A group of US researchers established a biorepository of 65 patient-derived rectal cancer organoid cultures from patients with primary, metastatic or recurrent disease. They showed that the biology and drug sensitivity of rectal cancer clinical isolates can be efficiently interrogated using an organoid-based, ex vivo platform coupled with in vivo endoluminal propagation in animals.
The authors wrote in study background that rectal cancers invading the perirectal tissues or lymph nodes are treated with trimodal therapy. Some patients with rectal cancer respond completely to chemoradiotherapy alone and can avoid surgery entirely, but others respond poorly and require radical surgery. Prospective identification of patients who would achieve a complete response after neoadjuvant therapy alone would enable more tailored treatment regimens and thereby minimise potential harm from overtreatment. The heterogeneity in clinical response and the morbidity associated with radical surgery highlight the need for more sophisticated modelling to predict response to standard therapies.
Few cell lines have been derived from rectal cancers. Despite the fact that rectal cancer is treated differently from colon cancer by using trimodal therapy in a neoadjuvant context, the preclinical development of treatments for rectal cancer has historically relied on colon cancer cell lines, highlighting the need to develop rectal cancer specific models. Furthermore, efforts to derive organoid biobanks have focused primarily on colon cancer specimens.
Given the paucity of xenografts models and the complete lack of endoluminal rectal cancer models, there is an additional need in rectal cancer research for an anatomically accurate in vivo model using patient-derived rectal cancer organoids. The rectum has unique venous drainage that gives rise predominantly to lung metastases.
Given recent success transplanting mouse colon cancer cells into the colon lumen, the study investigators set out to derive rectal cancer organoids from resected or biopsied rectal cancer and used them to establish ex vivo and in vivo rectal cancer models. They investigated the ability of such tumouroids to model the molecular and histologic features of human rectal cancers, as well as tumour initiation, invasion, and metastasis. They also investigated whether their ex vivo and in vivo platforms could be used to correlate with treatment response in individual patients within a time frame that could potentially inform clinical treatment decisions.
Rectal cancer tumouroids retained molecular features of the tumours from which they were derived, and their ex vivo responses to clinically relevant chemotherapy and radiation treatment correlated with the clinical responses noted in individual patients’ tumours.
Upon engraftment into murine rectal mucosa, human rectal cancer tumouroids gave rise to invasive rectal cancer followed by metastasis to lung and liver. Importantly, engrafted tumours displayed the heterogenous sensitivity to chemotherapy observed clinically.
The study team concluded that their work addresses an unmet need by establishing a rectal cancer specific ex vivo and in vivo biorepository that markedly increases the ability to study rectal cancer. The model molecularly resembles rectal cancer and establishes a relevant framework in which the disease can be studied. The methodology demonstrates options for eventual drug screening in a pre-clinical setting and reflects the clinical outcomes of the patients from whom they were derived. The study demonstrates determination of basic response parameters within weeks of derivation and can serve as a tool for therapeutic response modelling.
Ganesh K, Wu C, O’Rourke KP, et al. A rectal cancer organoid platform to study individual responses to chemoradiation. Nature Medicine 2019; 25:1607-1614.