Cancer Program

Director:  Robert C. Seeger, MD

Emerging Initiative

Right now, physicians at our hospital are working on an exciting alternative treatment for cancer - immunotherapy.

In immunotherapy, physicians could deliver a drug that would arm a patient's own immune system to fight cancer from within. 

Three years ago, Drs. Metelitsa and Seeger identified the cancer-fighting power of a subset of white blood cells called "invariant natural Killer T" (NTK) cells.  They discovered that:

• when these cells infiltrated the tumors of children diagnosed with neuroblastoma, these children fared much better
• when a cancer gene, MYCN, is expressed, NKT cells typically are not present
• NKT cells reside most abundantly in tumors that exhibit a specific protein (CCL2/MCP-1)
• CCL2 acts as a beacon for NKT cells, which mediate the body's own immune response against cancer.

Next Steps

Dr. Metelitsa's laboratory is the only laboratory in the United States studying NKT cells in pediatric disease.  Next, Dr. Metelitsa will:

1. Combine novel agents, which stimulate NKT cells, with an experimental cancer vaccine designed to galvanize a patient's own immune system to recognize and selectively attack tumor cells
2. Create a vaccine that results in the patient's body creating an "immunological memory" so that if any cancer cell survives and later attempts to reproduce itself, the patient's immune system will control it. 

Research Focus

The overall goals of this program are to:

1. understand the biology of childhood cancers and leukemias, and the interactions of malignant cells with host cells, especially in the tumor microenvironment
2. translate this knowledge into clinical applications in areas of diagnosis, risk assessment, and therapy.

Disease-oriented groups perform translational research with Developmental Therapeutics being an integral part of efforts in:

• Neural Tumors (brain, neuroblastoma, retinoblastoma)
• Acute Leukemia
• Bone/Soft Tissue Sarcomas

Emphasis is placed upon investigating these childhood malignancies because many patients with these diagnoses have very aggressive disease that often is not yet successfully treated.  The Health Promotions and Outcomes research component includes studies of quality of life during and after therapy and of interventions affecting such.

Accomplishments

Signaling in Leukemogenesis
Principal Investigators:  Drs. Grofen and Heisterkamp
Drs. Groffen and Heisterkamp investigate the Bcr/Abl fusion protein, which causes chronic myelogenous leukemia and Philadelphia-chromosome positive acute lymphoblastic leukemia. They reported that the alpha catalytic subunit of protein kinase CKII, which is involved in leukemogenesis, strongly and specifically forms a complex with Bcr. Inhibition of Bcr/Abl P190 in lymphoma cells using imatinib (Gleevec, STI-571) reduced CKIIalpha activity, and a highly selective inhibitor of CKIIalpha inhibited the growth of murine lymphoid cells expressing Bcr/Abl. This work shows that CKIIalpha plays an important role in the proliferation of Bcr/Abl expressing cells, and suggests that inhibitors of CKIIalpha may have therapeutic potential in the treatment of Bcr/Abl-positive leukemia patients (Mishra, S et al, 2003).

Angiogenesis in Neuroblastoma
Principal Investigators:  Dr. DeClerck
Dr. DeClerck and colleagues found that matrix metalloproteinase-9 regulates the vascular architecture in neuroblastomas by promoting pericyte recruitment. They observed a significant decrease of tumor angiogenesis in immunodeficient RAG1/MMP-9 deficient mice implanted with neuroblastoma tumors that was due to an inhibition in the architecture of the tumor vasculature resulting in fewer and smaller blood vessels. These changes were Assoc.d with a 48% decrease in pericytes present along microvessels. They concluded that in neuroblastoma, stromally derived MMP-9 contributes to angiogenesis by promoting blood vessel morphogenesis and pericyte recruitment.  This research was featured on the front page of Cancer Research ( Chantrain, C et. al., 2004).

Immune Response in Neuroblastoma
Principal Investigators:  Drs. Metelitsa & Seeger
Drs. Metelitsa, Seeger, and colleagues showed for the first time that natural killer T cells infiltrate neuroblastomas expressing the chemokine CCL2. CD1d-restricted Valpha24-Jalpha18-invariant natural killer T cells (iNKTs) are potentially important in tumor immunity. 53% of tumors contained iNKTs, and oligonucleotide microarray analysis of the iNKT(+) and iNKT(-) tumors revealed that the former expressed higher levels of CCL2/MCP-1. Supernatants of neuroblastoma cell lines that produced CCL2 induced in vitro migration of iNKTs from blood of patients and normal adults; this was abrogated by an anti-CCL2 monoclonal antibody. CCL2 expression by tumors was found to inversely correlate with MYCN proto-oncogene amplification and expression, and MYCN-high/CCL2-low expression accurately predicted the absence of iNKTs (P < 0.001). This is the first demonstration that oncogene activation influences the infiltration of immune cells into tumors. (Metelitsa, L et al, 2004)

Signaling in Neuroblastoma Growth and Differentiation
Principal Investigators:  Dr. Bogenmann
Dr. Bogenmann found that the RET and TRKA pathways collaborate to regulate neuroblastoma differentiation. Activation of the RET receptor by glial cell line-derived neurotrophic factor (GDNF) increased expression of the RET receptor complex and induced growth cessation. Furthermore, GDNF synergizes with ciliary neurotrophic factor (CNTF) to enhance TRKA receptor expression, thereby strengthening the differentiation signal derived from nerve growth factor (NGF) interaction with TRKA. Differentiated neuroblastoma cells downregulated expression of the MYCN gene concurrent with the arrest of cell proliferation and expression of neuron-specific markers. This work shows the importance of these signaling pathways in neuroblastoma growth and maturation (Peterson, S et al, 2004).

Brain Tumor Clinical Trials
Principal Investigators:  Dr. Finlay
Dr. Finlay and colleagues reported that thiotepa-based high-dose chemotherapy with autologous stem-cell rescue can effectively treat patients with recurrent or progressive CNS germ cell tumors. Seven of nine (78%) patients with germinoma survived disease-free after high-dose chemotherapy with a median survival of 48 months. Patients with germinoma fared better than those with nongerminomatous germ cell tumors, and those with complete response to high-dose chemotherapy also had significantly better outcome compared with patients with only a partial response or stable disease. This trial demonstrates that dose escalation of chemotherapy followed by stem cell rescue is effective therapy for patients with recurrent CNS germinomas (Modak S et al, 2004).

Members