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1.
Cancer Discov ; 11(3): 545-559, 2021 03.
Article in English | MEDLINE | ID: mdl-33277309

ABSTRACT

The use of targeted small-molecule therapeutics and immunotherapeutics has been limited to date in pediatric oncology. Recently, the number of pediatric approvals has risen, and regulatory initiatives in the United States and Europe have aimed to increase the study of novel anticancer therapies in children. Challenges of drug development in children include the rarity of individual cancer diagnoses and the high prevalence of difficult-to-drug targets, including transcription factors and epigenetic regulators. Ongoing pediatric adaptation of biomarker-driven trial designs and further exploration of agents targeting non-kinase drivers constitute high-priority objectives for future pediatric oncology drug development. SIGNIFICANCE: Increasing attention to drug development for children with cancer by regulators and pharmaceutical companies holds the promise of accelerating the availability of new therapies for children with cancer, potentially improving survival and decreasing the acute and chronic toxicities of therapy. However, unique approaches are necessary to study novel therapies in children that take into account low patient numbers, the pediatric cancer genomic landscape and tumor microenvironment, and the need for pediatric formulations. It is also critical to evaluate the potential for unique toxicities in growing hosts without affecting the pace of discovery for children with these life-threatening diseases.


Subject(s)
Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Drug Development , Neoplasms/drug therapy , Age Factors , Animals , Biomarkers, Tumor , Child , Clinical Trials as Topic , Combined Modality Therapy , Disease Susceptibility , Drug Development/legislation & jurisprudence , Drug Development/methods , Drug Evaluation, Preclinical , Drug and Narcotic Control , Genomics/methods , Humans , Molecular Targeted Therapy/adverse effects , Molecular Targeted Therapy/methods , Neoplasms/etiology , Pediatrics , Treatment Outcome
2.
Expert Opin Drug Discov ; 12(8): 801-811, 2017 08.
Article in English | MEDLINE | ID: mdl-28604107

ABSTRACT

INTRODUCTION: Neuroblastoma, the commonest paediatric extra-cranial tumour, remains a leading cause of death from cancer in children. There is an urgent need to develop new drugs to improve cure rates and reduce long-term toxicity and to incorporate molecularly targeted therapies into treatment. Many potential drugs are becoming available, but have to be prioritised for clinical trials due to the relatively small numbers of patients. Areas covered: The current drug development model has been slow, associated with significant attrition, and few new drugs have been developed for neuroblastoma. The Neuroblastoma New Drug Development Strategy (NDDS) has: 1) established a group with expertise in drug development; 2) prioritised targets and drugs according to tumour biology (target expression, dependency, pre-clinical data; potential combinations; biomarkers), identifying as priority targets ALK, MEK, CDK4/6, MDM2, MYCN (druggable by BET bromodomain, aurora kinase, mTORC1/2) BIRC5 and checkpoint kinase 1; 3) promoted clinical trials with target-prioritised drugs. Drugs showing activity can be rapidly transitioned via parallel randomised trials into front-line studies. Expert opinion: The Neuroblastoma NDDS is based on the premise that optimal drug development is reliant on knowledge of tumour biology and prioritisation. This approach will accelerate neuroblastoma drug development and other poor prognosis childhood malignancies.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Design , Neuroblastoma/drug therapy , Adolescent , Antineoplastic Agents/adverse effects , Child , Drug Evaluation, Preclinical/methods , Humans , Molecular Targeted Therapy , Neuroblastoma/pathology , Prognosis , Randomized Controlled Trials as Topic , Time Factors
3.
Expert Opin Drug Discov ; 10(5): 483-95, 2015 May.
Article in English | MEDLINE | ID: mdl-25840490

ABSTRACT

INTRODUCTION: Cancer is a leading cause of death in childhood. Encouraging progress has been made in the treatment of childhood malignancies, but there is an unmet need for new drugs to improve survival and reduce treatment-associated toxicities. Drug development in paediatric oncology has specific requirements with regard to the patient population and the regulatory background and presents several unique challenges that need addressing. AREAS COVERED: This review discusses the current framework of paediatric oncology drug development and some of the specific challenges in pre-clinical and clinical research. The authors discuss the recent developments in the targeting of various signalling pathways. These pathways represent a selection of targets that have been identified by pre-clinical and clinical investigators to be highly relevant in paediatric malignancies. EXPERT OPINION: The development of targeted agents in paediatric oncology must be driven by knowledge of tumour biology. Predictive and pharmacodynamic biomarkers should be incorporated within paediatric early clinical trials wherever possible. Faster dose-escalation, limited numbers of cohorts and novel adaptive designs can help to make paediatric early clinical trials more efficient. Close collaboration between academic/clinical researchers, the pharmaceutical industry, regulatory bodies and parent groups are crucial in overcoming the challenges associated with paediatric oncology drug development.


Subject(s)
Antineoplastic Agents/therapeutic use , Drug Design , Neoplasms/drug therapy , Age Factors , Animals , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacology , Biomarkers, Tumor/metabolism , Child , Drug Discovery/methods , Drug Evaluation, Preclinical/methods , Humans , Molecular Targeted Therapy , Neoplasms/pathology , Survival Rate
4.
Curr Drug Targets ; 15(1): 114-23, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24387312

ABSTRACT

p53 is one of the main regulators of apoptosis, senescence, cell cycle arrest and DNA repair. The expression, function and stabilization of p53 are governed by a complex network of regulators including p14(ARF) and MDM2. MDM2 is the main negative regulator of p53 activity and stability. Unlike tumours in adults, which tend to overcome p53 regulation by p53 mutations, the paediatric tumours neuroblastoma and sarcoma frequently retain wild type p53. Nevertheless, in childhood cancer the p53 pathway is commonly impaired due to upstream MDM2-p14(ARF)-p53 network aberrations. In contrast, aberrations of the p53 downstream pathway are very rare. In cancer cells with intact p53 downstream function MDM2 inhibition, and subsequent rapid increases in nuclear p53 levels, potently "re-activate" dormant apoptotic pathways and rapidly induce apoptotic cell death. As a result MDM2-p53 interaction inhibitors, including cis-imidazolines analogs (Nutlins), are potentially very effective agents in neuroblastoma and sarcomas. Predictive biomarkers are important as a lack of p53 mutations appears to reliably predict response to these inhibitors. Tumours should be screened for p53 mutations in children considered for MDM2-p53 interaction inhibitors. In addition, it is essential that other predictive biomarkers are investigated. The serum concentration of macrophage inhibitory cytokine- 1 (MIC-1) may be a good pharmacodynamic biomarker based on recent findings. In conclusion, targeting the interaction between p53 and its main negative regulator MDM2 represents a major new therapeutic approach in poor prognosis paediatric malignancies without p53 mutations.


Subject(s)
Biomarkers, Tumor/metabolism , Neuroblastoma/metabolism , Proto-Oncogene Proteins c-mdm2/metabolism , Tumor Suppressor Protein p53/metabolism , Antineoplastic Agents/therapeutic use , Child , Drug Evaluation, Preclinical , Drug Resistance, Neoplasm , Humans , Imidazoles/metabolism , Neuroblastoma/blood supply , Neuroblastoma/drug therapy , Piperazines/metabolism , Protein Binding
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