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 Children’s Oncology Group
Jan 20, 2016
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
Children’s Oncology Group
Control 10 M Retinoic Acid
High-Dose, Pulse Retinoic Acid Induces Neuroblastoma Differentiation
Regulation of Transcription by Retinoids
Transcriptional Repression
RARE
ATRA
RAR
CPB/p300
9-cis-RAACTR
Activation of
Transcription
RXR
AGGTCA 5bp AGGTCA
RARE
RXR RAR
SMRTor
N-coR
mSin3a
HDAC1
AGGTCA 5bp AGGTCA
Naturally Occurring Retinoids
all trans-retinoic acid
retinol (vitamin A)retinal
9-cis-retinoic acid
13-cis-retinoic acid
10 M Retinoic AcidControl
Retinoic Acid Induces Prolonged Differentiation and Growth Arrest in SMS-LHN
Day 28 (RA for 14 days, control passed x 4)
13-cis-Retinoic Acid Causes Sustained Growth Arrest of Neuroblastoma
• Neuroblastoma cell line given two pulses (2 weeks each) of 5 M 13-cis-retinoic acid
• MYCN protein expression by immunoblotting was down-regulated
• Phase I study achieved levels of 7.2 + 5.3 M peak and 4.1 + 2.7 M trough
DAYS
0 14 28 42 56 70 84 98 112126
% C
ON
TR
OL
0
20
40
60
80
100
RA RA
0 14 28 42 56 70 84 98 112126
CE
LL
NU
MB
ER
103
104
105
106
107
108
109
1010
Control
13-cis-RA
13-cis-RA
MYCN Expression
Pharmacokinetics of 13-cis-Retinoic Acid
Pharmacokinetics of 13-cis-Retinoic Acid
13-cis-RA Shows Stable AUC During Therapy
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 96:424, 2007
• Extemporaneous liquid formulations have been associated with toxicity likely due to metabolism to ATRA
Drug Antagonism by 13-cis-RA in Neuroblastoma
SMS-KCNR
SMS-SAN
High-Risk Neuroblastoma Burden During Therapy
13-cis-RA ?LONG-TERM SURVIVAL
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
Acknowledgements
Clinical Trials
Judy VillablancaKate MatthayBob SeegerChildren’s Oncology Group
Pharmacokinetics
Vas AvramisAnis Khan
The Patients and Parents who Participated in our Clinical Trials