Using cloning technology to prevent esophageal cancer

By Dr. Liji Thomas, MDOct 2 2019

A team of researchers at the University of Houston is replicating the genetic mechanism underlying the transformation of benign esophageal cells into a malignant tumor. The aim is to find out vulnerable spots in the pathway that can be hit by new drugs early in the process of tumor formation.

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Esophageal cancer is responsible for thousands of deaths, and the National Cancer Institute estimates that it will kill 16,000 people in the US in 2019. As a result, research into the molecular mechanisms that drive the development of esophageal malignancies is underway in numerous locations.

Our cloning provides unprecedented resolution to genomic changes accompanying this evolution and provides multiple advantages for drug discovery.”

Frank McKeon

A pioneer in the field of stem cells, McKeon has confidence that the cloning process will speed up the development of drugs to give patients with early stages of this malignancy a much better chance at a cure.

How esophageal cancer begins

In most cases, esophageal cancer claims the patient’s life within a year. The events that culminate in this dreaded illness begin with a premalignant condition of the esophageal cells called Barrett’s esophagus, or intestinal metaplasia. Here, the normal squamous epithelium of the esophagus is converted into columnar epithelium with mucus-producing goblet cells, characteristic of the intestine. This typically changes into cells with abnormal characteristics (called ‘dysplasia’), and over about two decades, the metaplasia contains one or more areas that have transformed into a malignant tumor – esophageal adenocarcinoma. The entire sequence of events is called the Correa sequence.

The current research compresses the timescale using cloning methods that were first produced to model the human gut. These techniques are used to produce clones of stem cells from endoscopically obtained biopsy specimens of Barrett’s esophagus, esophageal dysplasia, and esophageal adenocarcinoma. The use of these clones along with molecular genetic methods has enabled the team to reconstruct the whole sequence of malignant transformation with unparalleled precision.

The cloned cells allow researchers to understand the genetic changes that occur at each stage of this process, which exposes new targets for drug development. They have demonstrated that these abnormal cells arise from a distinct cell line, rather than from the local esophageal epithelium. This means that if these stem cells are targeted, the cancer itself can be prevented at an early stage. This is the basis of screening for chemicals that can selectively kill these cell populations without harming normal healthy cells.

Importantly, the research process also uses cell clones derived from the liver and gut tissues to rule out unacceptably toxic drugs before they progress too far in the drug development pathway. These are the organs most severely affected by most chemotherapeutic agents. The research team’s unique access to cell clones gives them the edge in testing new drugs early in the process and discarding those which are too harsh on the normal cells. Thus, the ones that are taken forward will be the ones that are most likely to yield good results, which will drastically reduce the time frame for new drug development.

The importance of the research

Nobody can really manage esophageal cancer; it is most often linked with bad outcomes. We need to get at it at these earlier stages to see if we can address it in a pre-emptive way. The cloned stem cells of Barrett's, dysplasia, and adenocarcinoma have enabled powerful forms of drug screens as well as in vivo models of the Correa sequence to validate lead combinations that specifically and simultaneously target the entire Correa sequence lineage.”

Frank McKeon

In other words, the cloned cells are used to test various candidate drugs and find out which of them are active against one or more of these cells, both in vitro and in living cell models. They can then be combined to find the ideal array that will destroy cells across the whole sequence at the same time, reducing the chances of recurrence.