Can Conditionally Reprogramming Cells Expand the Scope of Precision Oncology?

The approach works by transforming the condition of normal and tumor cells into a highly proliferative “reprogrammed stem-like” condition that still has the original karyotypes.

Although precision oncology has transformed care for a variety of patients, the promise of the practice remains limited to up to 20% of patients with solid tumors, leading researchers to continue to search for new approaches to expanding its reach. In a recent paper published in Frontiers in Oncology, a researcher outlined the potential usability of conditional cell reprogramming (CR).

The approach, which uses a co-culture of irradiated Swiss-3T3-J2 mouse fibroblast cells and digested primary nonpathogenic or pathogenic cells with the Rho-associated serine–threonine protein kinase inhibitor Y-27632, works by transforming the condition of normal and tumor cells into a highly proliferative “reprogrammed stem-like” condition that still has the original karyotypes. When the conditions of the reprogrammed cells are removed, the cells are again able to differentiate.

“Until the CR method development, it was difficult to make a fast and easy-to-perform method that has a high success rate in a single model system. The CR method that was developed at Georgetown University satisfies the above criteria by being fast and easy and having a high success rate,” explained the researcher, noting that CR provides new advantages for precision oncology, particularly in cases of unsolved genetic profiles.

The use of CR was first documented when researchers used the technology to create paired cell lines to try and reveal possible treatment strategies for a patient with progressive recurrent respiratory papillomatosis, which is chemotherapy resistant. Through CR, the group of researchers decided on treatment with vorinostat, which was cytotoxic on the conditional reprogrammed cells compared with the normal cells. After 3 months of treatment, the patient had stable disease.

Since its first use, CR has been used in salivary gland, breast, bladder, and lung cancers. In one instance, researchers used the approach in luminal-B breast cancer, which carries a poor prognosis owing to a lack of targeted treatments. The researchers used the primary tumor for CR cells in order to create a xenograft model that used both the cells and the xenograft for drug sensitivity evaluation.

“Although there are very important features and uses of CR technology in different areas, CR still has many challenges, and the optimization of CR culture is needed when growing different types of primary cells,” wrote the researcher, noting that one of the ongoing challenges is being able to maintain a culture of certain malignant primary cells. Some research has shown that “CR preferentially supported the outgrowth of nonmalignant epithelial cells from nasopharyngeal carcinoma biopsy.”

The researcher also highlighted the inability to discriminate tumor cells from normal populations, creating concern for tumor tissues that are mixed with normal tissues, although they note that certain measures can be taken to mitigate this challenge. For example, the researchers say that by optimizing culture conditions to favor the growth of prostate cancer cells and removing serum from the medium, the normal cells will differentiate while the prostate tumor cells grow “as a mesenchymal morphologic phenotype and then reversed back to epithelial morphology in CR condition.”

Reference

Alkhilaiwi F. Conditionally reprogrammed cells and robotic high-throughput screening for precision cancer therapy. Front Oncol. Published online October 19, 2021. doi:10.3389/fonc.2021.761986