Diffuse Intrinsic Pontine Glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and choosing therapies based on assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic make-up of this brain cancer with nearly 80% harboring a K27M-H3.3 or K27M-H3.1 mutation. However, DIPGs are still thought of as one disease with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs we integrated whole-genome-sequencing with methylation, expression and copy-number profiling, discovering that DIPGs are three molecularly distinct subgroups (H3-K27M, Silent, MYCN) and uncovering a novel recurrent activating mutation in the activin receptor ACVR1, in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer.

Background Recurrent medulloblastoma is a daunting therapeutic challenge as it is almost universally fatal. Recent studies confirmed that medulloblastoma comprises four distinct subgroups. We sought to delineate subgroup specific differences in medulloblastoma recurrence patterns. Methods We retrospectively identified a discovery cohort of all recurrent medulloblastomas at the Hospital for Sick Children between 1994-2012, and performed molecular subgrouping on FFPE tissues using a nanoString-based assay. The anatomical site of recurrence (local tumour bed or leptomeningeal metastasis), time to recurrence and survival post-recurrence were determined in a subgroup specific fashion. Subgroup specific recurrence patterns were confirmed in two independent, non-overlapping FFPE validation cohorts. Where possible molecular subgrouping was performed on tissue obtained from both the initial surgery and at recurrence. Results A screening cohort of 30 recurrent medulloblastomas was assembled; nine with local recurrences, and 21 metastatic. When re-analysed in a subgroup specific manner, local recurrences were more frequent in SHH tumours (8/9, 88%) and metastatic recurrences were more common in Group 3 and 4 (17/20 [85%] with one WNT, p=0.0014, local vs metastatic recurrence, SHH vs Group 3 vs Group 4). The subgroup specific location of recurrence was confirmed in a multicenter validation cohort (p=0·0013 for local vs metastatic recurrence SHH vs Group 3 vs Group 4, n=77), and a second independent validation cohort comprising 96 recurrences (p<0·0001 for local vs metastatic recurrence SHH vs Group 3 vs Group 4, n=96). Treatment with craniospinal irradiation at diagnosis was not significantly associated with the anatomical pattern of recurrence. Survival post recurrence was significantly longer in Group 4 patients (p=0·013) as confirmed in a multicenter validation cohort (p=0·0075). Strikingly, subgroup affiliation remained stable at recurrence in all 34 cases with available matched primary and recurrent pairs. Conclusions Medulloblastoma does not switch subgroup at the time of recurrence further highlighting the stability of the four principle medulloblastoma subgroups. Significant differences in the location and timing of recurrence across medulloblastoma subgroups were observed which have potential treatment ramifications. Specifically, intensified local (posterior fossa) therapy should be tested in the initial treatment of SHH patients. Refinement of therapy for Groups 3 and 4 should focus on the metastatic compartment, as it is the near universal cause of patient deaths.

Akt/PKB is a serine/threonine kinase that promotes tumor cell growth by phosphorylating transcription factors and cell cycle proteins. There is particular interest in finding tumor-specific substrates for Akt to understand how this protein functions in cancer and to provide new avenues for therapeutic targeting. Our laboratory sought to identify novel Akt substrates that are expressed in breast cancer. In this study, we determined that activated Akt is positively correlated with the protein expression of the transcription/translation factor Y-box binding protein-1 (YB-1) in primary breast cancer by screening tumor tissue microarrays. We therefore questioned whether Akt and YB-1 might be functionally linked. Herein, we illustrate that activated Akt binds to and phosphorylates the YB-1 cold shock domain at Ser102. We then addressed the functional significance of disrupting Ser102 by mutating it to Ala102. Following the stable expression of Flag:YB-1 and Flag:YB-1 (Ala102) in MCF-7 cells, we observed that disruption of the Akt phosphorylation site on YB-1 suppressed tumor cell growth in soft agar and in monolayer. This correlated with an inhibition of nuclear translocation by the YB-1(Ala102) mutant. In conclusion, YB-1 is a new Akt substrate and disruption of this specific site inhibits tumor cell growth.

Drugs that target the insulin-like growth factor-I receptor (IGF-IR) and/or insulin receptor (IR) are currently under investigation for a variety of malignancies including breast cancer. Although we have previously reported that IGF-IR expression in primary breast tumors is common, the activation status of this receptor has not been examined in relation to survival. Phosphorylated IGF-IR/IR (P-IGF-IR/IR) and its downstream signaling partner phospho-S6 (P-S6) were evaluated immunohistochemically in tumor tissue microarrays representing 438 cases of invasive breast cancer. P-IGF-IR/IR (n = 114; P = 0.046) and total levels of IR (n = 122; P = 0.009) were indicative of poor survival, whereas total IGF-IR (n = 112; P = 0.304) was not. P-IGF-IR/IR and P-S6 were coordinately expressed in primary breast tumors (likelihood ratio, 11.57; P = 6.70 Â 10 À4