Neuroblastoma and Small Cell Carcinoma of the Lung SCLC Differences and Similarities

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Neuroblastoma and Small Cell Carcinoma of the
Lung (SCLC)Differences and Similarities

• C. Patrick Reynolds, MD PhD

1901
2001
ChildrensHospitalLosAngeles
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"Smoking kills. If you're killed, you've lost
a very important part of your life."
Brooke Shields,
in an interview for an anti-smoking campaign.
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Tissues Derived from Neural Crest Stem Cells
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International Neuroblastoma Staging System (INSS)
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Sites of Disease
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Spectrum of Neuroblastoma Differentiation
Normal Tissue
Neuroblastue
Initial Differentiationue
Ganglion Cellue
Tumor
Undifferentiated Neuroblastoma
Neuroblastoma (pseudorosettes)
Ganglioneuroma
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Excellent Survival for Localized Neuroblastoma
Treated with Minimal Therapy
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Overall Survival
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P

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Perez et al, JCO, 1818-26 1999
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myc Oncogenes
v-myc - oncogene in rapidly transforming
avian myelocytomatosis virus
c-myc - cellular cognate of v-myc MYCN -
homologous sequence to c-myc in NB cells L-myc
- homologous sequence to c-myc in SCLC cells

• short-lived nuclear transcription factors
• all can bind to mad, max
• all can bind to CACGTG

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MYCN Genomic Amplification
Chr 2p24
HSR
MYCN
Double minutes

• Approximately 25 of primary tumors
• Associated with advanced stage of disease,
  rapid tumor progression, and a poor prognosis

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MYCN Amplification Correlates With Poor Survival
in Infants with Stage 4 Neuroblastoma
P lt 0.0001
Schmidt, JCO 2000
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Drug Resistance In Human Neuroblastoma Cell Lines
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p53 Function and Response to Cytotoxic Drugs in
Neuroblastoma Cell Lines
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Molecular Biological Features
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Improving Survival for Stage 4 Neuroblastoma
Patients gt 1 Year of Age at Diagnosis
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Childrens Cancer Group Data
0.8
Probability of Overall Survival

0.6
0.4
1986-1995 N 675
0.2
1978-1985 N 507
P lt 0.001
0
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3
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10
Years from Diagnosis

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High-Dose, Pulse Retinoic Acid Induces
Neuroblastoma Differentiation
Control
10 mM Retinoic Acid
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(No Transcript)
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Initial Response Rates to Modern Combination
Chemotherapy
Neuroblastoma 80 to 90 SCLC 80 to 90
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Clinical Activity of Drugs
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Syngergistic Cytotoxicity of Safingol 4-HPR for
Drug-Resistant Neuroblastoma Cell Lines
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Activity of Fenretinide and Safingol Against
Cell Lines From Adult Cancers
Mauer et al J Natl Cancer Inst 921897, 2000
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There are Substantial Similarities Between
Neuroblastoma and Small Cell Lung Carcinoma in
Metastatic Sites Neuroendocrine
markers/antigens Molecular Biological
Features Initial Response Rates to
Chemotherapy Profile of Clinically Active Drugs
These similarities suggest that drugs
developed for either disease should be strongly
considered for clinical testing in the other.