Reference Detail

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-Eugène C, Janoueix-Lerosey I, Decaudin D, Nemati 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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	29	7	2023 Apr 03	1317-1331	Clin Cancer Res

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 anaplastic lymphoma kinase (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 have suggested that ALK inhibitor resistance can be overcome through activation of the p53-MDM2 pathway.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	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 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 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 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 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 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 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
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