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Next-Generation Sequencing of Pediatric Cancer Patients Could Transform Treatment Paradigms

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NEW YORK (GenomeWeb) – Increased access to next-generation sequencing has revealed that despite the vast molecular differences that often exist between adult and pediatric cancers, cancers in children can sometimes display the same molecular biomarkers as those found in adults. Researchers are putting this knowledge to use by repurposing drugs that were originally developed for adult patients and giving them to pediatric patients.

Projects such as the Treehouse Childhood Cancer Initiative and St. Jude Children's Research Hospital's sequencing of more than 10,000 whole genomes from pediatric cancer patients and survivors are giving researchers and clinicians a better idea of what drives pediatric cancers. But if there's one thing these sequencing efforts have shown, it's that knowing the biology behind these cancers and treating them are two separate things.

Though some childhood cancers have similar mutations as adult cancers, the tissue of origin is often completely different. For example, although ALK mutations are common in lung cancer in adults, they tend to drive neuroblastomas in children. And the BRAF mutations that underlie melanomas in adults can sometimes crop up in pediatric brain tumors.

"It's still cancer, but no child will ever develop an ALK-driven lung cancer," said Andrew Kung, chair of the pediatrics department at Memorial Sloan Kettering Cancer Center. Instead, he added, "we could potentially use those same drugs [that were developed for ALK-driven lung cancers in adults] in ALK-driven neuroblastoma."

This kind of thinking has led to what could become a new treatment paradigm for childhood cancers: using NGS tools to discover an actionable treatment target, and then repurposing drugs that were originally developed for adults and putting them to use in relevant pediatric cancer cases.

"It's not that we're just willy-nilly using drugs off-label," Kung said. "Repurposing [drugs] is the ability to leverage the fact that ALK as a driver is common between a pediatric disease and an adult disease, and we can leverage the fact that companies have developed many ALK inhibitors."

Kung's group uses the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay — a hybridization capture-based NGS assay for targeted deep sequencing of all exons and selected introns of nearly 500 cancer genes — to sequence pediatric cancer patients that come to the center for treatment. Using the assay and other tools available to MSKCC's genomics program, Kung and his colleagues have discovered multiple novel alterations which they've been able to treat using existing adult drugs under compassionate use measures. In some instances, he noted, the patients showed dramatic clinical responses.

In May, Kung and a team from MSKCC, the New York Genome Center, Columbia University, and elsewhere reported in Cancer Discovery the case of a 12-year-old girl with a histopathologically indeterminate epithelioid neoplasm. They found that she had a novel fusion between the LAMTOR1 and AKT1 genes, and she became the first pediatric patient to be treated with the oral ATP-competitive pan-AKT inhibitor ipatasertib, an experimental cancer drug being developed by Roche. The treatment led to a dramatic regression in the tumor, demonstrating that the fusion resulted in activation of AKT1 and was an oncogenic driver that could be therapeutically targeted.

"The sequencing in that case allowed us to move directly to application of the potential therapeutic in the actual child, foregoing five or six years of laboratory investigation," Kung said. "We advanced to a point where we could do the therapeutic experiment in the patient."

Elaine Mardis, co-executive director of the Institute for Genomic Medicine at Nationwide Children's Hospital, said that this type of sequencing could lead to finding new ways to treat kids with cancer in many different settings.

At the annual meeting of the American Association for Cancer Research in Atlanta in April, Mardis detailed her center's efforts to combine DNA and RNA sequencing in the clinical cancer care setting in order to help patients. She presented a case of a patient whose oncologist submitted him for participation in her team's sequencing protocol after he'd had what appeared to be a second recurrence of medulloblastoma. Mardis and her colleagues eventually found that the patient's recurrence was actually a secondary malignancy, and were able to recommend a course of therapy to the oncologist.

There's a lot to consider when deciding how to prioritize treatments for children based on sequencing results, Mardis said. If it's a very rare tumor, for example, then most likely there's no standard of care treatment. "There, our oncologists have the most opportunity to take advantage of anything that we can identify through molecular testing," she said, adding that for tumors that are more common and have standard of care options, doctors focus on using sequencing to identify new options once the kids become refractory.

She noted that even after the sequencing data has helped to determine the best course of action for treatment, oncologists still have to adjust dosages to be suitable for children, to decrease side effects but maintain the efficacies of the drugs.

"We certainly don't want to be harming anyone unnecessarily with pharmaceuticals that are not suitable for their treatment," Mardis said. "But the more kids on the planet that go through this type of analysis, the more treatments that are determined that way, the more we can increase our level of confidence that a given target would respond to a given therapy, assuming that that data gets shared out through normal mechanisms such as databases or in the peer-reviewed literature."

Indeed, there are large-scale efforts under way to systematically match pediatric cancer patients to available treatments. In the run-up to the American Society of Clinical Oncology's annual meeting in Chicago earlier this month, the National Cancer Institute-Children's Oncology Group released an interim analysis of its Pediatric Molecular Analysis for Therapy Choice (MATCH) study — a precision medicine clinical trial for pediatric cancer. The researchers found that 24 percent of participants were eligible to receive treatment with a targeted therapy, a match rate significantly higher than the 10 percent they expected at the outset of the trial.

And in Europe, the multicentric, prospective proof-of-concept MoleculAr Profiling for Pediatric and Young Adult Cancer Treatment Stratification (MAPPYACTS) study was able to place patients into treatment arms at a similar rate as the Pediatric NCI-MATCH trial. MAPPYACTS, which was discussed at the ASCO meeting, aimed to defined molecular profiles of pediatric recurrent or refractory malignancies, and suggest treatment. From February 2016 to October 2018, researchers enrolled 500 patients through 17 cancer centers in France, Italy, and Ireland. They found actionable genetic alterations in about 74 percent of the patients. As of April 2019, 28 percent of those patients had been matched to at least one targeted therapeutic agent.

Keeping the old, asking for new

But even these efforts are likely not enough. Although the match rates through the NCI and MAPPYACTS studies are higher than researchers anticipated, it is an undeniable fact that adult and pediatric cancers differ in many ways, and the treatments that are available aren't sufficient.

"Most of the largest whole-genome and whole-exome sequencing efforts with childhood cancer has fairly convincingly shown that only less than half of the drivers of pediatric cancers are actually shared with adult cancers," Kung said.

Indeed, Mardis explained, pediatric cancers are more commonly driven by either fusion proteins or by epigenetic changes — both methylation and chromatin remodeling — not all of which are very well understood. "This combination of fusion drivers and epigenetic drivers is also coupled with the fact that, typically when you're looking for somatic mutations of the type that we normally expect to find in adult cancers, there are very, very few," she said.

Given those differences, it's not surprising that the available treatments — especially those that have been developed with adult cancers in mind — don't fill all the gaps. But getting pediatric-specific therapies in development may not be as simple as finding an actionable cancer driver and devising a clinical trial.

When it comes to precision oncology for pediatrics, which relies on treatments that target tumor markers that are increasingly rare in the general population, there's also a problem of incentives. "The challenge that we face in pediatrics [is that] because pediatric cancers are rare, there are very few commercial entities that are going to be incentivized to develop therapies and drugs for very rare conditions," Kung said.

We've made far more progress on the precision part and not enough progress on the medicine part.

"The other problem that we face is that many of the drivers of pediatric cancers are not amenable to current drug development and so are considered undruggable. So, whether some of the emerging technologies to target the previously undruggable targets will actually allow us to develop those new drugs, that remains to be seen."

One bright spot on the horizon that could help to ameliorate this issue is the Research to Accelerate Cures and Equity (RACE) for Children Act of 2017, which was signed into law by the US government as part of the 2017 FDA Reauthorization Act as an update to the Pediatric Research Equity Act. The RACE Act states that the US Food and Drug Administration may now require pediatric assessments when the molecular targets of drugs under FDA review are substantially relevant to children's cancers.

"There's usually a six- to eight-year lag between the first testing in adults and the first testing in kids. And that's the gap that we need to improve," Kung added. "My mantra is that in the whole precision medicine paradigm, at least for pediatrics, we've made far more progress on the precision part and not enough progress on the medicine part." The RACE Act is likely to compel more trials of drugs for pediatric cancer patients, he noted.

Mardis concurred. Part of the reason for the difficulty in getting pediatric cancer clinical trials sponsored is that the rarity of these cancers in the general population makes it hard to accrue a significant number of patients for statistical power, she said. But she believes the RACE Act could help to change this dynamic.

In with the very new

There is also a new generation of therapeutics, such as immunotherapies and CAR T cells, that have worked very well in adult patients and are now being considered for the treatment of children.

So far, checkpoint blockade therapy hasn't really been tried in pediatric cancer patients because patients who typically respond to checkpoint blockade inhibitors tend to have an elevated mutation rate — melanomas due to UV damage or lung cancer and bladder cancer due to smoking-related DNA damage, Mardis said. Because childhood cancers have significantly lower mutation rates than adult cancers, the tacit assumption until now has been that these patients likely wouldn't respond to these treatments.

However, she added, this isn't the case in some kids. New research from a team at Toronto's Hospital for Sick Children has shown that some kids have either a germline pathogenic mutation in polymerase epsilon or in their brain tumors which elevates the level of mutations, Mardis said. This type of cancer may respond well to checkpoint inhibition.

"The other aspect that we've been looking at carefully is that when you have secondary cancers that either go through alkylating chemotherapy — which increases the mutation rate in the recurrent tumor — or through radiation therapy — which also gives sometimes not a secondary tumor, but a second primary tumor — there is an elevated level of immune infiltration," she noted. "So, we think by comparing the primary to the secondary, or the primary to the second primary, we may be able to build a case for a clinical trial for kids in the checkpoint blockade space."

However, there may also be some downsides to immunotherapies in the pediatric space. Taking the brakes off the immune system can result in an enhanced inflammatory state and some autoimmune issues, Kung noted, which is a problem for adults taking immunotherapeutic agents as well.

Indeed, he added, in terms of immune-oncology agents, CAR T cells may be a better option for pediatric cancer patients. The first FDA-approved CAR T therapy was Novartis' tisagenlecleucel (Kymriah), which is used to treat childhood acute lymphoblastic leukemia.

Mardis concurred, noting that Nationwide Children's and many other pediatric hospitals are actively working on various immunotherapeutic approaches besides checkpoint blockade, such as CAR T cells. "In the engineered cell therapy space, there's a lot of activity at our hospital around engineering natural killer cells, and also to have this unique and highly targeted impact towards cancer cells only," she said. "I think these have a lot more appeal in the pediatric setting because they're highly selective."

But even beyond CAR T, she added, some researchers are even looking at using oncolytic viruses such as herpes and other modified viruses that have a tropism towards human cells, and can be used to display unique targets on the surface of the cell that would attract the immune system and signal for cell destruction.

"Those [approaches] are nascent, but I think if you look broadly at immunotherapy, we do have some very interesting possibilities that are emerging from basic research," Mardis added.

Importantly, Kung noted, none of these therapies will be a silver bullet to cure all pediatric cancers.

"I think that all these approaches will have application to certain subsets of cancer," he said. "None of those techniques will be a panacea in terms of being able to address all the targets that drive pediatric cancers. This is the lesson that we've learned the last 50 years of cancer research — it's only by finding specific approaches that are amenable to specific subsets of cancers and then combining those with existing therapies that we actually make progress."

Should all kids be sequenced?

Given the impact NGS testing has had on advancing understanding of pediatric cancer biology and treatment approaches, Kung is convinced that every child with cancer should "absolutely" be sequenced with NGS tools.

"I would go even further to say that that panel testing such as MSK-IMPACT should be the starting point in terms of assessing kids with cancer, but I think that more comprehensive approaches are actually necessary for children with cancer," he said, adding that many in the field are pushing ahead with more comprehensive approaches, such as whole-genome sequencing and RNA sequencing to try to capture structural variants, translocations, and copy number changes that seem to be very common drivers of pediatric cancers.

Mardis seemingly favors a more targeted approach to the application of NGS in pediatric cancers.

"I would say that the kids who really should get sequenced right now are kids with rare cancers where they just haven't been characterized by large-scale studies, because you never know what you're going to find," she said. "In some cases, we've found some targetable fusion drivers in kids with very rare types of sarcoma where they are amenable to a targeted therapy just based on that fusion, but either the tumor type hasn't been studied enough to identify that fusion, or it has and this is just a novel result."

Another setting in which NGS testing would be beneficial, she added, is in children with relapsed or refractory disease — for example, kids who get the standard of care for leukemia but never achieve a complete remission, so they can't go through subsequent therapy such as a bone marrow transplant.

"We really need to ultimately tackle this problem of secondary cancers in kids who go through extensive chemotherapy because they also have significantly elevated health-related sequelae throughout the rest of their lives that are a result of that therapy," she noted. "They also have an elevated risk for secondary cancers. So, if we could get to the point where we're actually looking more at targeted therapies, rather than broad-spectrum cytotoxic chemotherapies, I think this would be transformational in terms of kids who have cancer at a very young age actually going on to lead normal and healthy lives."

Whatever the correct approach is, Kung added, sequencing alone isn't the solution.

"Just sequencing the genomes of a bunch of kids is not precision medicine," he said. "Precision medicine is only fulfilled at the point that we are able to not only figure out what went wrong but also match that to therapeutic options."

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