Jackson Lab geneticist and biologist Ewelina Bolcun-Filas in her office in Bar Harbor. Bolcun-Filas recieved a $200,000 grant to continue looking for a way to protect fertility for girls undergoing cancer treatment. ELLSWORTH AMERICAN PHOTO BY KATE COUGH

Researcher seeks to protect fertility



ELLSWORTH — Childhood cancer is a tragedy, but it is no longer necessarily a death sentence. This year, out of the roughly 11,000 children under 15 diagnosed in the United States, around 80 percent are expected to survive five years or more beyond their diagnosis.

That, of course, is great news, said Dr. Subha Mazzone, a pediatric oncologist at Northern Light Eastern Maine Medical Center in Bangor.

But it also means patients are increasingly dealing with lifelong side effects of the very treatments that saved them. Chemotherapy and radiation are designed to be toxic in order to kill cancer cells. But that toxicity can also affect other organs and cause lasting damage.

“We do all of these things to beat the cancer,” said Mazzone, “but we’re dealing with a lot of late effects and side effects because of cancer. Only 1 in 5 pediatric cancer survivors come out of it unscathed, without a chronic medical condition.”

Mazzone runs a clinic at Northern Light in Bangor to help connect pediatric cancer survivors with resources to help deal with ongoing medical issues related to their cancer treatment.

“Their bodies tend to age earlier. We’re seeing early heart disease, liver disease, cataracts,” said Mazzone. “Learning problems are huge.”

There’s one topic, however, that often doesn’t get as much attention as others: fertility and puberty.

Jackson Lab researcher Ewelina Bolcun-Filas said parents of young girls do not often immediately wonder whether a cancer treatment will eventually make it difficult for their daughter to get pregnant, or put her at risk for menopause in her 30s.

“If you’re a parent and the doctor tells you your kid needs a bone marrow transplant and they will [undergo radiation treatment] tomorrow,” said Bolcun-Filas, “sometimes there isn’t enough time to think about toxicity or ‘later’”.

“There’s a lot of things that are not always considered at the time of treatment,” said Bolcun-Filas. “But you do have to think about the future. You do this treatment so your child survives and then you want your child to have a normal life.”

“What we need and what we don’t have is a way to really protect young females,” said Mazzone. “Egg freezing is the only option right now.”

But preparation for egg freezing can take weeks, delaying cancer treatment. It’s invasive, sometimes requiring surgery, and families usually have to pay for the procedure out of pocket, as well as pay an annual storage fee to keep the eggs frozen.

And for younger girls who haven’t yet gone through puberty, it’s very difficult to retrieve the eggs, said Bolcun-Filas, because “they can’t be preserved the same way.”

In those patients, the surgeon must remove a whole ovary, slice it into pieces, and cryopreserve the sections that contain immature eggs.

“Later,” said Bolcun-Filas, “when the child is healthy they can take those little bits of ovary and put them to the other ovary. Those pieces will graft back and restart said growth.”

But even that doesn’t necessarily guarantee that the woman will be able to have children, said Bolcun-Filas, or that the ovary will produce the hormones necessary for normal development.

“It can just last a couple of ovulation cycles — it depends on how many eggs are in that piece.” Plus, she added, “There’s always a risk of reintroducing cancer cells,” and the grafted ovary “may not produce enough hormones for puberty,” which can present its own host of problems.

“Survivors have a long life, hopefully, ahead of them,” said Bolcun-Filas. “If we can preserve their egg supplies and ovarian function for a longer period of time they won’t be battling menopause when they’re in their 30s.”

That’s where her research at The Jackson Laboratory comes in.

The geneticist has been studying the causes of infertility for most of her career, but several years ago, she began wondering if there was a way to prevent damage to eggs during treatment, something that didn’t involve removing eggs or ovaries.

So Bolcun-Filas, who was then working at Cornell University in New York, began looking into a protein that functions as a “quality checkpoint” during the eggs’ development.

When an oocyte (an immature egg) is developing, it divides twice, a process known as meiosis. During that division, the DNA strands of the oocyte undergo pre-programmed breaks that are then repaired.

Certain proteins monitor the DNA break-and-repair process during oocyte (future egg) development, acting as “quality checkpoints,” said Bolcun-Filas, to make sure that the breaks have been repaired properly so that the eggs can develop normally.

But cancer treatments, particularly radiation, can also induce breaks in the DNA of developing eggs.

“If immature eggs acquire breaks,” explained Bolcun-Filas, “this quality-control mechanism will automatically eliminate them from the egg pool, so we don’t accumulate potentially bad eggs.”

When a lot of developing eggs are damaged all at once during cancer treatment, explained Bolcun-Filas, the repair proteins can’t keep up, and the quality checkpoint triggers a process that results in the cell’s death.

Because a woman has only a set amount of eggs and cannot make more, those eggs are lost forever.

So Bolcun-Filas began looking into a way to disable a particular quality checkpoint protein during cancer treatment, allowing repair mechanisms more time to fix the damaged cells and prevent them from being destroyed.

After years of research, Bolcun-Filas and her team found that turning off the gene for a certain checkpoint protein, known as kinase CHK2, prevented the death of immature eggs exposed to radiation, preserving fertility in mice.

“This protein seems largely dispensable,” she explained. “There are other proteins that can supplement its function and mice lacking CHK2 are healthy and fertile.”

But nothing is simple in science, cautioned Bolcun-Filas, and there are still a lot of questions to answer and steps to take.

“For now we just have a proof of principle that this could work,” she said.

“In [a laboratory] culture we can clearly see that it helps. We know that in principle this treatment could prevent loss of eggs.”

Her team is now looking into which types of cancer treatments the therapy will be effective for, as well as identifying a drug that would do the same, which has presented its own problems.

“With humans it’s always harder,” said Bolcun-Filas. “So far we haven’t found an inhibitor that will not be toxic. It also has side effects on its own.”

“From human studies it seems that there is an increased risk of certain cancers when this gene is defective in humans, if it’s completely switched off,” said Bolcun-Filas. “But we would be doing just temporary switching.”

There’s also the question of whether the eggs that survive will be viable and healthy going forward.

“We are preventing eggs from dying, but what actually happens to them?”

But despite the complications and the likely long road ahead, Bolcun-Filas is optimistic, and so are her backers: her team recently received a $200,000 grant from the V Foundation for Cancer Research to continue her work. She is also part of a growing field known as oncofertility, which looks to expand fertility options for cancer survivors.

“Maybe fertility doesn’t seem to be a big problem because we don’t talk about it,” said Bolcun-Filas.

“But when you think about health, overall, increased risk of other diseases and normal life fertility is still important.”

It’s not only about allowing cancer survivors to have their own biological children, said Bolcun-Filas, although that’s a crucial aspect.

But, she added, “There’s more beyond that. There’s general health, sexual health, there’s a lot of things that we don’t talk about. Educating people is super important.”

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