‘We now know our enemy’: UBC study offers new hope for treating relapsed childhood leukemia

A single-cell genomic analysis led by Dr. Marco Marra (pictured) reveals how pediatric leukemia changes at relapse, guiding the development of new treatments.

New therapies have dramatically improved survival rates among children with pediatric acute myeloid leukemia (pAML)—a cancer that starts in the blood-forming cells of the bone marrow. But in cases where the cancer returns, doctors, children and their families are faced with a new set of challenges.

“We have effective treatments for children battling AML, but for some, although the cancer shrinks and the patient may go into remission, the cancer can unfortunately return,” says Dr. Marco Marra, professor of medical genetics at UBC’s faculty of medicine and a member of the Michael Smith Laboratories. “These recurring cancers are more difficult to treat and the initial therapies are no longer effective. For such patients, the outlook is often poor.”

Why pAML returns after a period of remission—and why it comes back resistant to conventional treatments—are key questions Dr. Marra and his team at UBC’s Michael Smith Laboratories are racing to answer.

Now, in a recent study published in Cancer Cell, Dr. Marra’s team has made a key discovery that may eventually help treat patients with pAML who experience relapse.

“We found that the cancer cells at relapse took on characteristics that are very different from what we saw at initial diagnosis, before treatment,” explains Dr. Marra, who is also a Canada Research Chair in Genome Science. “Knowing how cancer changes at relapse may give us new insight into how we can target it, possibly anticipate who may be at risk of relapse, and perhaps, in the future, even prevent relapse from happening.”

Guiding new treatment possibilities

The findings stem from a long-standing collaboration between Dr. Marra and Dr. Soheil Meshinchi’s team at the Fred Hutchinson Cancer Research Center in Seattle. Dr. Meshinchi was part of clinical trials testing pAML therapies, and through that work, had built a collection of rare bone marrow samples at three distinct points in time during a child’s cancer journey: at initial diagnosis, upon remission, and in cases where the disease relapsed.

“This was an incredibly rare opportunity. Researchers don’t often have access to multiple time points in a patient’s journey with cancer, and rarer still are examples where all the patients have been treated the same way. These samples provided a rare look at how the cancer evolves over time in multiple patients,” says Dr. Marra.

Using advanced single-cell sequencing at Canada’s Michael Smith Genome Sciences Centre, Dr. Marra and his team analyzed the cellular and genetic composition of the samples at each of the three time periods. This allowed them to pinpoint how the cancer had changed in response to treatment and when it relapsed.

“We now know our enemy, and that means we can be rational about how we target it. That gives me a lot of hope that we will be able to develop better treatments for children battling this devastating disease.”

– Dr. Marco Marra

“Cancers are not uniform in composition. They’re better thought of as a diverse community of cells, even within a single patient,” says Dr. Marra. “With the remarkable precision enabled by single-cell genomics, we were able to identify and characterize the individual cells that make up that diverse community of cells.”

What emerged was a portrait of a highly adaptable cancer. Upon relapse, pAML cells were observed to revert to a more “primitive” state, resembling an earlier stage of blood cell development, known as progenitor cells or stem-like cells.

“In the cancer cells, we saw a shift toward an earlier point in the cell lineage,” says Dr. Marra. “These types of cells don’t divide as rapidly, perhaps making them less susceptible to treatments, including the one used in the clinical trial, and allowing them to survive.”

How the cancer changed over time was dependent on the specific genetic alterations driving the leukemia, underscoring the complex genetic diversity of pAML. Dr. Marra says research insights into the cancer’s evolution will one day help inform the development of precision treatment strategies.

“We can look specifically at these progenitor-like cells that we know are a primary driver of relapse in some patients. We can ask: What are their characteristics? What are their vulnerabilities? Can we deploy existing drugs against those targets, or can we develop entirely new drugs?”

“We now know our enemy, and that means we can be rational about how we target it. That gives me a lot of hope that we will be able to develop better treatments for children battling this devastating disease.”

Dr. Marra and his colleagues gratefully acknowledge the participation of patients and their families, without whom this work would not have been possible.

This study was supported by the Canadian Institutes of Health Research and Genome Canada, with additional support to the researchers from BC Cancer, the BC Cancer Foundation, the Canada Research Chairs program, the Canada Foundation for Innovation, Genome BC and Michael Smith Health Research BC.

This story was originally posted by the UBC Faculty of Medicine.