Potential Therapies for Anaplastic Lymphoma Kinase-Driven Tumors in Children: Progress to Date

Lowe, Eric; Lim, Megan S.

doi:10.1007/s40272-013-0027-3

Cited by 8 publications

(7 citation statements)

References 46 publications

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“…A number of different chemotherapy regimens have been trialled, but none have been able to breach an OS of 90% and 70% EFS (Lowe & Lim, ; Prokoph et al , ). It is therefore unlikely that modifying current trial protocols further will improve these statistics but modifications could improve the acute side‐effects of therapy.…”

Section: Current Avenues For Treatment; Breaking the Ceiling?mentioning

confidence: 99%

From bench to bedside: the past, present and future of therapy for systemic paediatric ALCL, ALK+

et al. 2019

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Anaplastic large cell lymphoma (ALCL) is a T cell Non-Hodgkin Lymphoma that mainly presents in paediatric and young adult patients. The majority of cases express a chimeric fusion protein resulting in hyperactivation of anaplastic lymphoma kinase (ALK) as the consequence of a chromosomal translocation. Rarer cases lack expression of ALK fusion proteins and are categorised as ALCL, ALKÀ. An adapted regimen of an historic chemotherapy backbone is still used to this day, yielding overall survival (OS) of over 90% but with event-free survival (EFS) at an unacceptable 70%, improving little over the past 30 years. It is clear that continued adaption of current therapies will probably not improve these statistics and, for progress to be made, integration of biology with the design and implementation of future clinical trials is required. Indeed, advances in our understanding of the biology of ALCL are outstripping our ability to clinically translate them; laboratory-based research has highlighted a plethora of potential therapeutic targets but, with high survival rates combined with a scarcity of funding and patients to implement paediatric trials of novel agents, progress is slow. However, advances must be made to reduce the side-effects of intensive chemotherapy regimens whilst maintaining, if not improving, OS and EFS.

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Section: Current Avenues For Treatment; Breaking the Ceiling?mentioning

confidence: 99%

From bench to bedside: the past, present and future of therapy for systemic paediatric ALCL, ALK+

et al. 2019

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“…However, NPM-ALK accounts for more than 75% of the ALK+ ALCL cases reported 9,10. Expression of ALK rearrangements in ALCL ranges from 65%–85% and is predominant in pediatric cases 10.…”

Section: Oncogenic Role Of Alk and Current Therapiesmentioning

confidence: 99%

ALK-driven tumors and targeted therapy: focus on crizotinib

Murga‐Zamalloa¹,

Lim²

2014

PGPM

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Receptor tyrosine kinases have emerged as promising therapeutic targets for a diverse set of tumors. Overactivation of the tyrosine kinase anaplastic lymphoma kinase (ALK) has been reported in several types of malignancies such as anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, neuroblastoma, and non-small-cell lung carcinoma. Further characterization of the molecular role of ALK has revealed an oncogenic signaling signature that results in tumor dependence on ALK. ALK-positive tumors display a different behavior than their ALK-negative counterparts; however, the specific role of ALK in some of these tumors remains to be elucidated. Although more studies are required to establish selective targeting of ALK as a definitive therapeutic option, initial trials have shown extraordinary results in the majority of cases.

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“…Oncogenic ALK transformation is mediated by interactions with downstream molecules that trigger substantial intracellular signaling cascades. 3 Activating mutations or translocations of ALK gene have been identified in many ALK-driven tumors in children, 4 including the acute lymphoblastic leukemia (ALL). 5,6 In recent years, targeting ALK with small-molecule kinase inhibitors has been becoming a potential therapeutics strategy for the treatment of ALK-driven pediatric ALL.…”

Section: Introductionmentioning

confidence: 99%

QSAR‐based targeting anaplastic lymphoma kinase (ALK) variants with noncognate inhibitors in pediatric acute lymphoblastic leukemia

Wang

Zhuo

Han

et al. 2016

Journal of Chemometrics

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Human anaplastic lymphoma kinase (ALK) is a potential target for the treatment of pediatric acute lymphoblastic leukemia. However, a number of residue mutations in ALK kinase domain have been observed to cause drug resistance in pediatric acute lymphoblastic leukemia chemotherapy. Here, a chemometrics quantitative structure‐activity relationship predictor was developed using a structure‐based panel of kinase‐inhibitor activity data. The predictor was validated rigorously through internal cross‐validation and external blind test to ensure its statistical reliability, which was then used to computationally construct a systematic activity profile of 13 noncognate kinase inhibitors against both wild‐type ALKwt and cancer‐related variants ALKvt. It is revealed that most noncognate inhibitors exhibit weak potency on ALKwt, but some of them are able to selectively target ALKvt over ALKwt. The chemometrics findings were then evaluated by using a kinase inhibition protocol; results showed that few noncognate inhibitors are 2‐ to 5‐fold higher potent against ALK variant than wild‐type kinase.

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Potential Therapies for Anaplastic Lymphoma Kinase-Driven Tumors in Children: Progress to Date

Cited by 8 publications

References 46 publications

From bench to bedside: the past, present and future of therapy for systemic paediatric ALCL, ALK+

From bench to bedside: the past, present and future of therapy for systemic paediatric ALCL, ALK+

ALK-driven tumors and targeted therapy: focus on crizotinib

QSAR‐based targeting anaplastic lymphoma kinase (ALK) variants with noncognate inhibitors in pediatric acute lymphoblastic leukemia

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