TY - JOUR
T1 - Accelerating drug development for neuroblastoma
T2 - Summary of the Second Neuroblastoma Drug Development Strategy forum from Innovative Therapies for Children with Cancer and International Society of Paediatric Oncology Europe Neuroblastoma
AU - Moreno, Lucas
AU - Barone, Giuseppe
AU - DuBois, Steven G.
AU - Molenaar, Jan
AU - Fischer, Matthias
AU - Schulte, Johannes
AU - Eggert, Angelika
AU - Schleiermacher, Gudrun
AU - Speleman, Frank
AU - Chesler, Louis
AU - Geoerger, Birgit
AU - Hogarty, Michael D.
AU - Irwin, Meredith S.
AU - Bird, Nick
AU - Blanchard, Guy B.
AU - Buckland, Sean
AU - Caron, Hubert
AU - Davis, Susan
AU - De Wilde, Bram
AU - Deubzer, Hedwig E.
AU - Dolman, Emmy
AU - Eilers, Martin
AU - George, Rani E.
AU - George, Sally
AU - Jaroslav, Štěrba
AU - Maris, John M.
AU - Marshall, Lynley
AU - Merchant, Melinda
AU - Mortimer, Peter
AU - Owens, Cormac
AU - Philpott, Anna
AU - Poon, Evon
AU - Shay, Jerry W.
AU - Tonelli, Roberto
AU - Valteau-Couanet, Dominique
AU - Vassal, Gilles
AU - Park, Julie R.
AU - Pearson, Andrew D. J.
PY - 2020/9
Y1 - 2020/9
N2 - Only one class of targeted agents (anti-GD2 antibodies) has been incorporated into front-line therapy for neuroblastoma since the 1980s. The Neuroblastoma New Drug Development Strategy (NDDS) initiative commenced in 2012 to accelerate the development of new drugs for neuroblastoma. Advances have occurred, with eight of nine high-priority targets being evaluated in paediatric trials including anaplastic lymphoma kinase inhibitors being investigated in front-line, but significant challenges remain. This article reports the conclusions of the second NDDS forum, which expanded across the Atlantic to further develop the initiative. Pre-clinical and clinical data for 40 genetic targets and mechanisms of action were prioritised and drugs were identified for early-phase trials. Strategies to develop drugs targeting TERT, telomere maintenance, ATRX, alternative lengthening of telomeres (ALT), BRIP1 and RRM2 as well as direct targeting of MYCN are high priority and should be championed for drug discovery. Promising pre-clinical data suggest that targeting of ALT by ATM or PARP inhibition may be potential strategies. Drugs targeting CDK2/9, CDK7, ATR and telomere maintenance should enter paediatric clinical development rapidly. Optimising the response to anti-GD2 by combinations with chemotherapy, targeted agents and other immunological targets are crucial. Delivering this strategy in the face of small patient cohorts, genomically defined subpopulations and a large number of permutations of combination trials, demands even greater international collaboration. In conclusion, the NDDS provides an internationally agreed, biologically driven selection of prioritised genetic targets and drugs. Improvements in the strategy for conducting trials in neuroblastoma will accelerate bringing these new drugs more rapidly to front-line therapy.
AB - Only one class of targeted agents (anti-GD2 antibodies) has been incorporated into front-line therapy for neuroblastoma since the 1980s. The Neuroblastoma New Drug Development Strategy (NDDS) initiative commenced in 2012 to accelerate the development of new drugs for neuroblastoma. Advances have occurred, with eight of nine high-priority targets being evaluated in paediatric trials including anaplastic lymphoma kinase inhibitors being investigated in front-line, but significant challenges remain. This article reports the conclusions of the second NDDS forum, which expanded across the Atlantic to further develop the initiative. Pre-clinical and clinical data for 40 genetic targets and mechanisms of action were prioritised and drugs were identified for early-phase trials. Strategies to develop drugs targeting TERT, telomere maintenance, ATRX, alternative lengthening of telomeres (ALT), BRIP1 and RRM2 as well as direct targeting of MYCN are high priority and should be championed for drug discovery. Promising pre-clinical data suggest that targeting of ALT by ATM or PARP inhibition may be potential strategies. Drugs targeting CDK2/9, CDK7, ATR and telomere maintenance should enter paediatric clinical development rapidly. Optimising the response to anti-GD2 by combinations with chemotherapy, targeted agents and other immunological targets are crucial. Delivering this strategy in the face of small patient cohorts, genomically defined subpopulations and a large number of permutations of combination trials, demands even greater international collaboration. In conclusion, the NDDS provides an internationally agreed, biologically driven selection of prioritised genetic targets and drugs. Improvements in the strategy for conducting trials in neuroblastoma will accelerate bringing these new drugs more rapidly to front-line therapy.
KW - Clinical trials
KW - Drug development
KW - Epigenetics
KW - MYCN
KW - Neuroblastoma
KW - Phase I
KW - Preclinical testing
UR - http://www.scopus.com/inward/record.url?scp=85087483562&partnerID=8YFLogxK
U2 - 10.1016/j.ejca.2020.05.010
DO - 10.1016/j.ejca.2020.05.010
M3 - Review article
C2 - 32653773
AN - SCOPUS:85087483562
SN - 0959-8049
VL - 136
SP - 52
EP - 68
JO - European Journal of Cancer
JF - European Journal of Cancer
ER -