title: Beyond high-dose methotrexate and brain radiotherapy: novel targets and agents for primary CNS lymphoma.
abstract: BACKGROUND
  While there has been significant progress in outcomes for patients diagnosed with primary central nervous system (CNS) lymphoma (PCNSL), survival rates will likely plateau with the current armamentarium of agents used to treat these patients. Moreover, given that PCNSL increasingly impacts an older population, a significant proportion of patients are not eligible for intensive therapies such as high-dose chemotherapy or whole-brain radiation. There is a need for the development of novel agents, which target key survival pathways in order to continue to make progress in this disease.
  
  
  METHODS
  We reviewed the key molecular pathways and genomic aberrations in PCNSL in order to identify candidate targets. We focused on molecules and pathways that have been identified and confirmed by more than one investigator or methodology.
  
  
  RESULTS
  While PCNSL tumors usually express a BCL6+, MUM1+ 'activated, germinal center' immunophenotype, they exhibit multiple shared genetic properties with ABC-type diffuse large B-cell lymphomas. Candidate targets and pathways include NFkB, the B-cell receptor, the JAK/STAT pathway, IRF4, BCL-6 as well as PIM kinases. Elements of the tumor microenvironment that may be exploited therapeutically include chemokine pathways, as well as macrophage and T-cell responses.
  
  
  CONCLUSIONS
  There is a significant need for developing novel therapies in PCNSL, given that an increasing proportion of patients are not eligible for high-dose chemotherapy and brain radiation is associated with detrimental cognitive side-effects. We provide an overview of potential drug targets and novel agents that may be integrated with existing strategies in order to make further progress in this disease.
authors.affiliation: Pathology Unit and Unit of Lymphoid Malignancies, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Ponzoni
authors.forename: S
authors.initials: S
authors.lastname: Issa
authors.forename: T T
authors.initials: TT
authors.lastname: Batchelor
authors.forename: J L
authors.initials: JL
authors.lastname: Rubenstein
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D016543:Central Nervous System Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D059248:Chemoradiotherapy; D006801:Humans; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008727:Methotrexate / Q000008:administration & dosage*; D010641:Phenotype; D059016:Tumor Microenvironment
chemical_list: D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate
keywords: B-cell receptor; novel agents; primary CNS lymphoma; protein kinases; tumor microenvironment