New targets and targeted drugs for the treatment of cancer: an outlook to pediatric oncology

Novel drugs and treatment modalities are urgently needed to further improve survival of children with cancer. In medical oncology, an increased understanding of the molecular basis of cancer is driving the development of new drugs that target relevant signaling pathways in cancer cells and tumor microenvironment. Small-molecule modulators of signal transduction and monoclonal antibodies against various cellular targets have been approved in adult cancers in recent years. These drugs are now starting to be considered for the use in children. Despite the biological differences between adult and pediatric cancers, common cellular pathways have emerged from experimental research. Thus, insights into clinical experience with molecular targeted drugs in adults may help to accelerate progress in pediatric oncology. Here, the authors review molecules and pathways for which drugs are approved for adult cancer treatment and provide links to existing and potential applications in pediatric oncology.     

Treatment and biology of pediatric acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. In the past ALL was intractable but now the survival probability is as high as 80–90%. Improved supportive care, treatment stratification based on relapse risk, biological features of leukemic cells, and optimization of treatment regimens by nationwide and international collaboration have contributed to this dramatic improvement. While including traditional risk factors (e.g. age and leukocyte count at diagnosis), the treatment has been modified based on biological characteristics (aneuploidy and translocation) and treatment response (assessed by minimal residual disease). Treatment for pediatric ALL typically consists of induction therapy with steroids, vincristine, and asparaginase with or without anthracycline, followed by multi‐agent consolidation including high‐dose methotrexate and re‐induction therapy. After consolidation, less intensive maintenance therapy is required for 1–2 years to maintain event‐free survival. Recently, using advanced genomic analysis technology, novel sentinel genomic alterations that may provide more precise stratification or therapeutic targets, were identified. Moreover, in the last decade germline variations have been recognized as similarly important contributors to understanding the etiology and sensitivity of ALL to treatment. A more individualized approach based on genomic features (somatic and germline) and treatment response, the introduction of newly developed agents such as molecular targeted drugs or immunotherapy, and social support including long‐term follow up are required for further improvement.     

Acute myeloid leukemia in children: Current status and future directions

Acute myeloid leukemia (AML) accounts for 25% of pediatric leukemia and affects approximately 180 patients annually in Japan. The treatment outcome for pediatric AML has improved through advances in chemotherapy, hematopoietic stem cell transplantation (HSCT), supportive care, and optimal risk stratification. Currently, clinical pediatric AML studies are conducted separately according to the AML subtypes: de novo AML, acute promyelocytic leukemia (APL), and myeloid leukemia with Down syndrome (ML‐DS). Children with de novo AML are treated mainly with anthracyclines and cytarabine, in some cases with HSCT, and the overall survival (OS) rate now approaches 70%. Children with APL are treated with an all‐trans retinoic acid (ATRA)‐combined regimen with an 80–90% OS. Children with ML‐DS are treated with a less intensive regimen compared with non‐DS patients, and the OS is approximately 80%. HSCT in first remission is restricted to children with high‐risk de novo AML only. To further improve outcomes, it will be necessary to combine more accurate risk stratification strategies using molecular genetic analysis with assessment of minimum residual disease, and the introduction of new drugs in international collaborative clinical trials.     

Clinical pharmacology of cancer chemotherapy in children

The pharmacokinetics of most anticancer drugs are highly variable in children, and are commonly different when children are compared to adults. Several recent studies have demonstrated that variability in systemic exposure due to interpatient pharmacokinetic variability, may be related to the probability of oncolytic effects or toxicity for some anticancer drugs. This review has exemplified differences in the clinical pharmacology of several anticancer drugs, when children are compared to adults. Such age-related differences in the pharmacokinetics and pharmacodynamics of these drugs, together with biologic differences between pediatric and adult cancers, provide the rationale for systematically conducting pediatric phase I through IV studies of anticancer drugs and denote the risks of relying on adult trials to identify new therapeutic strategies for childhood cancers.     

Update on new treatments and developments in childhood brain tumors

PURPOSE OF REVIEW: Childhood primary central nervous system tumors remain a therapeutic conundrum. As the second most common pediatric cancer, brain tumors lead to significantly worse survival and long-term effects compared with those seen with hematologic malignancies and other solid tumors. This review discusses current management strategies in three pediatric brain tumors, the long-term effects of therapy, as well as novel laboratory findings that may alter future treatment strategies. RECENT FINDINGS: The current literature focuses on tactics to predict those at risk of treatment failure and long-term effects. By analyzing tumors at a molecular genetics level rather than traditional histology, new data have begun to emerge on methods to begin to consider targeted therapies, tailored to the individual child. Furthermore, as survivorship has improved with current radiation and chemotherapy regimens, long-term effects have been identified and merit clinical attention. SUMMARY: Even though long-term survival for children with a brain tumor approaches 70%, the need for improved treatment regimens is striking. Secondary malignancies, neurocognitive deficits and treatment failure continue to afflict these children and young adults. The current review will inform clinicians of the challenges faced by basic scientists and clinicians when treating brain tumors, and point to future research directions.     

Recent advances in the treatment of childhood brain tumors

Pediatric brain tumors are the commonest cause of cancer-related death in children. The last four decades have seen only a 35% increase in 5-year survival rate of children with these tumors. The therapeutic successes achieved are due to advances in neuroimaging, surgical techniques, radiotherapy, and induction of newer chemotherapeutic agents along with molecular targeted therapy. Neuroimaging advances include the use of MRA, MRS, DSA, and PET scans. With the use of stereotactic surgery, intraoperative mapping, and imaging, surgical resection has improved with significant decrease in morbidity. A major development has been the use of precision guided radiotherapy utilizing technologies like 3D-CRT, SRS, and IMRT, thereby decreasing radiation to normal tissues. Induction of newer drugs and high-dose chemotherapy with peripheral stem cell support has improved survival and delayed radiation in younger children and infants with brain tumors. Intense ongoing research is profiling novel molecular targets for therapeutic intervention. Newer therapeutic strategies like blood brain barrier disruption, immunotherapy, and gene therapy are in clinical trials. This review article intends to give the reader an overview of current therapeutic strategies and research involved in the treatment of children with brain tumors.     

Insights into pediatric rhabdomyosarcoma research: Challenges and goals

Overall survival rates for pediatric patients with high‐risk or relapsed rhabdomyosarcoma (RMS) have not improved significantly since the 1980s. Recent studies have identified a number of targetable vulnerabilities in RMS, but these discoveries have infrequently translated into clinical trials. We propose streamlining the process by which agents are selected for clinical evaluation in RMS. We believe that strong consideration should be given to the development of combination therapies that add biologically targeted agents to conventional cytotoxic drugs. One example of this type of combination is the addition of the WEE1 inhibitor AZD1775 to the conventional cytotoxic chemotherapeutics, vincristine and irinotecan.     

Principles of chemotherapy

Combination chemotherapy is the mainstay of treatment for most childhood cancer, either alone or in combination with surgery and radiotherapy. Sequential national and international studies of combinations of cytotoxic drugs have resulted in improvements in the outcomes for childhood cancer. These improvements have required careful attention to be paid to the maintenance of dose intensity and the optimisation of supportive care to manage acute toxicity. Increased understanding of the molecular basis of childhood cancer is now leading to the introduction of more targeted anti-cancer drugs, usually in combination with existing conventional agents. This will allow the remaining stubbornly drug–resistant childhood cancers to be treated more effectively, but will also allow does reduction of conventional agents in sensitive tumour types, reducing both acute and chronic toxicity. Increasing understanding of both pharmacokinetics and pharmacogenomics offers the opportunity for more personalized anti-cancer treatment, to optimize drug dosing for an individual, and to reduce their toxicity. This review will give an outline of the molecular basis for anticancer drug action, will look at some specific types of cytotoxic agent, and describe the principles for combining these into treatment protocols. It will describe short and long term side effects of chemotherapy, and how these often limit what can be given. The importance of pharmacokinetics, in understanding how drugs are handled by children of different ages, and increasingly these days, as a means of individualising drug dosing, will be discussed. Finally the growing importance of pharmacogenomics as a way of predicting both response and toxicity will be described.     

Cancer drugs approved for use in children: Impact of legislative initiatives and future opportunities

It is well appreciated that the number of anticancer drugs approved for use in children is a fraction of the number approved for use in cancers that occur in adults. We address this fact by summarizing the relevant U.S. legislation that provides the framework for the evaluation and approval of drugs used to treat children with cancer. In total, the Food and Drug Administration (FDA) has approved 38 new drug applications for pediatric oncology indications, 12 of which were new molecular entities. FDA continues to collaborate with multistakeholders regarding the development of products intended for pediatric cancer and encourages the submission of marketing applications.     

Pediatric oncology clinical trial participation where the geography is vast: Development of a clinical research system for tertiary and satellite centers in Ontario,Canada

Opportunities for participation in clinical trials are a core component of the care of children with cancer. In Ontario, many pediatric patients live long distances from their cancer center. This paper describes the work that was done in order to allow patients participating in Children's Oncology Group trials to receive care, including research protocol related care, jointly between the tertiary pediatric cancer center and the closer‐to‐home satellite center. The system is a pragmatic risk‐based model, supporting excellence in care while ensuring good conduct of the research in compliance with applicable regulations and guidelines, including ethics oversight.     

New anticoagulants: a pediatric perspective

Unfractionated heparin and vitamin K antagonists such as warfarin have been used as the anticoagulants of choice for over five decades. Subsequently, low molecular weight heparins (LMWHs) became widely available and have provided several advantages, especially in infants and children. The field of anticoagulation, however, has undergone a major revolution with better understanding of the structure of coagulation proteins and the development of a host of new drugs with highly specific actions. Many of these drugs have undergone extensive clinical testing in adults and have been approved for specific indications in adults. Unfortunately, clinical data and the reported use of these drugs in children are extremely limited. A lack of familiarity with the actions and pharmacokinetic properties of these drugs could be a major contributing factor. This review focuses on several of the new anticoagulants, with a special emphasis on those that could be potentially beneficial in pediatric patients with thromboembolic disorders. The need for well-designed trials with large-scale participation by pediatric hematologists in order to improve the antithrombotic care of young infants and children is also emphasized.     

Curing childhood acute myeloid leukemia (AML) at the half-way point: promises to keep and miles to go before we sleep

Childhood and adolescent acute myeloid leukemia (AML) is traditionally one of the hardest childhood cancers to successfully treat and had an overall survival well under 10% in the 1960s. Initial progress was made by three major events: (1) active chemotherapeutic agents were identified which led to remissions for the first time in this disease; (2) cooperative groups were instituted leading to important clinical trials; and (3) several single institutions began experimenting with the role of allogeneic matched sibling donor (MSD) BMT as effective intensification. Over the last 25 years, the cure rate has improved from <20% to 50% or higher. Most of the clinical research during this time of great advancement focused on two major themes: (1) the role of aggressive induction therapy in not only improving CR rates but in post-remission outcomes; and (2) the role of aggressive post-remission therapy in further improving survival, with an emphasis on high-dose Ara C-based chemotherapy, BMT, and supportive care. But we have "miles to go before we sleep." Some of the challenges that will lead to ongoing reduction of population-based mortality for AML through young adulthood include: (1) improving access of adolescents to pediatric AML therapy; (2) stratification by prognostic factors; (3) individualized therapy based on individual genetics and leukemia cell biology; (4) and the use of novel therapies including targeted immuno-conjugates and "small molecules" which disrupt abnormal signal transduction pathways. This brief review looks at both the advances over the last three decades as well as discusses the challenges moving forward for ultimately curing all children with this disease.     

Acute myeloid leukemia

Acute myeloid leukemia (AML) is a heterogeneous group of leukemias that result from clonal transformation of hematopoietic precursors through the acquisition of chromosomal rearrangements and multiple gene mutations. As a result of highly collaborative clinical research by pediatric cooperative cancer groups worldwide, disease-free survival has improved significantly during the past 3 decades. Further improvements in outcomes of children who have AML probably will reflect continued progress in understanding the biology of AML and the concomitant development of new molecularly targeted agents for use in combination with conventional chemotherapy drugs.     

The impact of clinical trial enrollment on specialty palliative care utilization in pediatric patients with high-grade gliomas

Background

Palliative care (PC) provides numerous benefits for children with cancer. Pediatric patients with high-grade glioma (HGG) are particularly well suited for early PC involvement given their high symptom burden and poor prognosis. However, studies continue to reveal that children with cancer, including HGG, have delayed PC involvement. We hypothesized that clinical trial enrollment may lead to a lack of or delay in PC involvement in this population.

Procedure

For each patient in our cohort of 43 pediatric patients with HGG, demographic, diagnostic, therapeutic, clinical trial enrollment, and PC information were collected. Statistical analysis was performed comparing PC characteristics between patients who did and did not enroll in a clinical trial.

Results

Seventy-two percent of patients had at least one visit with a PC provider. Fifty-six percent of patients enrolled in a clinical trial with HGG-directed therapy. Seventy-one percent of patients who enrolled in a clinical trial received specialty PC compared to 74% of non-trial participants (p = 1.000). Patients who enrolled in clinical trials received PC earlier in their disease course measured in days before death (mean = 177 days) compared to those who did not enroll (mean = 113 days, p = .180), though not statistically significant.

Conclusions

The prevalence of clinical trial enrollment is high in patients with HGG and will likely increase as the genomic/epigenomic landscape of these tumors is better understood. As such, our data reassuringly suggest that trial participation does not interfere with the receipt of specialty PC in this population.     

小分子靶向药JAK抑制剂在儿童风湿免疫性疾病中的应用

Janus激酶（Januskinases,JAK）抑制剂是一种小分子靶向药,可以抑制相关炎症因子信号传导通路而具备抗炎作用,目前已有多种JAK抑制剂上市用于包括风湿免疫性疾病在内的各系统疾病。作为新型靶向合成类改善病情抗风湿药物,JAK抑制剂已上市用于甲氨喋呤应答不足或不耐受的成人类风湿性关节炎,且在成人强直性脊柱炎、溃疡性结肠炎、皮肌炎、血管炎等多种风湿性疾病中均有应用,但在儿童风湿免疫性疾病中仍缺乏大规模临床证据。JAK抑制剂治疗幼年特发性关节炎已进入Ⅲ期临床试验,在治疗幼年型皮肌炎、系统性红斑狼疮、多发性大动脉炎也有报道,且是相关自身炎症性疾病的靶向药物。因此,JAK抑制剂在儿童风湿免疫性疾病中的应用具有广泛前景。     

Exploiting apoptosis pathways for the treatment of pediatric cancers

Resistance to apoptosis (programmed cell death) is a characteristic feature of human cancers including childhood malignancies. Further, evasion of apoptosis is a frequent cause of treatment resistance, since most anti‐cancer therapies, for example chemo‐ or radiotherapy act primarily by inducing apoptosis in cancer cells. Over the last two decades, the dissection of apoptosis pathways in pediatric tumors has resulted in the identification of many key molecules that may serve as molecular targets for drug discovery. Accordingly, components of the apoptotic cascade are currently exploited for the development of rationally designed molecular targeted therapies. This approach is expected to open new and more effective approaches for the treatment of childhood cancers. Pediatr Blood Cancer 2009;53:533–536. © 2009 Wiley‐Liss, Inc.     

Challenging the indiscriminate use of temozolomide in pediatric high‐grade gliomas: A review of past,current, and emerging therapies

Pediatric high‐grade gliomas (pHGG) constitute 8% to 12% of primary brain tumors in childhood. The most widely utilized treatment encompasses surgical resection followed by focal radiotherapy and temozolomide. However, experiences over past decades have not demonstrated improved outcomes. pHGG have been classified into different molecular subgroups defined by mutations in histone 3, IDH gene, MAPK pathway, and others, thereby providing a rationale for various targeted therapies. Additionally, immunotherapy and drug repurposing have also become attractive adjunctive treatments. This review focuses on past, present, and emerging treatments for pHGG integrating molecular research with the mainstream pediatric drug development in Europe and the United States to sketch a way forward in the development of novel therapeutic approaches. The implementation of randomized clinical trials with adaptive designs, underpinned by a robust biological rationale, and harnessing collaboration between the pharmaceutical industry, academia, regulators and patients/parents organizations will be essential to improve the outcomes for these children.     

Pediatric oncology for the general pediatrician

Since its establishment as a pediatric subspecialty oncology has become the near exclusive domain of specialized tertiary centers. This has greatly aided progress in the field with formation of exemplary and highly focused international consortia that have continued to streamline clinical research efforts. Recently, the rate of progress in terms of further improvements in overall outcome has paradoxically slowed. Novel strategies are therefore needed to assure continued advances. On the one hand, international and global consortia of subspecialists will continue to focus on the development of much needed improved therapies for those disease groups that have not yet seen their prognosis brighten, and on the other hand, there is a trend to invest in the development of joint-care initiatives that assure cost-effective access to standard therapy for all. This will require closer involvement of the general pediatrician in certain aspects of cancer care in its broadest sense. We hope the upcoming series will aid this process by highlighting selected topics in pediatric oncology that are likely to gain even more relevance for the general pediatrician in the years to come. They include: screening strategies for cancer predisposition syndromes; molecular diagnosis and risk-adjustment of therapy for acute leukemia in childhood; an overview of new agents in clinical development; and the impact of cancer treatment on fertility and available preservation options.     

Pediatric oncology: current views and outcomes

The extraordinary explosion of molecular and cellular insights may provide potentially exploitable opportunities to meet the challenge of curing and ultimately preventing all cancer in children. This article describes the various approaches in developing molecular therapy targeted at common childhood cancers.