Neuroblastoma Markers: detection and quantification of rare neuroblastoma cells in blood and bone marrow as an early surrogate of response to treatment
Immunotherapy of Neuroblastoma: natural killer cells, macrophages, anti-tumor antibodies and tumor microevenironment
Molecular Testing - Biomarkers Treatment failure for patients with neuroblastoma frequently occurs because tumor cells are able to survive and grow in bone marrow despite rigorous chemotherapy regimens. Currently, we are conducting research to determine whether a molecular test developed in our laboratory to measure the expression of five genes active in neuroblastoma (but which are inactive in normal bone marrow or blood cells) will help us to evaluate and predict treatment outcomes. My laboratory in The Saban Research Institute at Children's Hospital Los Angeles serves as the only nationwide resource dedicated to detecting neuroblastoma cells in bone marrow, blood, and in blood stem cell products.
Tumor Microenvironment and Chemotherapy Very often, when cancer develops, normal cells in the cancer's microenvironment (surrounding blood vessels, connective tissues and white blood cells) can be tapped to actually promote the growth and spread of cancer cells. My research develops strategies that prevent macrophages, a kind of white blood cell, in the microenvironment from helping neuroblastoma cells grow and resist therapy. We have found that blocking the signals between macrophages and tumor cells renders the tumor cells more sensitive to chemotherapy.
Tumor Microenvironment and Immunotherapy Our immunotherapy studies are based upon the concept that the immune system can eliminate cancer cells (Yin) or promote their growth (Yang). To eliminate neuroblastoma cells, we use antibodies to target tumor cells and seek to enhance this strategy with natural killer cells working together with the antibodies. For the best anti-tumor effect, it is important to suppress the tumor promoting activities of macrophages (Yang) in the microenvironment. Currently, we are testing two new immunotherapy approaches to determine whether they are helping in removing tumor cells that remain in the body even after high-dose chemotherapy has been administered.
Using lenalidomide, an immune modulator, in combination with an anti-neuroblastoma antibody.
Growing the patient’s own natural killer cells in large numbers in the laboratory and then re-infusing them along with lenalidomide and an anti-neuroblastoma antibody.
Children’s Hospital Los Angeles serves as the headquarters for a North American consortium of 15 pediatric cancer institutions (New Approaches to Neuroblastoma Therapy) dedicated to advancing treatment for children with high-risk neuroblastoma. In my role as Principal Investigator of the NCI-funded Program Project Grant that provides funding for the NANT consortium, I co-chair the Scientific Review Committee, which sets directions and reviews clinical trial proposals.
KEY CONTRIBUTIONS AND ACHIEVEMENTS
In collaboration with molecular biologists and clinical investigators, we made the seminal discovery that the MYCN oncogene, a cancer gene, in neuroblastoma tumors could be used to predict the chance of survival for a patient. This was the first time a human cancer gene was shown to predict outcome for patients.
Collaborating with laboratory and clinical investigators, we developed new strategies for treating children with high-risk neuroblastoma that utilizes high-dose chemotherapy followed by a vitamin A-like drug to kill small numbers of tumor cells that remain after chemotherapy. This strategy was shown in a nationwide study during the 1990s with the Children's Cancer Group to improve survival, and it became the "gold standard" for treating high-risk neuroblastoma worldwide.
We contributed to the development of antibody immunotherapy for neuroblastoma, which, when added to the above "gold standard" treatment, further improves survival of patients.
1.National Cancer Institute (NCI) Program Project Cancer Grant - $11 million
The five-year grant from the National Cancer Institute will allow laboratory and clinical investigators working together to study the underlying biology and to develop new therapies that target the cellular processes driving high-risk neuroblastoma. Read full press release
2. National Cancer Institute Tumor Microenvironment Network - $2.5 million This grant will support research conducted, in tandem with City of Hope, to investigate drug resistance in neuroblastoma.
3. National Cancer Institute R33 grant - $1.36 million
This award supports development and testing of a robust biomarker assay that simultaneously quantifies “tumor load” by expression of tumor cell genes and “microenvironment” by expression of normal marrow and blood cell genes (TaqMan® Low Density Array, TLDA). We anticipate that this TLDA assay will become an integral biomarker tool for evaluating response to new therapeutic strategies and for predicting outcome of children with high-risk neuroblastoma.
Generous support from donors and foundations often forms seed funding for research that demonstrates that a particular line of research would be fruitful for peer-reviewed support. I am grateful to have received support from my research through the generosity of:
Alex's Lemonade Stand Foundation
Nautica Malibu Triathlon
St. Baldrick's Foundation
T.J. Martell Foundation
2011 Mellon Mentoring Award, University of Southern California
2008 Distinguished Alumni Citation, Willamette University
2001 H. Russell Smith Award for Innovation in Pediatric Biomedical Research
Revised risk estimation and treatment stratification of low- and intermediate-risk neuroblastoma patients by integrating clinical and molecular prognostic markers. Oberthuer A, Juraeva D, Hero B, Volland R, Carolina S, Schmidt R, Faldum A, Kahlert Y, Engesser A, Asgharzadeh S, Seeger RC, Ohira M, Nakagawara A, Scaruffi P, Tonini GP, Janoueix-Lerosey I, Delattre O, Schleiermacher G, Vandesompele J, Speleman F, Noguera R, Piqueras M, Benard J, Valent A, Avigad S, Yaniv I, Grundy RG, Ortmann M, Shao C, Schwab M, Eils R, Simon T, Theissen J, Berthold F, Westermann F, Brors B, Fischer M. Clin Cancer Res. 2014 Sep 17. pii: clincanres.0817.2014. [Epub ahead of print] PMID: 25231397 [PubMed - as supplied by publisher]
Age-Dependent Prognostic Effect by Mitosis-Karyorrhexis Index (MKI) in Neuroblastoma: A Report from the Children's Oncology Group. Teshiba R, Kawano S, Wang L, He L, Naranjo A, London WB, Seeger RC, Gastier-Foster JM, Look AT, Hogarty MD, Cohn SL, Maris JM, Park JR, Shimada H. Pediatr Dev Pathol. 2014 Sep 10. [Epub ahead of print] PMID: 25207821 [PubMed - as supplied by publisher]
Lenalidomide overcomes suppression of human natural killer cell anti-tumor functions by neuroblastoma microenvironment-associated IL-6 and TGFβ1.Xu Y, Sun J, Sheard MA, Tran HC, Wan Z, Liu WY, Asgharzadeh S, Sposto R, Wu HW, Seeger RC. Cancer Immunol Immunother. 2013 Oct;62(10):1637-48. doi: 10.1007/s00262-013-1466-y. Epub 2013 Aug 27. PMID: 23982484 [PubMed - indexed for MEDLINE]
Neuroblastoma of undifferentiated subtype, prognostic significance of prominent nucleolar formation, and MYC/MYCN protein expression: a report from the Children's Oncology Group.Wang LL, Suganuma R, Ikegaki N, Tang X, Naranjo A, McGrady P, London WB, Hogarty MD, Gastier-Foster JM, Look AT, Park JR, Maris JM, Cohn SL, Seeger RC, Shimada H. Cancer. 2013 Oct 15;119(20):3718-26. doi: 10.1002/cncr.28251. Epub 2013 Jul 30. PMID: 23901000 [PubMed - indexed for MEDLINE]
Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial. Kreissman SG, Seeger RC, Matthay KK, London WB, Sposto R, Grupp SA, Haas-Kogan DA, Laquaglia MP, Yu AL, Diller L, Buxton A, Park JR, Cohn SL, Maris JM, Reynolds CP, Villablanca JG. Lancet Oncol. 2013 Sep;14(10):999-1008. doi: 10.1016/S1470-2045(13)70309-7. Epub 2013 Jul 25. PMID: 23890779 [PubMed - indexed for MEDLINE]
Cancer Program The Saban Research Institute
Division of Hematology Oncology
4650 Sunset Boulevard
Los Angeles, Calif. 90027
Robert C. Seeger, MD
Director, Cancer Research Program
The Saban Research Institute
Head, Division of Basic and Translational Research
Children's Center for Cancer and Blood Diseases PubMed Link