by Eric P. Hoffman & Ruth I. Hoffman
Source: Fall/Winter 2006 CCCF Newsletter
Candlelighters National Office, together with the International Union Against Cancer (www.uicc.org), sponsored a workshop to discuss targeted therapeutics in pediatric cancer. The workshop was attended by representatives from pediatric cancer foundations from the US, Egypt, Turkey, Bangladesh, Tanzania, Italy, as well as physician experts in pediatric cancer, representatives from the National Institutes of Health, and the Institute of Medicine, and research scientists.
The workshop began with a welcome by Isabel Mortara, Executive Director, UICC, Geneva Switzerland. Ruth Hoffman, Candelighters’ Executive Director, then gave an overview of the ‘problem,’ namely that current treatments for childhood cancer focus on toxic chemotherapies. While these therapies have proven relatively successful in increasing the five year survival rate for some specific cancers (Acute Lymphocytic Leukemia for example), they have had little or no success in other cancers (brainstem glioma, stage IV neuroblastoma, AML). Also, the toxic chemicals damage normal tissues in the child, leading to many ‘late effects’ that impact the future life of the growing child. Targeted therapeutics promises to more selectively destroy the cancer at a molecular level, and shows promise for the many childhood tumors that are refractory to these treatments.
Salma Choudhury, Founder of Ashic Foundation in Bangladesh, described the status of pediatric oncology in Bangladesh, pointing out that the substantial support systems and patient care required for the severe toxic chemotherapies are difficult to provide in Bangladesh. Targeted therapeutics promise to be more ‘transportable’ to the less developed countries, much like targeted AIDS drugs are beginning to be distributed throughout Africa.
Dr. Eric Hoffman, Director, Research Center for Genetic Medicine at Children’s National Medical Center, Washington D.C., then provided an overview of the theory and practice of the high throughput drug screening methods used to develop targeted therapeutics (see page 2 of this newsletter). The first session was closed by Dr. Raul Ribeiro, Director of the International Outreach Program at St. Jude Children’s Research Hospital who described efforts to distribute ATRA to treat Acute Promyelocytic Leukemia (APL) in developing countries.
The second session of the workshop focused on three cancers that remain difficult to treat: neuroblastoma IV, brain tumors, and AML. Physician/scientist experts on each of these cancers gave a ‘state of the science’ presentation, where they described treatment success rates (or lack thereof), late effects, and progress towards targeted therapeutics.
Dr. Javed Khan, Head, Oncogenomics Section at the National Cancer Institute (NCI), provided an overview of his highly successful efforts to develop a collaborative international group working on neuroblastoma, with the goal of developing impressive molecular data on a large number of tumors. Dr. Khan had organized a workshop 6 months previously, where the first important steps of ‘standardizing’ the methods for obtaining patient tumor and blood specimens, and generating the large amounts of DNA information (SNPs, CGH, re-sequencing), mRNA data (mRNA profiling) and proteomic data, integrated with clinical and laboratory information on each subject. The resulting data resource should prove ideal for ‘target identification,’ the first critical step in development of targeted therapeutics. A follow up workshop is planned for May 2007, to begin to implement the neuroblastoma consortium action plan.
Dr. Roger Packer, Chairman of Neurology at Children’s National Medical Center in Washington D.C., then described the status of therapeutics for brain tumors. He pointed out that survival remains quite poor for many types of pediatric brain tumors. For example 10% of children diagnosed with a brain stem glioma survive 18 months. For those that do survive, the aggressive surgery, radiation, and chemotherapy often reduces the cognitive functioning of the child. The Pediatric Brain Tumor Consortium (PBTC) is a collaborative network that has begun to generate mRNA and proteomics data for target identification. Recent efforts to develop centralized public access databases for target identification in brain tumors were receiving foundation support, and he was optimistic that many of the brain tumors could be pushed into the targeted therapeutics HTS pipeline in the near future.
Dr. Robert Arceci, Director of Pediatric Oncology, Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore MD described the history of progress in treating patients with AML along with some of the challenges. Current approaches to treatment cure approximately 50% of children with AML but the treatments are extremely intensive. Alternative approaches to more selectively targeting AML without damaging normal tissues were discussed, including the critical importance of targeting the key stem cells in AML. Some of the new approaches being tested include antibody targeting, reversal of drug resistance proteins, inhibiting receptors that drive leukemic cell survival, differentiation therapies and vaccine approaches. The issue of how to test these various new approaches in such a rare disease with many different subtypes remains an additional challenge, which is likely to require increased international collaborations.
Dr. Malcolm Smith, Associate Branch Chief, CTEP NCI, Bethesda MD, ended the formal presentations. He described efforts to develop xenograft models for pre-clinical studies in mice. Briefly, cells from patient tumors are injected into mice where they begin to form human tumors in the mouse. Drugs can then be tested on these xenograft models to see which drugs are effective in killing the tumor.
Following the presentations, there was active discussion and debate lasting over an hour, with many attendees at the workshop asking questions and providing their insights and opinions.
All left the workshop with an increasing awareness of the need for a collaborative research initiative in targeted therapeutic programs for pediatric cancer. All agreed that forming a national and international collaborative consortia, much like Dr. Khan described for neuroblastoma, was a critical first step. Additional key short-term goals were dialogue regarding synergism between efforts on different cancer types (e.g. what can the brain tumor consortium learn from the neuroblastoma consortium?), and the value of comprehensive database with worldwide public access to the large amounts of data generated. The possibility of ‘parallelizing target identification’ and other parts of the HTS pipeline through a world-wide effort facilitated by the internet provide considerable promise that the difficult cancers could be beat.
Candlelighters will continue to follow through with the recommendations from the meeting, including the planning of a workshop of database experts to discuss the feasibility of designing a publicly accessible, standardized database structure for integrated genomics information.