Thursday , March 4 2021

Cancer stem cells are dependent on amino acid metabolism and this has proven their Achilles heel.



Think about energy metabolism, such as batch poppers: Catching something, releasing an explosion. Most of your cells cut sugar to release energy. Sometimes they dissolve the fat, but during the pinch, the cells can be metabolised by the protein.

Cancer cells are slightly different. First, most cancer cells continue to depend on glucose, but switch from "cellular respiration" (which requires oxygen) to "glycolysis" (which can happen with or without oxygen). Colorado University Cancer Center Research, published today in the journal Cancer cell shows that cancer stem cells use the third approach: they are used by cellular breathing, but from the metabolism of sugar to the protein metabolite, or more precisely with amino acids, which are protein constituents.

Whole cells do not need to metabolize proteins. The current study shows that cancer cells need to metabolize the protein. And this difference is the Achilles heel, which allows researchers to target cancer cells without harming healthy cells – this approach has already proven effective in clinical trials on acute myeloid leukemia and promises of other forms of cancer, including breast, pancreas and liver.

"In acute myeloid leukemia, we have achieved quite good results in killing most of the cancerous cells, but a small population of cancer cells is specially equipped to resist these therapies, and these stem cells often survive to restore the condition later. He needed a way to specifically targeting cancer cells, and it seems that this could be the case, "says Craig Jordan, Ph.D., researcher at the Cancer Center at Colorado University, head of the Department of Hematology and Nancy Carroll Allen, Hematology Professor at the University of Colorado Medical School.

In fact, Jordan has spent more than 20 years in defining the scientific basis for this attack on cancer stem cells, and now, with its striking, important publications, its team has not only created a better understanding of these rigid cells, but also treatment that can change the acute myeloid leukemia and possibly other cancer treatment standards. In a recent clinical study, patients with acute myeloid leukemia who did not have bone marrow transplant candidates were treated with venticolaks, which inhibits the ability of cells to absorb amino acids.

"Traditional chemotherapy is not effective for most patients with acute myeloid leukemia. The new results with venticolaks appear to be very promising," says Jordan. The results of clinical trials are also published in the journal Natural Medicine, with the first author Daniela Poland, MD. The current study cycle has clarified why the clinical trial was so successful.

Very substantially, several studies conducted by the first author of Courtney Jones, PhD and other laboratories in Jordan showed that leukemia stem cells do not (or may not be able to) migrate from breathing to glycolysis, such as more mature cancerous cells. Instead, they switch from glucose metabolism to amino acid metabolism – in fact, they are entirely dependent on the metabolism of amino acids to energy, so much so that when the ability of the leukemia stem cells to absorb amino acids is stopped, these cells die.

"The Courtney study is an important step in understanding how to better eliminate leukemia stem cells. With my conclusions as a basis, I believe that we can now move on to create even more effective therapies," Jordan says.

The use of Venetoclax interrupts the leukemia stem cells so that they can be used for the amino acid energy. In the laboratory and now in the clinic, when researchers treated AML patients with venetoclaca, leukemia stem cells die. Important since whole cells are not dependent on amino acid metabolism, venetocklex has destroyed leukemia stem cells without harming healthy cells.

Interestingly, there were only AML patients treated with venetoclac, since they were treated for such a dramatic reaction for the first time.

Firstly, when patients were first treated with other therapies, leukemia stem cells were installed to diversify and some take lipid metabolism, "says John.

When these patients were then treated with venetoclac, the drug killed cancerous stem cells that continued to be dependent on amino acid metabolism but were not effective against cancerous stem cells that switched to lipid metabolism. Exactly, if lipid metabolism made it possible to save these cells and, even if a small leukemia stem cell population were able to resist therapy, they could later resume disease growth.

The future of the group hopes to explore the possibility of inhibiting lipid metabolism along with the metabolism of amino acids for use in AML patients whose cancer has resisted or relapsed after previous therapies.

"In this paper, we report on important scientific characteristics describing the vulnerability of these leukemia stem cells, and in the Nature Medicine paper, we describe the treatment that successfully exploits this vulnerability," says Jordan. "We believe that this kind of therapy is just the beginning of what can become a completely new type of treatment for leukemia. Now, our task is to optimize this treatment in acute myeloid leukemia, while extending it to other conditions where cancer cells continue to guide the development of cancer , growth and recurrence. "

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