13 July 2018

Tumor organoids

A testing ground for individual anti-cancer therapy

Maria Perepechaeva, "First-hand Science"

In recent years, much has been said about personalized therapy, including cancer. However, in practice, alas, there are many problems. For example, until now it was not very clear how to "try on" a particular treatment regimen for a particular patient? Of course, it is possible to grow a cell culture from a patient's cancer cells, but after all, a tumor is not a simple cluster of cells, it is usually structurally organized. And here the modern technology of growing three-dimensional cellular structures comes to the rescue: the resulting organoids are much more similar to real malignant neoplasms than cell cultures obtained in the traditional way.

Organoids, three-dimensional structures obtained from cancer cells of a particular patient, open up new prospects for personalized treatment of cancer patients, since they can be used to search for the most optimal strategy for cancer therapy with greater efficiency. Recently, scientists have once again shown the benefits of this approach using the example of a rare variant prostate cancer (Puca et al., Patient derived organoids to model rare prostate cancer phenotypes).


An image of prostate cancer organoids demonstrating the expression of synaptophysin (colored green), a marker protein of neuroendocrine cells. Photo: Beltran Lab (from the press release of Weill Cornell Medicine Tumors Grown in the Lab Provide Insights on Rare Prostate Cancer – VM).

In general, prostate cancer arising from the secretory epithelium of this organ belongs to the most common oncological diseases. An imbalance of sex hormones in the body plays an important role in its development. The growth of both normal and cancerous prostate cells directly depends on the level of the main male hormone testosterone. Therefore, treatment methods aimed at reducing the effect of this hormone are now widely used. These include the removal of testes that produce testosterone, the effect on the pituitary gland involved in endocrine regulation, as well as the direct blockade of the function of testosterone itself (for example, with the help of drugs that disrupt the binding of the hormone to the androgen receptor that can directly interact with nuclear DNA).

Unfortunately, although the tumor usually initially responds well to such therapy, later it can "adapt" to the lack of testosterone, which seriously complicates treatment. In addition, such tumors can, although not often, transform into a very aggressive type, which today is practically untreatable. In this variant of the disease, neuroendocrine cells begin to multiply, diffusely located under the secretory epithelium, in which the AR gene, which encodes the androgen receptor, is not active.

Scientists from the Weill Cornell Medical College (USA), who are searching for methods of treating this dangerous type of prostate cancer, turned to the technologies of tumor organoids. Usually, organoids are obtained from undifferentiated stem cells, prompting them to turn into structures similar to certain organs (liver, brain, etc.). But from cancer cells, you can grow the likenesses of malignant tumors.

In this case, the researchers obtained organoids from tumor cells of patients with metastatic neuroendocrine prostate cancer. Using the genome sequencing technique, they made sure that the organoid cells retained all the molecular features of the patient's tumor, including the genetic profile and features of epigenetic ("supra-genomic") regulation. This similarity was confirmed by the same sensitivity to a particular anti-cancer drug, which was demonstrated by organoids and tumors of patients, "donors" of cells.

At the next stage, an experimental drug was tested on organoids that reduces the activity of the EZH2 protein, which participates in chromatin remodeling by regulating the activity of cell differentiation genes. In the cells of many types of cancer, including prostate cancer, this protein is extremely active, promoting reproduction and increasing the viability of cancer cells.

The drug inhibiting EZH2 was able to kill tumor organoid cells, but it turned out that an effective dose would be toxic for patients. Experiments on organoids were continued in order to select options for combination therapy of a new drug with known antitumor agents. Screening analysis using 129 drugs showed the possible effectiveness of several options – there is something to work on further.

There are still many obstacles in the way of the new approach, including the imperfection of the technology itself for obtaining tumor organoids (so far, researchers have successfully grown organoids from the cells of 4 out of 25 patients). Nevertheless, the results already obtained confirm the prospects of tumor organoids as models for finding therapeutic targets and a "polygon" for working out the optimal individual treatment strategy.

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