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Ref Type Journal Article
PMID (36602782)
Authors Tucker ER, Jiménez I, Chen L, Bellini A, Gorrini C, Calton E, Gao Q, Che H, Poon E, Jamin Y, Martins Da Costa B, Barker K, Shrestha S, Hutchinson JC, Dhariwal S, Goodman A, Del Nery E, Gestraud P, Bhalshankar J, Iddir Y, Saberi-Ansari E, Saint-Charles A, Geoerger B, Marques Da Costa ME, Pierre-Eugene C, Janoueix-Lerosey I, Decaudin D, Némati F, Carcaboso AM, Surdez D, Delattre O, George SL, Chesler L, Tweddle DA, Schleiermacher G
Title Combination Therapies Targeting Alk-Aberrant Neuroblastoma in Preclinical Models.
URL
Abstract Text ALK activating mutations are identified in approximately 10% of newly diagnosed neuroblastomas and ALK amplifications in a further 1-2% of cases. Lorlatinib, a third generation ALK inhibitor, will soon be given alongside induction chemotherapy for children with ALK-aberrant neuroblastoma. However, resistance to single agent treatment has been reported and therapies that improve the response duration are urgently required. We studied the preclinical combination of lorlatinib with chemotherapy, or with the MDM2 inhibitor, idasanutlin, as recent data has suggested that ALK inhibitor resistance can be overcome through activation of the p53-MDM2 pathway.To study the preclinical activity of ALK inhibitors alone and combined with chemotherapy or idasanutlin.We compared different ALK inhibitors in preclinical models prior to evaluating lorlatinib in combination with chemotherapy or idasanutlin. We developed a triple chemotherapy (CAV: cyclophosphamide, doxorubicin and vincristine) in vivo dosing schedule and applied this to both neuroblastoma genetically engineered mouse models (GEMM) and patient derived xenografts (PDX).Lorlatinib in combination with chemotherapy was synergistic in immunocompetent neuroblastoma GEMM. Significant growth inhibition in response to lorlatinib was only observed in the ALK-amplified PDX model with high ALK expression. In this PDX lorlatinib combined with idasanutlin resulted in complete tumor regression and significantly delayed tumor regrowth.In our preclinical neuroblastoma models, high ALK expression was associated with lorlatinib response alone or in combination with either chemotherapy or idasanutlin. The synergy between MDM2 and ALK inhibition warrants further evaluation of this combination as a potential clinical approach for children with neuroblastoma.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ALK amp neuroblastoma no benefit Cyclophosphamide + Doxorubicin + Lorlatinib + Vincristine Sulfate Preclinical - Pdx Actionable In a preclinical study, addition of Cytoxan (cyclophosphamide), Adriamycin (doxorubicin), and Oncovin (vincristine) to Lorbrena (lorlatinib) did not improve tumor growth inhibition in a patient-derived xenograft (PDX) model of neuroblastoma with ALK amplification and overexpression (PMID: 36602782). 36602782
ALK amp neuroblastoma sensitive Lorlatinib Preclinical - Pdx & cell culture Actionable In a preclinical study, Lorbrena (lorlatinib) inhibited viability of a panel of ALK-amplified neuroblastoma cell lines in culture, and inhibited tumor growth in a patient-derived xenograft (PDX) model (PMID: 36602782). 36602782
ALK R1275Q TP53 wild-type neuroblastoma sensitive Alectinib + Idasanutlin Preclinical - Cell culture Actionable In a preclinical study, Alecensa (alectinib) and Idasanutlin (RG7388) synergistically inhibited growth of a TP53 wild-type neuroblastoma cell line harboring ALK R1275Q in culture (PMID: 36602782). 36602782
ALK R1275Q TP53 wild-type neuroblastoma sensitive Idasanutlin + TAE684 Preclinical - Cell culture Actionable In a preclinical study, the combination of TAE684 and Idasanutlin (RG7388) inhibited growth of a TP53 wild-type neuroblastoma cell line harboring ALK R1275Q in culture (PMID: 36602782). 36602782
ALK F1174C neuroblastoma predicted - sensitive Cyclophosphamide + Doxorubicin + Lorlatinib + Vincristine Sulfate Preclinical - Pdx Actionable In a preclinical study, the combination of Lorbrena (lorlatinib), Cytoxan (cyclophosphamide), Adriamycin (doxorubicin), and Oncovin (vincristine) resulted in modest inhibition of tumor growth in a patient-derived xenograft (PDX) model of neuroblastoma harboring ALK F1174C (PMID: 36602782). 36602782
ALK F1174L TP53 wild-type neuroblastoma sensitive Alectinib + Idasanutlin Preclinical - Cell culture Actionable In a preclinical study, Alecensa (alectinib) and Idasanutlin (RG7388) synergistically inhibited growth and induced apoptosis in a TP53 wild-type neuroblastoma cell line harboring ALK F1174L in culture (PMID: 36602782). 36602782
ALK F1174C TP53 wild-type neuroblastoma resistant Idasanutlin + Lorlatinib Preclinical - Pdx Actionable In a preclinical study, a patient-derived xenograft (PDX) model of TP53 wild-type neuroblastoma harboring ALK F1174C was resistant to combination treatment with Lorbrena (lorlatinib) and Idasanutlin (RG7388) (PMID: 36602782). 36602782
ALK F1174V ALK amp TP53 wild-type neuroblastoma sensitive Idasanutlin + TAE684 Preclinical - Cell culture Actionable In a preclinical study, TAE684 and Idasanutlin (RG7388) synergistically inhibited growth of a TP53 wild-type neuroblastoma cell line harboring ALK F1174V and ALK amplification in culture (PMID: 36602782). 36602782
ALK F1174V ALK amp TP53 wild-type neuroblastoma sensitive Alectinib + Idasanutlin Preclinical - Cell culture Actionable In a preclinical study, Alecensa (alectinib) and Idasanutlin (RG7388) synergistically inhibited growth and induced apoptosis in a TP53 wild-type neuroblastoma cell line harboring ALK F1174V and ALK amplification in culture (PMID: 36602782). 36602782
ALK F1174L TP53 wild-type neuroblastoma sensitive Idasanutlin + TAE684 Case Reports/Case Series Actionable In a preclinical study, TAE684 and Idasanutlin (RG7388) synergistically inhibited growth and induced apoptosis in a TP53 wild-type neuroblastoma cell line harboring ALK F1174L in culture (PMID: 36602782). 36602782
ALK F1174L neuroblastoma sensitive Cyclophosphamide + Doxorubicin + Lorlatinib + Vincristine Sulfate Preclinical Actionable In a preclinical study, the combination of Lorbrena (lorlatinib), Cytoxan (cyclophosphamide), Adriamycin (doxorubicin), and Oncovin (vincristine) resulted in an early tumor response, and improved survival in a genetically engineered mouse model of neuroblastoma harboring ALK F1174L (PMID: 36602782). 36602782
ALK amp TP53 wild-type neuroblastoma sensitive Alectinib + Idasanutlin Preclinical - Cell culture Actionable In a preclinical study, Alecensa (alectinib) and Idasanutlin (RG7388) synergistically inhibited growth of a TP53 wild-type neuroblastoma cell line with ALK amplification in culture (PMID: 36602782). 36602782
ALK amp TP53 wild-type neuroblastoma sensitive Idasanutlin + Lorlatinib Preclinical - Pdx Actionable In a preclinical study, combination treatment with Lorbrena (lorlatinib) and Idasanutlin (RG7388) resulted in an additive effect on tumor growth inhibition with complete remission in a patient-derived xenograft (PDX) model of TP53 wild-type neuroblastoma with ALK amplification and overexpression (PMID: 36602782). 36602782