Taking on the Challenge to Develop New Therapies for Pediatric Solid Tumors


Both pediatric brain cancers and sarcomas have an extremely dismal outcome in the relapse setting, according to Catherine Bollard, MD. A new Cancer Grand Challenge aims to address the issue with the development of new therapies.

Catherine Bollard, MD

Catherine Bollard, MD

Limited therapies are available to treat pediatric solid tumors, and therapies are even scarcer for rare tumors, according to Catherine Bollard, MD. Over the next 5 years, developing treatments for these cancers will become an important research focus, thanks to a $25 million grant awarded through Cancer Grand Challenges, a program funded by the National Cancer Institute and Cancer Research UK.

“The Cancer Grand Challenges program is something that comes out every couple of years, and they come up with a list of challenges that need to be addressed in the field. Normally, there’s about 20 Cancer Grand Challenges, and groups come together to [develop] the list. Although it’s a different list every [few] years, there are some common themes,” Bollard told Targeted OncologyTM (TO) in an interview. Bollard is director of the Center for Cancer and Immunology Research and director of the Program for Cell Enhancement and Technologies for Immunotherapy at Children’s National in Washington, DC.

Lead inestigator, Bollard, and the team of researchers who applied for a grant (the NexTGen team) will attempt to tackle the development of new therapies to treat pediatric brain tumors and sarcomas.1

“We picked 2 big buckets of solid tumors where we think there is the most need, and those are pediatric brain cancers and pediatric sarcomas,” Bollard said. “Both of those disease buckets have an extremely dismal outcome in the relapse setting.”

Treating Pediatric Brain Cancers

Jeffrey Dome, MD, PhD

Jeffrey Dome, MD, PhD

Research shows that many pediatric brain tumors can be rare and heterogeneous, making the development of precision medicine for these tumors a difficult task.2 Recent trials of immunotherapy for pediatric brain cancers have been early-phase studies investigating the safety and tolerability of new drugs but are too small and early to be practice changing.3 In terms of targeted therapies, the only success has been for the treatment of medulloblastoma, according to Jeffrey Dome, MD, PhD.

“Brain tumors collectively are the second most common pediatric cancer, so it’s a big bucket of the cancers that we treat,” Dome, senior vice president of the Center for Cancer and Blood Disorders and division chief of oncology at Children’s National said in an interview with TO. “There are different types of brain tumors, and we’ve had mixed success with treatments. One of the more successfully treated brain tumors is medulloblastoma, [for which] overall survival rates are over 80%, although there are high-risk groups,” Dome said.


The standard-of-care treatment for medulloblastoma is surgical resection, cytotoxic chemotherapy, and radiation therapy. The 5-year overall survival (OS) rate for patients with average-risk disease is 80% to 85%. Patients with high-risk disease have a 5-year OS rate of 60% to 70%. Still, treatment failure and relapse occur in up to one-third of patients, with only “approximately 10% of patients surviving beyond 5 years post relapse.”4

According to a 2021 analysis of 329 child and infant patients with medulloblastoma treated in the phase 3 SJMB03 trial (NCT00085202) and the phase 2 SJYC07 trial (NCT00602667), 22% of patients from the SJMB03 trial relapsed as did 66% of patients from theSJYC07 cohort. These data emphasize the need for new therapies in the recurrent setting. Median postrelapse survival was only 1.14 years (IQR, 0.30-2.36) for patients in the SJMB03 trial and 2.12 years (IQR, 0.39-not available) for patients in the SJYC07 trial.4

Molecular subtypes were a prominent factor in both studies. At baseline, 43% of patients in the SJMB03 trial had a mutation in the sonic hedgehog (SHH) pathway and 15% had Wnt tumors. In the SJYC07 trial, 35% of patients had SHH mutations and 9% had Wnt tumors.4

Oncologists who treat pediatric patients with medulloblastoma encounter alterations in the GLI1, GLI2, SUFU, and PTCH1 genes, which all activate the SHH pathway. Even though TP53 mutations and MYC amplifications are also seen in these patients, alterations in the SHH pathway are more reliable targets, so multiple hedgehog pathway inhibitors are being investigated as potential treatment options.5

Vismodegib (Erivedge) and sonidegib (Odomzo) are both smoothened inhibitors of the SHH pathway that are being studied in pediatric patients with medulloblastoma. Historic results from adult and pediatric patients treated with vismodegib in the phase 2 PBTC-025B (NCT00939484) study and the phase 2 PBTC-032 study (NCT01239316) showed that the agent was active in recurrent or refractory SHH-mutated medulloblastoma in adults. Accrual of pediatric patients was low, which limited the findings. One pediatric patient in the PBTC-032 study had a partial response and 2 pediatric patients, in the PBTC-032 study had transient responses, which suggested that vismodegib may be active in the pediatric medulloblastoma population, according to investigators.6

In a phase 1 trial that investigated sonidegib for relapsed medulloblastoma, 30 pediatric patients were included, and the treatment was well tolerated. Preliminary activity was also shown with sonidegib in the study. The overall response rate in the pediatric population was 18.8% (95% CI, 4.0%-45.7%), which include 2 complete responses. Eleven pediatric patients also achieved stable disease.7

Efforts to pinpoint relevant targets for pediatric medulloblastoma are underway in ongoing studies (TABLE).

precision medicine for medulloblastoma, studies in Medulloblastoma, targeted therapy for Medulloblastoma

TABLE. Precision Medicine Studies for Medulloblastoma

Gliomas and craniopharyngiomas

Knowledge around the molecular biology of pediatric brain cancers such as gliomas has grown in recent years. The oncology field now has information about which biomarkers are important when developing new targeted therapies.

For low-grade gliomas, the types of therapies that target alterations in the PI3K/AKT/mTOR signaling pathway have demonstrated efficacy and safety. Selumetinib (Koselugo), a MEK inhibitor, was investigated in a phase 2 study (NCT01089101). In the trial, 25 patients with recurrent optic pathway and hypothalamic low-grade gliomas without NF1 activation were treated with selumetinib 25 mg/m2. The treatment was tolerable and elicited durable responses.8

Six out of 25 patients treated with selumetinib achieved a partial response, 14 patients had stable disease, and 5 had progressive disease. At 2 years, the estimated progression-free survival (PFS) rate in the overall population was 9.3% and the estimated OS rate was 100%. The most common toxicities observed in the study were grade 1/2 creatine phosphokinase elevation, anemia, diarrhea, headache, nausea/emesis, fatigue, aspartate and alanine aminotransferase increases, hypoalbuminemia, and rash.8

The mTOR inhibitor everolimus (Afinitor) has also shown promise for the treatment of low-grade gliomas. In the phase 2 POETIC study (NCT01734512), everolimus 5 mg/m2 once daily was well tolerated and found to be a good alternative treatment for patients with multiple recurrent, radiographically progressive pediatric low-grade gliomas. At a median follow-up of 1.8 years (range, 0.2-6.7), the estimated 5-year PFS rate was 11% and the estimated 5-year OS rate was 6%.9

Out of 17 patients in the POETIC study, 15 had a grade 3 adverse event and 5 experienced a grade 4 toxicity. The grade 3 toxicities related to everolimus were mucositis and neutropenia.9

Kenneth Jay Cohen, MD, MBA

Kenneth Jay Cohen, MD, MBA

Although patients with low-grade glioma have a favorable prognosis and a 10-year survival rate of between 85% and 96%, oncologists have lingering questions about how to sufficiently penetrate the blood-brain barrier, what the optimal doses of available therapies are, and how long treatment should be administered.9 Additionally, none of the recent studies in the low-grade glioma space have the potential to be practice changing, but according to Kenneth Jay Cohen, MD, MBA, these trials could be on the horizon.

“Revolutionary trials are often trials that dramatically improve the outcome for patients or redefine the standard of care for a particular condition. I’m not sure there are recent examples of the former. There are trials that are in the process of being published that will likely change the standard of care for the treatment of children with low-grade gliomas with specific molecular features,” Cohen said in an interview with TO. Cohen is the clinical director of pediatric oncology and a professor of oncology at Johns Hopkins Medicine in Baltimore, Maryland.

Moreover, unanswered questions remain in low-grade glioma about mechanisms of resistance to available therapies and what combination therapies may be helpful for overcoming resistance.9 And there is even more work to be done with high-grade gliomas, according to Dome.

“There’s a big group of brain tumors [for which] treatment is not successful, and we really haven’t made any progress in the past few decades. One of those tumor types is called diffuse intrinsic pontine glioma, and another one is these high-grade gliomas like glioblastoma multiforme,” Dome explained. “For those types of tumors, the treatments haven’t been successful. The mainstays of therapy are chemotherapy, radiation therapy, and surgery, and that hasn’t changed over the decades.”

With some understanding that high-grade gliomas can express MET fusions harbor activating PI3K and H3K27M mutations, researchers are working to develop agents to treat such tumors. For example, the MET inhibitor PLB1001 is being investigated for the treatment of PTPRZ1-MET fusion gene–positive recurrent high-grade gliomas (NCT02978261), including diffuse intrinsic pontine glioma and glioblastoma. The PI3K/mTOR inhibitor paxalisib (GDC-0084) is also being evaluated in a first-in-human study (NCT03696355).10

“New therapies are urgently needed [to take] advantage of the growing understanding of the molecular underpinnings of most brain tumors. One such target, H3K27M-altered tumors, if able to be successfully targeted would have a dramatic impact on the outcome for children with one of the most aggressive brain tumor subtypes,” Cohen said.

A phase 2 study is evaluating the novel agent ONC201 (NCT03416530) in H3K27M-altered glioblastoma.10

CraniopharyngiomasThe 10-year survival rate for pediatric craniopharyngiomas ranges from 64% to 92%, but for patients with tumor progression or those with recurrent disease, treatment options are limited. To date, research has identified BRAF/MEK inhibition and IL-6 receptor inhibition as potential avenues to follow when developing new therapies.10

There are 2 ongoing studies in this area. A phase 2 study (NCT03224767) is evaluating cobimetinib (Cotellic) for the treatment of ˆ V600E–mutated craniopharyngiomas, and a phase 1 study (NCT03970226) is evaluating tocilizumab (Actemra) for the treatment of children with newly diagnosed or recurrent/progressive adamantinomatous craniopharyngioma.

Treating Sarcoma

“This is another area where we have not had much success over the past few decades,” Dome said about treating sarcoma. “There has been some success in treating localized sarcomas if they have not had a chance to metastasize or spread to other parts of the body. But the treatment of metastatic sarcomas has been limited. The survival rate has been stuck at about 20%. For decades, there have been several clinical trials that have introduced new chemotherapy drugs and intensified chemotherapy for these patients, but none of them have been successful.”

Treatment of sarcomas, Dome noted, is dependent upon the type of sarcoma as well as the subtype.


Little clinical data support the use of targeted therapies for pediatric osteosarcoma. Treatment is largely reliant on neoadjuvant or adjuvant chemotherapy and surgery.11

Data show that combining surgery with chemotherapy can achieve a long-term survival rate between 10% and 15%. But, as with brain tumors, up to 40% of patients experience recurrence. The prognosis for children with recurrent osteosarcoma is dismal.11

“This type of sarcoma has survival rates of 20% or less, and that is despite the delivery of very intensive chemotherapy. We have to think outside the box, and we have to come up with different therapies,” Dome said.

Treatment options for osteosarcoma have not changed in the past 30 years.11 Looking ahead in research, experts will better understand genetic alterations found in osteosarcoma and the biological and clinical behavior of the disease to allow new therapies to be developed.11 Based on preclinical research, IL-15 agents may be able to induce antitumor immune responses in patients with osteosarcoma.12,13

Soft Tissue Sarcomas

More advances have been made in soft tissue sarcomas than in osteosarcomas in recent years. Aside from chemotherapy—namely doxorubicin, with a response rate of 20% to 25%—immune checkpoint inhibitors (ICIs) have been successful for the treatment of soft tissue sarcomas.14 Most recently, one study of ICI therapy demonstrated a near doubling in median OS as well as better response rates compared with previous trials.15

In a single-arm, phase 1b/2 trial (NCT03277924), an ICI nivolumab (Opdivo) was used in combination with another ICI sunitinib (Sutent) for the treatment of pediatric and adult patients with advanced soft tissue sarcoma. Nivolumab was dosed at 3 mg/kg on day 15, followed by every 2 weeks, and sunitinib was dosed at 37.5 mg daily. At a median follow-up of 17 months (range, 4-26), the 6-month PFS rate was 48% (95% CI, 41%-55%) and the estimated median OS was 24 months with nivolumab and sunitinib. The most common grade 3/4 adverse events experienced by patients receiving the nivolumab-sunitinib combination were transaminitis (17.3%) and neutropenia (11.5%).

Other ICI combinations have been investigated for pediatric soft tissue sarcomas, but much of the research has been for adult patients. In the adult population, an ongoing challenge is overcoming ICI resistance.

“One strategy that is very interesting is to harness the immune system to fight these types of tumors,” Dome said. “The tumors express different antigens on the cells that could be targeted by T cells, and then perhaps the combination of chemotherapy and immunotherapy may enable us to move the needle and improve outcomes for these patients.

“Another is more targeted therapies using drugs not matching the immune system. For example, some of the most effective targeted therapies have been against a group of enzymes called tyrosine kinases. These have been most successful for leukemias. There are specific mutations that lead to an activation of this enzyme, and the enzyme is amenable to being targeted by drugs because they can inactivate enzymes.

“With a lot of the sarcomas, there’s no enzyme that’s activated,” Dome added. “The sarcoma is caused by chromosome translocations that create aberrant proteins that bind to DNA and cause a barren expression of genes, and that’s what drives the cancer. Up until now, there haven’t been great drugs that target those types of mutations, so several research teams are looking at new ways to target that type of mutation, not an enzyme activation, but dysregulation of a DNA transcription factor.”

Finding Targets and Developing Therapies

The NexTGen team has identified immunotherapy as a potential path forward for both pediatric brain cancers and sarcomas. Moreover, because limited therapies are available for children, the team will be taking notes for successes made in the adult populations.

“The big area of interest is immunotherapy and most critically T-cell therapies. The reason for that is in adult solid tumors, there’s certainly been great successes in the field of checkpoint inhibitors, which are a type of immune-based therapy and targeted small molecule therapies,” Bollard said.

B-cell maturation antigen chimeric antigen receptor T-cell therapies such as ciltacabtagene autoleucel (Carvykti), anti–PD-1/PD-L1 agents, and anti–CTLA-4 therapies are available for adults with solid tumors.

“Most types of therapy [has been] successful in pediatric solid tumors,” Bollard said. “The reason for that is because pediatric solid tumors are so biologically different and the number of mutations that pediatric solid tumors express is substantially different than adult solid tumors. As a result, there are not as many targets for small molecule therapies.”

Before the team can develop new immunotherapies for pediatric solid tumors, they first must research these diseases to have a better understanding of the molecular biology. Bollard told TO that this will be another important focus over the next 5 years.

“As part of the Cancer Grand Challenges, we are looking to identify new targets, and we’re also looking to better define the tumor microenvironment in these pediatric cancers,” Bollard explained. “It’s possible that if we’re able to better define the tumor microenvironment that there might be agents that are already in existence that we could use to kill off the immunosuppressive microenvironment. But we won’t know until we have better defined what’s going on in these cancers.

“There’s rarely been work done in this area because compared with the adult cancers, [fewer children] have these diseases,” Bollard continued. “As a result, there hasn’t been the same degree of funding poured into pediatric solid tumors as there has been for adult solid tumors. That’s why we see this Cancer Grand Challenges opportunity as progressive. It is going to make a meaningful impact on the outcomes for these children.”


1. Team science on a global scale. Cancer Grand Challenges website. Accessed Janaury 30, 2023. https://cancergrandchallenges.org/teams

2. Lauko A, Lo A, Ahluwalia MS, et al. Cancer cell heterogeneity & plasticity in glioblastoma and brain tumors. Semin Cancer Biol. 2022;82:162-175. doi:10.1016/j.semcancer.2021.02.014

3. Shaklita C, Hanzlik E, Kaplan S, et al. Immunotherapy for the treatment of pediatric brain tumors: a narrative review. Transl Pediatr. 2022;11(12):2040-2056. doi:10.21037/tp-22-86

4. Kumar R, Smith KS, Deng M, et al. Clinical Outcomes and patient-matched molecular composition of relapsed medulloblastoma. J Clin Oncol. 2021;39(7):807-821. doi:10.1200/JCO.20.01359

5. Sursal T, Ronecker JS, Dicpinigaitis AJ, et al. Molecular stratification of medulloblastoma: Clinical outcomes and therapeutic interventions. Anticancer Res. 2022;42(5):2225-2239. doi:10.21873/anticanres.15703

6. Robinson GW, Orr BA, Wu G, et al. Vismodegib exerts targeted efficacy against recurrent sonic hedgehog–subgroup medulloblastoma: results from phase II pediatric brain tumor consortium studies PBTC-025B and PBTC-032. J Clin Oncol. 2015;33(24):2646-2654. doi:10.1200/JCO.2014.60.1591

7. Kieran MW, Chisholm J, Casanova M, et al. Phase I study of oral sonidegib (LDE225) in pediatric brain and solid tumors and a phase II study in children and adults with relapsed medulloblastoma. Neuro Oncol. 2017;19(11);1542-1552. doi:10.1093/neuonc/nox109

8. Fangusaro J, Onar-Thomas A, Poussaint TY, et al. A phase II trial of selumetinib in children with recurrent optic pathway and hypothalamic low-grade glioma without NF1: a Pediatric Brain Tumor Consortium study. Neuro Oncol. 2021;23(10):1777-1788. doi:10.1093/neuonc/noab047

9. Wright KP, Yao X, London WB, et al. A POETIC Phase II study of continuous oral everolimus in recurrent, radiographically progressive pediatric low-grade glioma. Pediatr Blood Cancer. 2021;68(2):e28787. doi:10.1002/pbc.28787

10. Mueller T, Stucklin AS, Postlmayr A, et al. Advances in targeted therapies for pediatric brain tumors. Children (Basel). 2022;27;10(1):62. doi:10.3390/children1001006

11. Tarone L, Mareschi K, Tirtei, et al. Improving osteosarcoma treatment: comparative oncology in action. Life (Basel). 2022;14;12(12):2099. doi:10.3390/life12122099

12. Robinson TO, Schluns KS. The potential and promise of IL-15 in immuno-oncogenic therapies. Immunol Lett. 2017;190:159-168. doi:10.1016/j.imlet.2017.08.010

13. Waldmann, TA, Dubois S, Miljkovic MD, et al. IL-15 in the combination immunotherapy of cancer. Front Immunol. 2020;11:868. doi:10.3389/fimmu.2020.00868

14. Eulo V and Van Tine BA. Immune checkpoint inhibitor resistance in soft tissue sarcoma. Cancer Drug Resist. 2022;5(2):328-338. doi:10.20517/cdr.2021.127

15. Martin-Broto M, Hindi N, Grignani G, et al. Nivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-arm, phase Ib/II trial. J Immunother Cancer. 2020;8(2):e001561. doi:10.1136/jitc-2020-001561

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