Rational combination therapies targeting survival signaling in aggressive B-cell leukemia/lymphoma

The identification of oncogenic 'driver' mutations and activated survival pathways in selected aggressive B-cell malignancies directs the development of novel adjunctive therapies using targeted small molecule inhibitors. With a focus on diffuse large B-cell lymphoma 'not otherwise specified', Hodgkin lymphoma and childhood B-cell precursor acute lymphoblastic leukemia, this review will provide an up-to-date account of the current literature on the development of new molecularly targeted treatment modalities for aggressive B-cell malignancies.

Subclassification of B-cell malignancies depending on their particular genetic 'driver' lesions and transcriptional and/or signaling signatures has led to the development of targeted therapeutic approaches using small molecule inhibitors to amend current combination chemotherapy.

Treatment outcome with current combination chemotherapy is still poor for subsets of aggressive B-cell malignancies, and demands development of targeted therapeutic approaches. Advanced gene expression profiling and genomic sequencing have revealed a more detailed landscape of recurrent alterations, allowing a better subclassification of B-cell lymphomas and leukemias. Many alterations directly or indirectly lead to activation of survival signaling pathways and expression of key oncoproteins and prosurvival molecules, including Janus kinase-signal transducer and activator of transcription (JAK-STAT), phosphatidylinositol-3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR), avian myelocytomatosis viral oncogene homolog (MYC) and B-cell lymphoma 2 (BCLl-2). Small molecule inhibitors targeting these proteins and pathways are currently being tested in clinical trials and preclinically to improve chemotherapeutic regimes and treatment outcomes.