A newly report published in the journal Disease Models & Mechanisms from the Hallberg-Palmer research groups, working together with the Chesler lab at the Institute of Cancer Research, U.K. shows that a new ALK inhibitor, Lorlatinib (PF-06463922), shows remarkable pre-clinical efficacy in treatment of ALK-positive  neuroblasoma.  Lorlatinib was developed from the first ALK inhibitor, crizotinib (Xalkori), which was FDA approved for use in ALK-positive non-small-cell-lung-cancer 2011.

 

In neuroblastoma, activating mutations in the ALK kinase domain are typically refractory to crizotinib treatment, highlighting the need for more potent inhibitors. The next-generation ALK inhibitor Lorlatinib might be the answer; and in this work the research groups examined lorlatinib activity in ALK-driven neuroblastoma models in vitro and in vivo.

 

Lorlatinib has increased activity towards ALK mutants prevalent in neuroblastoma examined in both in vitro kinase assays and cell-based experiments examining ALK mutations.  In contrast to crizotinib, single agent administration of lorlatinib causes a dramatic tumor inhibition in mouse models of high-risk neuroblastoma. Taken together, the research groups show that lorlatinib is a potent inhibitor of crizotinib-resistant ALK mutations, and highlight an important new treatment option for neuroblastoma patients.

New manuscript accepted for publication in ONCOTARGET from the Hallberg-Palmer groups, which have investigated a second generation ALK inhibitor, brigatinib, in a neuroblastoma setting, March 2016.

Crizotinib, the first clinically approved ALK inhibitor for the treatment of ALK-positive lung cancer has had less dramatic responses in neuroblastoma. Here we investigate the efficacy of a second-generation ALK inhibitor, brigatinib, in a neuroblastoma setting. Employing neuroblastoma cell lines, mouse xenograft and Drosophila melanogaster model systems expressing different constitutively active ALK variants, we show clear and efficient inhibition of ALK activity by brigatinib. Similar abrogation of ALK activity was observed in vitro employing a set of different constitutively active ALK variants in biochemical assays. These results suggest that brigatinib is an effective inhibitor of ALK kinase activity in ALK addicted neuroblastoma that should be considered as a potential future therapeutic option for ALK-positive neuroblastoma patients alone or in combination with other treatments.

Comparison of the Anaplastic Lymphoma Kinase (ALK) mutations found in neuroblastoma with the secondary crizotinib-resistant mutations reported in non-small-cell-lung-cancer (NSCLC) and inflammatory myofibroblastic tumours (IMT) highlights some interesting features. Resistant mutations (red) generally cluster the inhibitor and ATP binding site (ADP, cyan) and strongly activating neuroblastoma-associated ALK mutations (blue) occur nearby or around the putative residues that are important for initial activation of ALK (αC-helix; green, A-loop; teal) activity. Two exceptions are the F1174 and G1269 mutations (purple), which are mutations found in both neuroblastoma and resistant NSCLC patients. Regulatory spine (light pink) and Catalytic spine (lime green) are shown.

Agenda for the NNBCR kick-off meeting in Gothenburg

Monday 21/9

 

09.20-09.40                     Gathering and “Fika” at Arvid Carlsson salen, Medicinareg. 3

 

Session 1,                        Chairs: Tommy Martinsson and Bengt Hallberg

Talks are 15 min., + 5 min discussion

 

09.50-10.00,                    Tommy Martinsson welcomes us and summarizes NNBCR, goals and targets

 

10.00-10.10,                    Presentations of participants

 

10.10-10.30,             NGS in neuroblastoma – The Gothenburg experience.

Susanne Fransson (group TM)

 

10.30-10.50,                    Inhibition of Rho kinase represses neuroblastoma growth by inducing differentiation and MYCN degradation.

Malin Wickström (JIJ)

 

10.50-11.10,                    Analysis of somatic structural alterations and their influence on gene expression in diverse human cancers.

Babak Alaei-Mahabad (EL)

 

11.10-11.30,                    The PPM1D encoded WIP1 phosphatase is a novel oncogene and potential therapeutic target in neuroblastoma and medulloblastoma.

Jelena Milosevic (PK)

 

11.30-11.50,             6p22 lncRNAs and neuroblastoma.

Tanmoy Mondal, (CK)

 

11.50-12.10,             CNK, a downstream target of ALK.

Georg Wolfstetter (RP)

 

 

12.10-13.30                     Lunch at “Lyktan”

 

 

 

Session 2,                        Chairs: Erik Lekholm and Chandrasekhar Kanduri

 

13.30-13.50,             PF-06463922 is a superior drug in a NB setting.

Jikui Guan (BH)

 

13.50-14.10,             ALK gene mutation in Neuroblastoma.

Niloufar Javanmardi (TM)

 

14.10-14.30,                    COX/mPGES- 1/PGE2 pathway depicts an inflammatory dependent high-risk neuroblastoma subset available for novel specific anti-inflammatory treatment.

Anna Kock (PK)

 

14.30-14.50,             Negative selection during tumor evolution.

Jimmy van den Eynden (EL)

 

 

14.50-15.10                     Coffee   

 

 

Session 3,                        Chairs: Per Kogner and Ruth Palmer

 

15.10-15.30,                    Targeting suppressive myeloid cells in neuroblastoma augments checkpoint blockade therapy.

Nina Eissler (JIJ)

 

15.30-15.50,                    Characterization of potential tumor suppressor on chromosome 17.

Kankadeb Mishra (CK)

 

15.50-16.10,             AP-26113, a player on the neuroblastoma field.

Joachim Siaw (BH)

 

16.10-16.30,            A Fam-tastic activator of ALK.

Ruth Palmer (RP)

 

16.30-16.50,             Discussions and Conclusions

 

 

Check in HOTEL             Clarion Hotel Post, Drottningtorget 10

 

 

19.00-                                Dinner at restaurant “El Corazon”, Kungstorget

 

Tuesday 22/9

 

Departure at own time.

 

 

09.00-13.00                     NNBCR PI meeting,

at Stina Stenhagen conf. room, Medicinaregatan 3,

 

First discussion regarding 12th of November, 2015 and future planning. Tommy will lead this

 

10.00                                 Coffee

 

 

12-ish                                Lunch at Lyktan – the end.

All consortium investigators gathered for the third NNBCR meeting in Gothenburg. The agenda included scientific updates and presentations, and plans were made for the website you are viewing right now.