Release date: 2018-06-15
A brain tumor called a malignant glioma is one of several cancers tested in a mouse "replacement".
Analysis of more than 1,000 mouse cancer models challenged the ability of human patients to respond to treatment.
The study, published in the journal Nature-Genetics, recently analyzed the genetic changes experienced by human tumors after they were transplanted into mouse hosts. This model, called human xenograft (PDX), is used in basic research and as a "stand-in" for individual patients. Researchers use these "alternatives" to test chemotherapy against tumors in patients, with a view to tailoring treatment plans for specific cancers.
However, the latest data from geneticists at the Harvard University-Massachusetts Institute's Broad Institute confirm that transplanting human cancer cells into mice alters cell evolution and is a way that may affect the response to chemotherapy. Plastic tumor genome.
“The original hypothesis is that what grows in PDX reflects most of the tumors in the patient,†said Todd Golub, the first author of the latest study, cancer geneticist. “But actually the tumor genome is largely re-established. shape."
No animal model is perfect. Researchers have always admitted that PDX has its own limitations. For example, to avoid immune attacks from foreign tumors, PDX is usually transplanted into mice that lack a functional immune system. This has led scientists to undermine the ability of immune cells to interact with tumors. However, given the success of cancer therapies that stimulate the immune system, the field is attracting increasing interest.
At the same time, PDX takes months to produce, making it too slow to act as a “stand-in†for patients who need immediate decisions about treatment.
Glioblastoma (a circular region in a patient's brain scan) is one of the cancers detected in a mouse model
However, previous studies have shown that PDX is an accurate and reliable replica of human tumors, providing researchers with an opportunity to explore the interaction of tumors with the surrounding environment. It is impossible to achieve this research using cells grown in a petri dish. The National Cancer Institute has developed a library of more than 100 PDXs and assigned them to researchers, while European scientists have launched EuropDX, a consortium of more than 1,500 models for more than 30 tumors.
The Hackensack Champion Oncology Company in New Jersey created a mouse "replacement" for individual patients and tested it for use by pharmaceutical companies in the study.
In the latest study, the cancer geneticist Rameen Beroukhim of Golub and the Broad Institute and his colleagues decided to analyze how PDX changed over time. They studied data from tumor cells. These cells are transplanted into mice and allowed to grow into tumors, which are then removed and re-transplanted into new mice - sometimes through multiple cycles.
Researchers look for changes in the number of copies of specific genes in cells. They performed this type of treatment on more than 1,000 PDX samples representing 24 cancers, and usually inferred the number of gene copies from data on gene expression.
Analysis has shown that tumors transplanted into mice have changed in a manner that is not common in the human body. For example, human brain tumors known as malignant gliomas often acquire additional copies of the chromosome. However, Beroukhim said that mouse PDX easily loses these extra copies over time.
Some genetic changes are also associated with how PDX responds to cancer drugs. Golub believes that for scientists who study many PDXs and look for genetic susceptibility to drug sensitivity, this finding is not indicative of a disaster. “This is not to say that PDX as a model should be abandoned,†Golub said. “But they are not a panacea.â€
Golub showed more concern about using PDX to predict the outcome of individual patients: "The latest research raises some important questions about how to interpret the results of the 'avatar'."
However, the results of a study of 92 patients by the founder of the Champion Oncology Company and the Johns Hopkins University School of Oncology David Sidransky showed an 87% association between the patient's drug response and the corresponding PDX. degree.
According to Sidransky, the genetic analysis carried out by Golub and his team may provide clues as to what other 15% of PDX has.
David Tuveson, a cancer researcher at Cold Spring Harbor Laboratory in New York, believes this work is very important. But he also suggested that the PDX method is changing.
Researchers are increasingly likely to transplant human tumors into similar locations in mouse "replacements", such as transplanting human pancreatic cancer cells into the mouse pancreas rather than simply transplanting them under the skin. According to Tuveson, this will make cancer cells more similar to the living environment of the original tumor.
At the same time, Carlos Caldas from the Cancer Institute at the University of Cambridge in the UK said that researchers will continue to use the PDX that has already been produced. Caldas said that his studies using breast cancer PDX did not find such a significant difference between PDX and the tumors that produced them. “We will continue to use these models to observe many activities. They are huge developments, not obstacles.â€
Source: TA said
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