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RESEARCH TOPICS

  • Biology of childhood cancer

  • 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

RESEARCH OVERVIEW

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.

  1. Using lenalidomide, an immune modulator, in combination with an anti-neuroblastoma antibody.
  2. 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.
     

Neuroblastoma Consortium

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

  1. 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. 

  2. 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.

  3. We contributed to the development of antibody immunotherapy for neuroblastoma, which, when added to the above "gold standard" treatment, further improves survival of patients.

     

CURRENT FUNDING

PEER-REVIEWED SUPPORT

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. 

PHILANTHROPIC SUPPORT

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:

  1. Alex's Lemonade Stand Foundation
  2. Bogart Foundation
  3. Nautica Malibu Triathlon
  4. St. Baldrick's Foundation
  5. T.J. Martell Foundation

 
AWARDS

  • 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
     

PUBLICATIONS

Check my PubMed link for a full list of publications

  1. Sorafenib inhibits endogenous and IL-6/S1P induced JAK2-STAT3 signaling in human neuroblastoma, associated with growth suppression and apoptosis.
    Yang F, Jove V, Buettner R, Xin H, Wu J, Wang Y, Nam S, Xu Y, Ara T, Declerck YA, Seeger R, Yu H, Jove R. Cancer Biol Ther. 2012 May 1;13(7). [Epub ahead of print].

  2. Common Variation at BARD1 Results in the Expression of an Oncogenic Isoform that Influences Neuroblastoma Susceptibility and Oncogenicity.
    Bosse KR, Diskin SJ, Cole KA, Wood AC, Schnepp RW, Norris G, Nguyen LB, Jagannathan J, Laquaglia M, Winter C, Diamond M, Hou C, Attiyeh EF, Mosse YP, Pineros V, Dizin E, Zhang Y, Asgharzadeh S, Seeger RC, Capasso M, Pawel BR, Devoto M, Hakonarson H, Rapport EF, Irminger-Finger I, Maris JM.
    Cancer Res. 2012 Feb 20. [Epub ahead of print]

  3. Immunology and immunotherapy of neuroblastoma.
    Seeger RC.
    Semin Cancer Biol. 2011 Oct;21(4):229-37. Epub 2011 Sep 28. Review.

  4. Genotypes of NK cell KIR receptors, their ligands, and Fcã receptors in the response of neuroblastoma patients to Hu14.18-IL2 immunotherapy.
    Delgado DC, Hank JA, Kolesar J, Lorentzen D, Gan J, Seo S, Kim K, Shusterman S, Gillies SD, Reisfeld RA, Yang R, Gadbaw B, DeSantes KB, London WB, Seeger RC, Maris JM, Sondel PM.
    Cancer Res. 2010 Dec 1;70(23):9554-61. Epub 2010 Oct 8.

  5. Antitumor activity of hu14.18-IL2 in patients with relapsed/refractory neuroblastoma: a Children's Oncology Group (COG) phase II study.
    Shusterman S, London WB, Gillies SD, Hank JA, Voss SD, Seeger RC, Reynolds CP, Kimball J, Albertini MR, Wagner B, Gan J, Eickhoff J, DeSantes KB, Cohn SL, Hecht T, Gadbaw B, Reisfeld RA, Maris JM, Sondel PM.
    J Clin Oncol. 2010 Nov 20;28(33):4969-75. Epub 2010 Oct 4.

CONTACT US

Cancer Program
The Saban Research Institute
Division of Hematology Oncology
4650 Sunset Boulevard
MS #57
Los Angeles, Calif.  90027
Fax: 323-361-4902

323-361-5618

PRINCIPAL INVESTIGATOR

Robert C. Seeger, MD

 

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

NIH Biosketch

Hematology Oncology

Collaborators