Ushering in the next generation of precision trials for pediatric cancer

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Science  15 Mar 2019:
Vol. 363, Issue 6432, pp. 1175-1181
DOI: 10.1126/science.aaw4153


Cancer treatment decisions are increasingly based on the genomic profile of the patient’s tumor, a strategy called “precision oncology.” Over the past few years, a growing number of clinical trials and case reports have provided evidence that precision oncology is an effective approach for at least some children with cancer. Here, we review key factors influencing pediatric drug development in the era of precision oncology. We describe an emerging regulatory framework that is accelerating the pace of clinical trials in children as well as design challenges that are specific to trials that involve young cancer patients. Last, we discuss new drug development approaches for pediatric cancers whose growth relies on proteins that are difficult to target therapeutically, such as transcription factors.

The landscape of genomic alterations in cancers that arise in children, adolescents, and young adults is slowly becoming clearer as a result of dedicated pediatric cancer genome-sequencing projects conducted over the past decade. Of particular note are two recent studies that produced a comprehensive picture of the genomic features that characterize many of the more common pediatric cancers (1, 2). Two major themes have emerged. First, pediatric cancers harbor certain genomic alterations that are rarely seen in adult cancers, and for many of these alterations, molecularly targeted therapies do not yet exist. Second, pediatric cancers share some genomic alterations and mutational gene signatures (definitions of this and other terms are provided in Box 1) with adult cancers, and for a subset of these alterations, molecularly targeted therapies already exist. Importantly, for only a small proportion (5 to 10%) of these pediatric cancers is there clinical trial evidence showing that the genomic alteration predicts the response to the targeted drug (3, 4). Thus, there is an urgent need for precision clinical trials in pediatric cancers.

Box 1

Glossary of terms.

  • 3+3 design: A commonly used rule-based design for phase 1 clinical trials in which patients are enrolled in cohorts of three patients, and decisions to increase or decrease the dose level for the next three participants are based on toxicities observed in those three patients.

  • Basket trial: A precision oncology trial design in which patients with many different cancer types are enrolled, the tumor is tested for a set of biomarkers of interest, and then patients are assigned to one of several clinical trial subprotocols based on the presence of a biomarker corresponding to a particular molecularly targeted therapy.

  • Bayesian model–based trial designs: A broad class of trial designs that use data known before the trial as well as data obtained during the conduct of the trial to adapt trial parameters as more information becomes available

  • BCR-ABL–like B cell lymphoblastic leukemia: A subtype of ALL that shares a gene expression signature of BCR-ABL–positive leukemia but does not express the BCR-ABL fusion. These leukemias will often express other kinase fusions.

  • Clinical laboratory: A laboratory with at least one of several certifications such as CAP (College of American Pathologists) or CLIA (Clinical Laboratory Improvement Amendment) that allow them to perform testing to be used for patient care decisions.

  • Continual reassessment method: One example of a Bayesian model–based trial design in which an initial mathematical model of the relationship between drug dose and probability of unacceptable toxicity is continually updated as new information becomes available to assign subsequent patients to a dose anticipated to have an unacceptable toxicity rate below a set rate.

  • First-in-child trial: The first clinical trial of a specific agent to include a pediatric population, traditionally considered patients <18 years of age.

  • First-in-human trial: The first clinical trial to test a specific agent in people.

  • Frontline trial: A clinical trial being conducted in a newly diagnosed patient population, in contradistinction to trials conducted in a relapsed patient population.

  • Mutational gene signature: Pattern of somatic mutations that can sometimes be linked to an underlying causative process, such as aging or carcinogens.

  • Novel-plus-novel combinations: Combinations of two novel targeted cancer agents, in contrast to either monotherapy trials or trials of a single novel agent plus conventional cytotoxic chemotherapy.

  • Pediatric Research Equity Act: U.S. legislation that authorizes the FDA to mandate pediatric drug development of drugs being developed for adults, if specific criteria are met.

  • PROTACs (proteolysis targeting chimeras): Heterobifunctional molecules that contain a chemical moiety that binds to the target protein of interest and is linked to a second moiety that binds to an E3 ligase, such as CRBN or VHL.

  • Rolling 6 design: A variation of the 3+3 design in which up to six participants may be enrolled to a dosing cohort before enrollment pauses to assess toxicity.

  • Safety run-in: An initial component of a phase 2 or phase 3 trial in which a small group of patients are treated with a previously untested regimen to evaluate toxicity before opening the trial to a larger group of participants.

  • Umbrella trial: A precision oncology trial design in which patients with a specific cancer type are enrolled, tumor is tested for a set of biomarkers of interest, and then patients are assigned to one of several clinical trial subprotocols based on the presence of a biomarker corresponding to a particular molecularly targeted therapy.

Several recent reviews provide a detailed discussion of ongoing and recently completed precision trials in pediatric cancers (57). These include “basket trials,” “umbrella trials,” and dedicated phase 1 and phase 2 trials of specific molecularly targeted drugs assessed only in those cancers harboring predefined genomic events (Box 1). The results of these initial trials support the idea that the application of precision oncology to pediatric cancer will, at least in some cases, be successful. For example, a pediatric phase 1 trial of larotrectinib, a selective TRK inhibitor, in patients age 1 month to 21 years whose tumors harbor a NTRK fusion gene had a 93% objective response rate; these results contributed to the recent U.S. Food and Drug Administration (FDA) approval of this drug for NTRK fusion–positive tumors regardless of tumor type and patient age (8, 9). Likewise, the anaplastic lymphoma kinase (ALK) inhibitor crizotinib has shown substantial activity in ALK fusion-positive inflammatory myofibroblastic tumors and anaplastic large cell lymphoma (10). Another example is the confirmed objective responses observed in recurrent and refractory pediatric cancers that harbor mutations in SMARCB1 (a gene encoding a chromatin remodeling protein) when treated with an inhibitor of EZH2, a key enzyme in the polycomb repressive complex 2 (11). The reported 38% objective response rate to the BRAF inhibitor dabrafenib in low-grade gliomas with the BRAF V600E mutation (12) provides additional evidence that relapsed and refractory pediatric cancers can respond to single-agent molecularly targeted therapies selected on the basis of a biomarker. Last, a recent report of dramatic responses to immune checkpoint inhibition in two children with an inherited deficiency in DNA mismatch repair demonstrates that the scope of success in precision pediatric oncology may extend beyond small-molecule inhibitors of protein kinases and chromatin modifiers (13).

Here, we review how lessons learned from the current approach to pediatric drug development and changes in the regulatory framework for pediatric trials are shaping pediatric cancer drug development in the era of precision oncology. We discuss opportunities and challenges that investigators will address in the next generation of precision trials in pediatric oncology. Last, we review our maturing understanding of genetic dependencies that maintain the malignant cell state in pediatric cancers. Although pediatric cancer can refer to cancer occurring in patients below 18 years of age and pediatric trials to be those with age of eligibility of age 18 years or younger, throughout this Review we use the term “pediatric cancer” broadly to mean cancers occurring more commonly in patients between birth and young adulthood as compared with their frequency in adult patients. These cancers are often managed in the pediatric oncology clinic, and clinical trials in these diseases need to take into account the social and biological aspects of development.

Accelerating early-phase trials in pediatric oncology

Access to targeted agents and appropriate dosing regimens relevant to the population of interest are critical components of a precision oncology strategy. In the context of pediatric oncology, dedicated pediatric phase 1 dose escalation trials have been the traditional starting point for clinical development of new anticancer drugs. These first-in-child trials have often lagged behind first-in-human trials by many years and, once initiated, have often used conventional designs (Box 1). For example, a standard approach has been to enroll unselected patients, begin dose escalation below the adult equivalent dose, and proceed through dose escalation in cohorts of three to six patients at a time [so called “3+3” or “rolling 6” designs (Box 1)] until a pediatric maximum tolerated dose (MTD) is established (14).

In recent years, newer approaches to trial design have been adopted to more efficiently establish a pediatric dose for further study. The most fundamental shift has been the recognition that many new oncology agents will not have a true MTD when tested in adults. In contrast to conventional cytotoxic chemotherapy agents, these targeted therapies are dosed at a recommended phase 2 dose (RP2D), which is often selected on the basis of considerations other than toxicity, such as pharmacokinetic, pharmacodynamic, or anticancer activity endpoints. For this category of agents, a pediatric dose escalation trial that starts below the adult RP2D and escalates based on a toxicity endpoint may require more patients as compared with a trial designed to confirm that the equivalent of the adult RP2D is appropriate to move forward for further pediatric testing (15). This approach has been particularly useful for pediatric testing of therapeutic monoclonal antibodies (16), although other classes of therapeutics without a clear toxicity ceiling can also be assessed in this manner. In parallel, Bayesian model–based trial designs appear to be increasing in frequency in pediatric cancer early-phase trials (Box 1). These designs include approaches, such as the continual reassessment method (CRM), that have been shown to more efficiently establish a recommended phase 2 dose in adult oncology trials (17), although data on their performance in pediatric oncology trials are lacking (Box 1).

Although these newer approaches to early-phase trial design more efficiently establish a pediatric dose, they do little to advance our understanding of which patients are most likely to benefit from a new therapy. To this end, additional design features are used to facilitate the establishment of an earlier signal of activity by selecting patient populations for a trial based on hypotheses generated from preclinical or adult clinical data. Given the overall rarity of pediatric cancers and the pace at which some of these diseases may progress, trial designs need to be able to enroll patients with specific molecular features or biomarkers of greatest interest without delay when such patients present for trial participation. Trial designs that allow patients who meet predefined molecular characteristics to enroll continuously may allow the trial population to be enriched with patients hypothesized to be most likely to benefit. This approach has the added benefit of preventing children with recurrent cancer from being placed on a lengthy waitlist for clinical trial slots, which can result in the child not being well enough to participate once their slot becomes available—a disservice both to the patient and to the trial. For example, the Dana-Farber Cancer Institute is leading a first-in-child study of the dual MDM2/MDMX inhibitor ALRN-6924 ( identifier NCT03654716). In this trial, unselected patients enroll to the primary dose-finding cohort. Patients whose tumors have defined molecular features (such as amplification of MDM2, a gene encoding an E3 ubiquitin-protein ligase that negatively regulates p53) enroll to the primary dose-finding cohort if a slot is available. If a slot is not available, such patients may enroll one dose level below the current dose level. Once a dose is established for further pediatric testing, this same trial includes an expansion cohort for these patients with defined molecular features. Other trials move seamlessly into formal phase 2 testing after dose determination in the phase 1 portion of the same trial. These phase 1/2 designs can reduce the time and expense associated with protocol development and may potentially use efficacy data from patients treated on the phase 1 portion at the defined pediatric dose to reduce the number of new patients needed to enroll during the phase 2 portion.

In parallel with these novel approaches to trial designs, recent efforts have facilitated or are anticipated to facilitate earlier pediatric evaluation of innovative agents. For example, the AcSé Programme in France provided children with off-label access to novel molecularly targeted therapies in the context of a prospective trial rather than in a series of single-patient compassionate access protocols. (18) The collective experience from these patients will be gathered to inform the field.

In both the United States and Europe, it has become increasingly clear that regulations designed to spur pediatric drug development more broadly have not had this desired effect in the context of pediatric oncology. In the United States, no pediatric oncology trials were conducted under the original Pediatric Research Equity Act (PREA) (Box 1). This outcome was a result of regulations that allowed waivers to pediatric development to be issued if the agent was being developed in adult cancer indications not relevant to children. A similar practice has also been allowed in Europe, with 147 such waivers issued over the course of 3 years in one review of the European experience (19). In response to this practice, the Research to Accelerate Cures and Equity for Children Act (RACE Act) was included as a provision in the 2017 U.S. FDA Reauthorization Act. The RACE Act gives the FDA authority to require pediatric evaluation of molecularly targeted agents with a mechanism of action relevant to pediatric cancers, even if the primary indication is exclusively seen in adults. Industry partners will need to adapt to this requirement, and there is already evidence that an age-agnostic drug development strategy can be successful. For example, the first-in-child trial of the selective TRK inhibitor larotrectinib in children with NTRK fusion–positive cancers occurred nearly in parallel with development in adults (8, 9). With the adoption of the RACE Act, the larotrectinib drug development paradigm provides an important model for future targeted therapies relevant to both adults and children. Last, pediatric precision oncology basket trials, such as the National Cancer Institute–Children’s Oncology Group (COG) Pediatric MATCH (NCT03155620) and the AcSe-ESMART study (NCT02813135), have in some cases completely supplanted formal pediatric phase 1 testing of agents and have instead incorporated molecularly targeted agents by using a dose analogous to the adult dose, adjusted for patient size.

Additional efforts have focused on adolescents with cancer (age 12 to 17 years) and their access to novel agents on clinical trials. Three recent position statements have reached the same conclusion that trial eligibility should start at age 12 years for agents or diseases relevant to an adolescent population (2022). The FDA has issued a draft guidance in line with these recommendations (23). The extent to which industry partners adopt this approach needs to be evaluated. In addition, academic partners will have to develop local strategies for implementing trials that simultaneously enroll patients being cared for in the pediatric and medical oncology clinics, given that clinical trials operations may not be integrated across these typically separate clinical care environments.

Incorporating combination therapy into precision trials

Treatment of cancer with single agents is often not curative; thus, a key priority in the next generation of precision trials is assessment of drug combinations at diagnosis or at the time of recurrence. Such trials might, for example, combine a molecularly targeted therapy with conventional cytotoxic chemotherapy or combine a molecularly targeted therapy with immunotherapy. The superior survival benefit provided by combination therapies in the era of precision oncology is supported by emerging evidence from trials in adult cancers. In adults with FLT3 internal tandem duplication (ITD)–positive acute myeloid leukemia (AML), patients randomized to receive the FLT3 inhibitor midostaurin in addition to standard therapy had an improved event-free survival (EFS) and overall survival (OS) compared with those who received standard therapy alone (24). In early-phase trials, high objective response rates and responses of long duration were observed in adults with metastatic BRAF mutant melanoma who received immune checkpoint inhibitors plus a BRAF inhibitor alone or immune checkpoint inhibitors plus BRAF and mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors (25, 26). Randomized trials that compare these combination approaches to immune checkpoint inhibitor therapy alone or to BRAF and MEK inhibitor therapy alone are ongoing (NCT03273153 and NCT02967692). Last, the combination of two molecularly targeted therapies in the same pathway may delay the development of resistance and reduce side effects, as is the case with several BRAF-plus-MEK inhibitor combination therapies that have been approved by the FDA for treatment of advanced BRAF V600 mutant melanoma (27, 28).

An illustrative example of an early-phase pediatric trial that uses a combination of a targeted therapy and chemotherapy is the first-in-child trial of the BCL2 inhibitor venetoclax, a drug that promotes cancer cell death (NCT03236857) (29). In this trial design, patients with recurrent disease begin treatment with venetoclax monotherapy. Patients with clinical benefit continue on monotherapy, whereas those who do not respond are eligible to continue on trial with a combination of venetoclax plus standard-of-care chemotherapy. This approach requires a smaller number of patients to provide safety and efficacy data on both monotherapy and combination therapy to inform future studies. However, the chemotherapy sensitivity of many pediatric tumors can pose challenges in the interpretation of trials evaluating a novel molecularly targeted agent plus chemotherapy. Unless the observed beneficial effect of the combination is so great that it could not have been explained with chemotherapy alone (the so-called “home run”), subsequent trials may still be needed to establish that the novel agent improves efficacy over that seen with chemotherapy alone. Further, compared with monotherapy trials of molecularly targeted agents, these combination trials cannot assess as directly the precision oncology hypothesis that selecting drug(s) on the basis of a molecular alteration is an efficacious strategy; this is because the nontargeted cytotoxic chemotherapy is expected to contribute to observed efficacy.

Some of these challenges are now being addressed in the context of frontline combination trials designed to study the role of molecularly targeted therapies in patients with newly diagnosed pediatric cancer (Box 1). For most pediatric malignancies, standard-of-care chemotherapy plays a key role in treatment at the time of initial diagnosis. Consequently, precision trials that aim to further improve outcomes for newly diagnosed patients, measured with EFS and OS, must combine molecularly targeted therapies and chemotherapy in patients whose cancers harbor specific predefined biomarkers. In the COG trial ANBL1531 (NCT03126916) for high-risk neuroblastoma, tumors are tested for mutation or amplification of ALK (a gene encoding a tyrosine kinase that drives the growth of a subset of these tumors), and patients with ALK aberrant disease are assigned to receive standard multimodality therapy plus the ALK inhibitor crizotinib. COG trial AALL1131 (NCT02883049) uses a complex testing strategy to identify patients with BCR-ABL–like B lymphoblastic leukemia and assign patients with these alterations to a protocol-specified treatment with chemotherapy plus dasatinib (Box 1). Patients with BCR-ABL–like B lymphoblastic leukemia enrolled on AALL1131 found to have JAK1/2 mutations or other genomic events such as CRLF2 fusions known to activate the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway are eligible for a companion COG phase 2 trial AALL1521 (NCT02723994) in which all patients receive standard chemotherapy plus the JAK/STAT inhibitor ruxolitinib. One other such frontline combination trial in pediatric oncology is the COG trial AAML1031 (NCT01371981), which evaluates the addition of sorafenib to multiagent chemotherapy in patients less than 30 years old with FLT3-ITD AML.

The statistical design of frontline combination trials in pediatric cancers must take into account small patient numbers that effectively prohibit the conduct of randomized controlled trials. In the aformentioned ANBL1531 trial, the outcome of patients with ALK aberrant tumors treated with crizotinib will be compared with contemporaneous patients enrolled to the trial with ALK wild-type tumors. This design relies on prior data demonstrating a negative prognostic effect of ALK aberrations in neuroblastoma (30); therefore, if a substantial improvement in outcome in the ALK aberrant cohort is observed, it can be attributed to the addition of crizotinib. In the AALL1131 trial, the outcome in the molecularly selected group will be reported without an attempt to compare with historical outcomes, whereas in the AALL1521 trial, the outcome of patients treated with chemotherapy+ruxolitinib will be compared with historical controls. It is noteworthy that these three initial trials of molecularly selected therapy added to standard frontline therapy are being conducted in two of the most common pediatric cancers, neuroblastoma and acute lymphoblastic leukemia (ALL). Nevertheless, the rarity of the molecular subsets of specific interest for these combination therapies posed challenges for conventional randomized designs.

These initial trials provide important lessons for future trials. In order for similar frontline trials to be designed for other pediatric cancers, we must first know the frequency of the genetic alterations that are biomarkers for the molecularly targeted agent in a single disease or set of diseases treated with the same standard chemotherapy backbone. Second, we must understand the outcome of the patient population with the biomarker of interest who have received treatment similar to that to be given on the trial protocol. Such clinical outcome data linked to the biomarker of interest were available to inform the design of the ANBL1531 and AALL1521 trials (3032) as a result of large-scale sequencing research efforts linked to prospective clinical trials. Last, because the chemotherapy regimens used at diagnosis are different and often more intense than those used at recurrence, the feasibility of using the novel agent in combination with standard-of-care agents must be assessed in separate pilot studies, in a safety run-in during the main trial (Box 1), or with the use of careful safety stopping rules during the conduct of the main trial to allow evaluation of the safety of combination chemotherapy plus the molecularly targeted therapy. In terms of assessing efficacy in the context of nonrandomized trials, a large effect size—that is, the aforementioned “home run”—will likely be needed to generate sufficiently convincing evidence to support the addition of the targeted therapy to chemotherapy as a new standard. To usher in the next generation of precision combination trials in pediatric cancers, it will be essential to conduct research that links genomic and other biomarker data and clinical outcomes data. For pediatric cancers that are even rarer than leukemia and neuroblastoma, these efforts will likely require international standardization of data elements and data sharing.

Whereas ongoing clinical trials are evaluating the safety and activity of combinations of molecularly targeted therapy with conventional cytotoxic chemotherapy, an emerging area for trials in the precision oncology era is study of combinations of novel molecularly targeted therapies (novel-plus-novel combinations) (Box 1) or molecularly targeted therapy used in combination with other cancer treatment modalities, such as surgery or radiation. Examples of ongoing novel-plus-novel precision trials in pediatric cancer are (i) a phase 2 trial of dabrafenib (a BRAF inhibitor) plus trametinib (a MEK inhibitor) for BRAF V600 mutant gliomas (NCT02684058) and (ii) the NEPENTHE trial (NCT02780128), which is evaluating several novel combinations in neuroblastoma (33). In adult cancers, trials that assess safety and efficacy of combinations of radiotherapy and novel agents, especially immune checkpoint inhibitors, are being pursued, and similar approaches have begun in pediatric oncology.

Target and drug discovery for pediatric cancers

As discussed above, precision medicine approaches have been applied with some success in a subset of pediatric cancers—particularly, cancers whose growth is driven by genetic alterations in protein kinase genes. However, as discussed in more detail in a Review by Sweet-Cordero and Biegel (34), pediatric cancers generally have fewer genetic alterations than adult cancers (1, 2), and drugs do not yet exist for the majority of potentially targetable genetic alterations in pediatric cancers. These are major challenges. Shown in Table 1 are examples of genomic events in pediatric cancers that are a high priority for drug development because they are required for cancer cell growth, occur at relatively high frequency, and/or are associated with poor prognosis. Many of these potential targets are not amenable to traditional drug development strategies and hence will require new approaches. For example, a common theme in pediatric cancers is the presence of a fusion oncoprotein produced as the result of an aberrant juxtaposition of genomic regions between or within chromosomes, often involving genes related to chromatin regulation. Many of these fusion events produce neomorphic, chimeric transcription factors that are notoriously difficult to target with small-molecule inhibitors because of their lack of enzymatic pockets. These fusion oncoproteins are often the primary driver of tumorigenesis and are accompanied by few other tumor-specific somatic mutations. Because these gene fusion events are essential for tumor cell survival, at least in principle, they are propitious drug targets. The remarkable clinical success of targeting NTRK kinase fusions, which are more readily tractable than transcription factor fusions, with TRK inhibitors speaks to the potential power of targeting other more pharmacologically challenging oncogenic fusions expressed in pediatric cancers, such as EWS-FLI, PAX-FOXO1, or SS18-SSX.

Table 1 Examples of genomic alterations that are high-priority drug targets for pediatric cancer.

These alterations are prioritized because (i) they are key drivers in cancer cell growth, (ii) they occur in a high percentage of tumors, and/or (iii) they are associated with poor prognosis. This list is not intended to be comprehensive. F, fusion; M, mutation; A, amplification; D, deletion; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; NSCLC, non–small-cell lung cancer; PARP, poly(ADP-ribose) polymerase; LSD1, lysine-specific demethylase 1; BET, bromodomain and extra-terminal domain motif; BMI-1, polycomb complex protein BMI-1; H3.3K27M, mutated histone H3.3; DOT1L, disruptor of telomeric silencing 1-like histone methyltransferase; IRAK, interleukin-1 receptor–associated kinase; EZH2, enhancer of zeste 2 polycomb repressive complex 2, a histone-lysine N-methyltransferase; BRD9, bromodomain 9; ATR, ataxia telangiectasia mutated and Rad3-related kinase; ACVR1, activin A receptor type I; and FGFR4, fibroblast growth factor receptor 4.

View this table:

An emerging drug development strategy focuses on eliminating the proteins that drive cancer cell growth by hijacking the cell’s normal protein degradation machinery. This strategy offers new hope for therapeutically targeting transcription factors that drive pediatric cancer cell growth, whether they are dysregulated through gene fusion events or through other mechanisms such as gene amplification (for example, MYCN in neuroblastoma). The success of this general approach is illustrated by acute promyelocytic leukemia (APL). The cytotoxic chemotherapy that was once standard of care for patients with APL has been replaced with arsenic trioxide and all-trans retinoic acid, providing greater efficacy and less toxicity than the prior cytotoxic regimens. These two drugs induce degradation of promyelocytic leukemia (PML)–retinoic acid receptor–α (RARα), the transcription factor fusion protein that drives leukemic cell growth (35). All-trans retinoic acid binds to RARα, inducing conformational changes, and arsenic trioxide binds to PML, inducing sumoylation. Each of these events leads to polyubiquitination, recruitment of ubiquitin ligases, and ultimately, degradation of the PML-RARα protein (36). More recently, it was discovered that phthalimide-based drugs—such as thalidomide and lenalidomide, which are used as treatments for multiple myeloma—also act by inducing protein degradation. The drugs bind to cereblon (CRBN), a component of a cullin-RING ubiquitin ligase complex, changing its substrate specificity to enhance binding to certain transcription factors (such as IKZF1 and IKZF3) and other proteins such as the kinase CK1α, leading to their degradation (37, 38). Efforts are now under way to identify additional small molecules that induce degradation of dysregulated transcription factors and other challenging cancer drug targets. A related approach being explored is PROTACs (proteolysis targeting chimeras): Heterobifunctional molecules that contain a chemical moiety that binds to the target protein of interest are linked to a second moiety that binds to an E3 ligase, such as CRBN or Von Hippel-Lindau (VHL) (39). PROTACs bring the target of interest in close proximity to the E3 ligase, leading to target protein ubiquitination and degradation by the proteasome. One advantage of a PROTACs degrader approach is that the molecule that binds to the target of interest need not inhibit it but rather can be engineered to degrade it. A number of examples of successful development of PROTACs designed against cancer targets have been reported (4043), and the first of these molecules is poised to enter early-phase clinical trials for adult cancers.

A third opportunity for drug development in pediatric cancer is the identification of previously unidentified therapeutic targets by using functional genomic approaches, such as CRISPR-Cas9 or short hairpin RNA screens, to knock out or knock down individual genes in cancer cells and then assess their phenotypic consequences. These screens can identify the key dependencies maintaining the cancer cell state. One hypothesis is that pediatric cancers, which generally have simpler genomes as compared with those of adult cancers, will have a higher signal-to-noise ratio with more consistent dependencies within a disease class. Early data emerging from a collaborative genome-scale CRISPR-Cas9 screen of more than 100 pediatric cancer cell lines have highlighted a strong dependency on MDM2/MDMX in TP53 wild-type cancers (44), prompting the development of the trial discussed above. This same screen revealed a dependency of a subset of neuroblastomas and SMARCB1-deficient cancers on EZH2 (45, 46) and a dependency of synovial sarcoma on BRD9 (47, 48).

Tumor profiling for biomarker identification in pediatric cancers

An essential requirement for a clinical trial of molecularly targeted therapies based on a genomically defined biomarker is tumor profiling (the testing of a tumor specimen, usually in a clinical laboratory and usually with next-generation sequencing techniques, to detect tumor-specific genomic alterations) (Box 1). There are a number of ways to approach the need for a tumor profile for trial enrollment, and the precision oncology trials discussed here exemplify this diversity. Tumor profiling can be integrated into the clinical trial. When integrated into the trial, profiling requires submission of a tumor specimen and is performed after enrollment and charged to the trial funds. The benefit of this approach is uniformity of testing methods and no cost for the patient. Tumor profiling may also be performed outside of the clinical trial, and patients may be enrolled on the basis of a preexisting test result demonstrating that their cancer harbors the biomarker of interest. Such molecular tumor profiling outside of the context of a clinical trial is becoming more common, but broad adoption awaits further research on clinical utility and a clearer understanding of insurance reimbursement. In both scenarios, availability of profiling results at the time of enrollment into the clinical trial being considered is critical. Availability of profiling results at key decision points is enabled by approaches that assess a broad range of genomic alterations, that have a rapid turn-around time, and that can be applied early in the course of disease.


The next generation of precision trials for pediatric cancers will likely enroll patients from the pediatric and adult oncology clinics simultaneously, enroll children earlier in the drug development life cycle, and involve more combination therapies (Fig. 1). These changes will require a supportive ecosystem. Key components include close interaction between industry and academia, governed by standards of transparency; funding mechanisms that facilitate collaboration between clinical trialists and laboratory investigators; local and national clinical trials infrastructures recognizing the increased likelihood of enrollment across medical and pediatric oncology clinics; and broad use of molecular profiling that includes new approaches such as liquid biopsies (for example, analysis of cell-free DNA in body fluids and analysis of circulating tumor cells). Last, the importance of investing in drug development specifically directed at molecular targets specific to pediatric cancers cannot be overstated.

Fig. 1 Evolution of precision trials for pediatric cancer.

Illustration: Kellie Holoski/Science

References and Notes

Acknowledgments: Competing interests: S.G.D. has received consulting fees from Loxo Oncology and travel expenses from Loxo Oncology and Roche. K.A.J. has received research funding from Amgen and Pfizer and travel expenses from Loxo Oncology; L.B.C. has received consulting fees from X-Chem Pharmaceuticals. K.S. has received consulting fees from Novartis and Rigel Pharmaceuticals and research funding from Novartis.
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