Any other cancer where more than three-quarters of patients are cured might seem to be a low research priority — compared to, say, cancers with an approximately 0 percent cure rate, such as adult glioblastoma. But childhood cancers are, well, childhood cancers.
“Today’s overall cure rate of 80 percent means than 1 in 5 children will die of their disease,” said Dr. James Downing, president and CEO of St. Jude Children’s Research Hospital in Memphis, Tenn. “So there is still a lot of work to be done.”
The pediatric cancer community applauded President Trump’s State of the Union promise of an additional $500 million over the next 10 years to fund research into cures for more childhood cancers. It wasn’t just because scientists generally don’t turn down extra money, and it wasn’t because of the emotional tug of dying children. Instead, experts say there are specific, actionable research questions that the additional funding could help them answer, including in two areas that the “cancer moonshot,” developed by the Obama administration, identified.
That’s because the overall high cure rate is largely driven by remarkable progress against childhood leukemia, but “in other pediatric cancers, the cure rates haven’t changed in 20 years,” said Downing, who served on the moonshot’s blue-ribbon panel.
The Trump administration is far from alone in believing that an additional research push could pay off. On Thursday, the American Cancer Society and the St. Baldrick’s Foundation, the largest charitable funder of childhood cancer research, announced that they were joining forces to raise $11 million to fund studies “that have the greatest potential to quickly deliver new and improved treatments for kids with cancer,” the groups said in a statement. The money would support, among other things, expanded clinical trials (just over half of children with cancer participate in a clinical trial, compared to about 5 percent of adults) and efforts to discover novel treatments.
Of every 100 cancers diagnosed in the U.S., one is in a child. About 11,060 children younger than 15 will be diagnosed with cancer in 2019, the American Cancer Society projects, and 1,190 will die (as will 606,880 adults).The 80 percent cure rate compares to just under 60 percent in the the mid-1970s. “Before, there were so few cures that doctors would let children go to the back of the ward and die,” Downing said.
But the success rates for different childhood cancers, measured by five-year survival, vary significantly. It is 98 percent for Hodgkin lymphoma, 95 percent for retinoblastoma (an eye cancer), 91 percent for acute lymphocytic leukemia (the most common pediatric cancer), and 90 percent for non-Hodgkin lymphoma. It’s just 80 percent for neuroblastoma, though, 70 percent for both osteosarcoma and rhabdomyosarcoma, and 66 percent for acute myeloid leukemia.
The National Institutes of Health is projected to spend $462 million in 2019 on childhood cancer research, compared to $433 million in 2017 and $486 million in 2018. (Not all of 2019’s grants have been entered into the recording system, so actual spending might not fall compared to last year.) An infusion of $50 million a year would therefore represent a roughly 10 percent increase, something Downing calls “a welcome supplement.”
If nothing else, it would send a signal to cancer biologists that their chances of winning National Cancer Institute funding has ticked up. Scientists are sometimes reluctant to jump into pediatric cancer research because, given the high cure rates, “they’re worried that they won’t get a high enough priority score to get funded,” believing that adult cancers with abysmal survival rates will prevail in the grants competition, said Dr. Lee Helman, a former NCI official and pediatric cancer specialist who is now at Children’s Hospital Los Angeles. “A little extra money for research could therefore bring more scientists into the field.”
Scientists don’t have countless ideas of how they would spend it, which is actually an encouraging sign: They have just a short and specific wish list.
One is to extend to children the remarkable progress that immunotherapies have made in some adults. Unleashing the immune system on cancer, as checkpoint inhibitor drugs such as Keytruda and Opdivo do, works most effectively when tumors are studded with surface proteins called antigens, which are produced by mutated genes. (Checkpoints are off-switches that keep T cells from devouring tumor cells, and the drugs block the switches, unleashing the immune system on tumors.) Immune cells recognize these antigens as foreign and therefore attack.
But “pediatric cancers have shown less responsiveness to these drugs because they have much less of a mutation burden than adult cancers do,” Downing said.
Also on the to-do list is identifying childhood-cancer-specific targets for CAR-T therapies, T cells that are genetically engineered to find and destroy particular tumor antigens: The first approved CAR-T, Novartis’s Kymriah, is for childhood acute lymphoblastic leukemia, and the hope is to expand CAR-T’s into solid cancers.
Pediatric cancers have also largely missed the “targeted therapy” revolution in cancer. Though it hasn’t been as successful as immunotherapies, this approach has yielded significant, and sometimes lifesaving, drugs such as Gleevec and Herceptin, which block the cancer-causing effects of a mutation.
A thorough analysis of the genetics of childhood cancers, led by St. Jude scientists, was published only last year, however, and to most everyone’s surprise they found that about half of the “driver mutations” — ones responsible for fueling a tumor’s uncontrolled growth — aren’t seen in adult cancers. “The genetic landscape of pediatric tumors is just different from adults,” said Helman, who oversees the pediatric cancer research funded by Stand Up to Cancer.
As a result, Downing said, “the whole idea that we can wait for molecularly targeted adult drugs to trickle down [and work in children] is thrown out the window.”
Instead, drugs that target the pediatric-specific driver genes will have to be discovered from scratch. “That’s hard, because pediatric cancers are relatively rare,” said Dr. Scott Armstrong of Boston Children’s Hospital and the Dana-Farber Cancer Institute. “Companies are interested, but they won’t direct the same amount of resources at a rare cancer as a common one” such as adult lung cancer.
Academic researchers, whom Trump’s additional money would likely fund, therefore “have to do more work [on a potential drug] before pharmaceutical companies will pick it up,” Armstrong said. “You have to de-risk it for them, making it as clear as clear can be that drug X has a high likelihood of success.” That, too, obviously takes money.
The one piece of good news from the 2018 study: Nearly half of childhood cancers harbor a “potentially druggable” genetic glitch, the researchers found. That offers hope that molecularly targeted therapies for childhood cancers might be in the cards. But finding them won’t be easy. Many of the aberrant proteins made by mutated genes in pediatric cancers are of an entirely different kind than the aberrant proteins in adult cancers, many of which belong to a family called kinases. (There are 50 approved cancer drugs that target kinases, including Pfizer’s Xalkori and Janssen’s Imbruvica.) In childhood cancers, Armstrong said, the proteins made by the cancer-causing genes “are of a type that has historically been undruggable,” meaning scientists haven’t found any molecule able to defeat them.
Trump said the new money he proposed would fund research, but other uses for the $500 million might actually speed the discovery of new therapies even more.
“I don’t think another $50 million a year for more studies will really move the needle,” said John Parker, managing director of Springhood, an early-stage investor in companies focused on children’s health. But putting that money toward tax incentives to induce pharmaceutical companies to work on childhood cancers could accelerate drug discovery, he said, as might “angel tax credits” that let investors write off any losing bets they make on startups with this focus. Both could draw much-needed investment, Parker said, possibly even a multiple of Trump’s $500 million.