Colorectal Cancer: A Biobank of Patient-derived Xenografts

Human colorectal cancer cells treated with a topoisomerase inhibitor and an inhibitor of the protein kinase ATR (ataxia telangiectasia and Rad3 related), a drug combination under study as a cancer therapy.
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According to GLOBOCAN 2018 data, colorectal cancer (CRC) is the third most deadly and fourth most commonly diagnosed cancer in the world. There were nearly 2 million new cases and about 1 million deaths in 2018. The incidence of CRC has been steadily rising worldwide, especially in developed and rapidly-developing countries. Obesity, sedentary lifestyle, and increased consumption of red meat, alcohol and tobacco are considered the driving factors of CRC. However, even in the face of growing incidence, recent advances in early detection and treatment options have reduced CRC mortality in developed nations1.

Current Standard of Care in CRC

Surgery remains the primary course of treatment most cases of CRC, but is no longer effective in advanced cases where cancer has metastasized. In addition, the efficacy of chemotherapy has also been stifled by the rapid evolution of drug resistance in these tumors. CRCs comprise a very heterogeneous group of neoplasms driven by a vast array of mutations. Since not all CRCs share similar driving mutations, a ‘on-size-fits-all’ therapy is not the best therapeutic approach2.

Targeted monoclonal antibodies, immune checkpoint inhibitors and CAR T-cell therapies have shown promising advances in individualized cancer treatment, however, only a few are available for standard clinical practice3. Therefore, a stronger understanding of the molecular evolution of CRC development andstudy of the tumor microenvironment can empower researchers and physicians to prevent and treat this deadly disease.

Patient-derived Xenografts – A Novel Tool for Cancer Therapy

The rapidly evolving field of personalized medicine is the future of oncological practice, and is not easily evaluable through traditional research methodology. Personalized medicine is based on the identification of patient groups based on the expression of specific biomarkers. Therefore, there is a need to study tumors in their native structure. Patient-derived xenografts (PDX) provide the answer to this need. PDX are generated by transplantation of fresh patient tumor specimens into immunocompromised mice, thereby circumventing the pitfalls of patient-derived monolayer cultures. PDX tumors have been shown to retain the tissue architecture of the original human tumors from which they were derived. In addition, they are able to accurately replicate tumor growth, tumor cell diversity and tumor progression. The histopathological features and gene expression profiles of PDX tumors are reported to be comparable with the original patient tumor. Therefore, PDX models have been successfully used for predicting drug sensitivity patterns of primary tumors. It is no surprise PDX have gained increased popularity and have been established for a variety of human cancers including breast, pancreatic, lung, and ovarian cancers4.

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A Biobank of CRC Patient-derived Xenografts

For CRCs, patient-derived cell and spheroid biobanks have been established previously5,6. However, there is a crucial need for a PDX biobank comprising of CRC samples across all stages of progression.  At the Personalized Oncology Division at the Water and Eliza Hall Institute of Medical Research, Abdirehman and colleagues describe the establishment of a PDX biobank containing stage I-IV chemotherapy-naive CRC tumors. The study has been published here.

The samples in the established biobank reflected the diversity of CRC patient clinical features, including age, gender, primary tumor location, presence of metastases at the time of diagnosis, and the differentiation state of the tumor. The group was able to successfully establish tumor xenografts and propagate the tumors in immunocompromised mice, and were able to achieve a success rate of 57%. This indicates that variations in tissue bulk, technical challenges of tissue collection, and tumor initiating cell content within transplanted samples are likely contribute to variability in PDX success rates. Importantly, the PDXs were able to successfully undergo serial transplantations, a hallmark of continued oncogenesis. The group also demonstrated the use of the PDX biobank to assess sensitivity to established chemotherapy (5-Fluorouracil) and the ability to select for resistant clones.

The authors described the significance of their studies as such: “Our PDX biobank could also be utilized to model intratumor heterogeneity and clonal selection in future studies, which commonly occur in CRC and may influence chemotherapy response. Similar to other studies, our CRC PDX tumors match patient response to 5-FU and can be utilized to understand response to targeted therapies, like cetuximab, an anti-EGFR antibody As such, this PDX biobank will unquestionably contribute to the pre-clinical characterization of numerous new therapeutics, and combinations thereof.” 7.

 

References

  1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68:394–424.
  2. Prashanth Rawla, Tagore Sunkara, Adam Barsouk. Epidemiology of colorectal cancer: incidence, mortality, survival, and risk factors. Prz Gastroenterol. 2019; 14(2): 89–103.
  3. Kosinski C, Li VS, Chan AS, et al. Gene expression patterns of human colon tops and basal crypts and BMP antagonists as intestinal stem cell niche factors. Proc Natl Acad Sci USA. 2007;104:15418–23.
  4. Jenna Bhimani, Katie Ball, Justin Stebbing. Patient-derived xenograft models – the future of personalised cancer treatment. British Journal of Cancer 2020; 122: 601–602
  5. De Angelis, M.L., Bruselles, A., Francescangeli, F. et al.Colorectal cancer spheroid biobanks: multi-level approaches to drug sensitivity studies. Cell Biol Toxicol2018; 34: 459–469
  6. Beshiri ML, Tice CM, Tran C, et al. A PDX/Organoid Biobank of Advanced Prostate Cancers Captures Genomic and Phenotypic Heterogeneity for Disease Modeling and Therapeutic Screening. Clin Cancer Res. 2018;24(17):4332-4345.
  7. Abdirahman SM, Christie M, Preaudet A, et al. A Biobank of Colorectal Cancer Patient-Derived Xenografts. Cancers (Basel). 2020; 12(9):E2340.