Improving the outcome for children with cancer: Development of targeted new agents

Abstract

The outcome for children with cancer has improved significantly over the past 60 years, with greater than 80% of patients today becoming 5-year survivors. Despite this progress, cancer remains the leading cause of death from disease in children in the United States, and significant short-term and long-term treatment toxicities continue to impact the majority of children with cancer. The development of targeted new agents offers the prospect of potentially more effective and less toxic treatment for children. More than a decade since imatinib mesylate was introduced into the treatment of children with Philadelphia chromosomepositive acute lymphoblastic leukemia, transforming its outcome, a range of targeted agents has undergone study in pediatric cancer patients. Early lessons learned from these studies include a better understanding of the adverse event profile of these drugs in children, the challenge of developing pediatric-specific formulations, and the continued reliance on successful development for adult cancer indications on pediatric drug development. The collaborative research infrastructure for children with cancer in the United States is well positioned to advance novel treatments into clinical investigations for a spectrum of rare and ultra-rare childhood cancers. A greater investment of resources in target discovery and validation can help drive much needed development of new, more effective treatments for children with cancer.

Feasibility and clinical integration of molecular profiling for target identification in pediatric solid tumors

“…Pediatric cancers are relatively rare, with an estimated incidence of 73–148 per million . The overall survival has increased over the past several decades because of multidisciplinary approaches and progress in specialized care using a combination of chemotherapy, surgery, and radiotherapy . The prognosis for children with certain types of cancer remains dismal, particularly for some highly aggressive tumors, after relapse and in most cases of metastatic disease.…”

“…Indeed, as for most pediatric anticancer drugs currently in use, experience in targeted therapies comes from adult trials, with an increasing number of drugs based on molecular alterations available also for children . Drug regulation has evolved, both in the United States and the European Union, with an increase in the number of available clinical trials, allowing more children to be included earlier in phase I–II trials …”

Dysregulation of BCL-2 family proteins by leukemia fusion genes

“…Therapy for ALL is one of the great success stories of modern chemotherapy, and overall cure rates are now Ͼ90% in developed countries, depending on molecular subtypes and clinical features (1). The extraordinary improvements in outcomes in ALL have unquestionably been driven by the treatment of patients on international collaborative clinical trials (2), which have made it possible to rapidly recruit sufficient numbers of patients to studies of new treatment regimes.…”

Immunotherapy in Pediatric Acute Leukemia: A Novel Magic Bullet or an Illusory Hope?

“…Contemporary therapy allows achieving complete remission in approximately 90% of patients with ALL and 70% with AML [1,2]. It is worth mentioning that 50 years ago acute leukemia was almost universally incurable [3]. The breakthrough has been achieved through standardized and optimized multi-agent therapeutic regimens and through therapy individualization according to the risk stratification.…”