Pre-Clinical Studies and Pharmacology of 13-Cis-Retinoic Acid in Neuroblastoma

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Pre-Clinical Studies and Pharmacology of
13-Cis-Retinoic Acid in Neuroblastoma

• C. Patrick Reynolds, MD PhD

Childrens Hospital Los Angeles University of
Southern California Childrens Oncology Group
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High-Dose, Pulse Retinoic Acid Induces
Neuroblastoma Differentiation
Control
10 mM Retinoic Acid
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Regulation of Transcription by Retinoids
Activation of Transcription
mSin3a
9-cis-RA
ACTR
HDAC1
SMRT or N-coR
ATRA
CPB/p300
Transcriptional Repression
RAR
RXR
RXR
RAR
AGGTCA 5bp AGGTCA
AGGTCA 5bp AGGTCA
RARE
RARE
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Naturally Occurring Retinoids
retinal
retinol (vitamin A)
all trans-retinoic acid
9-cis-retinoic acid
13-cis-retinoic acid
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Retinoic Acid Induces Prolonged Differentiation
and Growth Arrest in SMS-LHN
10 mM Retinoic Acid
Control
Day 28 (RA for 14 days, control passed x 4)
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13-cis-Retinoic Acid Causes Sustained Growth
Arrest of Neuroblastoma

• Neuroblastoma cell line given two pulses (2 weeks
  each) of 5 mM 13-cis-retinoic acid
• MYCN protein expression by immunoblotting was
  down-regulated
• Phase I study achieved levels of 7.2 5.3 mM
  peak and 4.1 2.7 mM trough

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Pharmacokinetics of 13-cis-Retinoic Acid
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Pharmacokinetics of 13-cis-Retinoic Acid
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13-cis-RA Shows Stable AUC During Therapy
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Formulation Sub-Optimal For Young Children

• Liquid in soft gelatin capsule (10, 20, 30, 40
  mg)
• Can be pierced and chewed or children trained to
  swallow
• Often must be squeezed into food for young
  children causing increased dosing variability
• Out-of-capsule administration may be associated
  with decreased 13-cis-RA levels
  Veal et al, Br J Cancer 96424, 2007
• Extemporaneous liquid formulations have been
  associated with toxicity likely due to metabolism
  to ATRA

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Drug Antagonism by 13-cis-RA in Neuroblastoma
SMS-KCNR
SMS-SAN
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High-Risk Neuroblastoma Burden During Therapy
13-cis-RA ?
LONG-TERM SURVIVAL
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How can 13-cis-RA For Neuroblastoma Be Improved ?

• Isotretinoin labeling should include recommended
  dosing and approaches to use of the existing
  formulation in pediatric oncology
• Pharmacokinetic and possibly pharmacogenomic
  studies could allow for PK and/or PG-guided
  dosing
• Further study on administration route (in or out
  of capsule) effects on PK are needed
• A stable formulation suitable for young children
  and safe for handling by women of child-bearing
  potential would be optimal

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Acknowledgements
Clinical Trials
Pharmacokinetics
Vas Avramis Anis Khan
Judy Villablanca Kate Matthay Bob
Seeger Childrens Oncology Group
The Patients and Parents who Participated in
our Clinical Trials