compare it to the sensitivity of the patient’s tumor,” Wetering told Cancer Therapy Advisor.
Garnet noted further that “Cancer is a diverse and complex disease and having a large collection of organoids is necessary to encompass this diversity to enable scientists and clinicians to develop new treatments.”
