Abstract Medulloblastoma is the most commonly diagnosed pediatric brain tumor. Although therapeutic advances have improved survival from this cancer, they result in devastating sequelae and, additionally, have proven inadequate in metastatic disease and recurrence where survival remains <5%. Effective therapies are urgently needed to improve outcomes in medulloblastoma. Medulloblastoma development is driven by dysregulation of normal cerebellar proliferation. Mutations in the sonic hedgehog (Shh) pathway are found in ~30% of these tumors and responsible for their aggressive growth. The poor outcomes in Shh-driven medulloblastoma have prompted the evaluation of Shh-targeting agents in their treatment – with limited success likely attributable in part to the upregulation of alternate survival pathways (e.g. Ras/MAPK and HIF-1α). These alternate mechanisms stimulate glycolysis, in part by increasing the activity of the 6-phosphofructo-2-kinase/fructose-2,6 bisphosphatases (PFKFB1-4) to produce fructose-2,6-bisphosphate (F26BP), a potent activator of the rate-limiting glycolytic enzyme, 6-phosphofructo-1-kinase. In recent studies, we have determined that the PFKFB4 enzyme is highly expressed in patient-derived Shh medulloblastomas. We have found that hypoxia, through HIF-1α, strongly induced PFKFB4 expression in Shh-driven medulloblastoma cells and that silencing PFKFB4 suppressed F26BP, glycolysis and proliferation in normoxia and, more markedly, in hypoxia, indicating that PFKFB4 may be required for growth under hypoxia. We found that simultaneously silencing PFKFB4 and Shh pathway effectors significantly reduced cell survival and that co-targeting PFKFB4 (with a novel inhibitor) and Shh effectors synergistically decreased cell viability. In order to simulate Shh antagonist resistance, we have now subjected Shh medulloblastoma cells to prolonged Shh inhibitor exposure and found that these cells exhibit increased proliferation, glycolysis and PFKFB4. Studies are underway to delineate their metabolic alterations. Taken together, our data indicate that targeting PFKFB4 may be a valid therapeutic option in aggressive, treatment-resistant medulloblastoma and strongly support the further examination of PFKFB4 inhibitors in these tumors.
Heparin-induced antibodies (HIA) are responsible for causing heparin-induced thrombocytopenia and thrombosis. Research has shown that the temporality of heparin-induced antibodies does not follow the classic immunologic response. The immunobiology of HIA generation remains unclear with varying in vitro and in vivo data. Outpatients undergoing hemodialysis (HD) are exposed to heparin chronically. The HIA immune response can therefore be investigated in vivo in this population.We examined the time between the start of HD using unfractionated heparin and HIA levels in 212 outpatients during a 6-year period. Antibodies were detected on enzyme-linked immunosorbent assay. HIA levels were analyzed to determine significance of the trend over time. HIA subgroups were also analyzed for correlation with subsequent thrombotic events and platelet count during follow up.Overall, the HIA response in HD was found to peak early with waning antibody response despite continued exposure to heparin. The peak prevalence of a strong immune response (optical density > 1.000) was early and short lived, while weaker immune response (optical density 0.400-1.000) persisted for the first 6 months then declined. The mean follow-up time per patient was 2.3 ± 1.4 years. Despite circulating HIA, including high titers, no patients developed HIT in this sample. There was no association between HIA and thrombocytopenia. There was increased incidence of thrombosis in patients with strong HIA compared to other groups, but this did not achieve statistical significance.The data suggest a significant temporal pattern of HIA in outpatients undergoing HD using unfractionated heparin. Positive HIA was not found to be significantly associated with thrombocytopenia or thrombosis risk in these patients. However, while not achieving statistical significance, subsequent thrombotic events occurred most frequently in the strong positive HIA group (optical density > 1.000). Further research into HIA and risk of thrombosis in this population is needed.
The combination of de novo hepatic dysfunction and AML in a medically fit patient presents an unusual predicament. Cases present with obstructive jaundice and imaging typically shows diffuse hepatosplenomegaly, with some cases visualizing myeloid sarcomas causing biliary ductal dilatation. Guidelines for use of anthracyclines in hepatic dysfunction recommend dose reduction based on bilirubin blood levels, either to 50% or even omitting anthracycline. Randomized data however has shown that reduction of anthracycline in AML induction decreases overall survival and lowers remission rate. This case suggests, along withthe literature reviewed, that some medically fit patients with hepatic dysfunction benefit from and tolerate intensive induction therapy well without toxicity.
Abstract Background Recurrent pericarditis (RP) is managed with nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids (CS), and colchicine; up to 15% of pericarditis patients experience multiple recurrences. Interleukin 1 (IL-1) is an important cytokine in the pathophysiology of RP. Rilonacept (KPL-914) is a recombinant fusion protein which binds IL-1α and IL-1β. An ongoing Phase 2 study of rilonacept demonstrated improvements in RP symptoms and inflammation. Purpose To evaluate the efficacy and safety of subcutaneous (SC) rilonacept in patients with RP in a Phase 3, randomized, placebo-controlled trial. Methods RHAPSODY is a double-blind, placebo-controlled, randomized-withdrawal trial; ∼50 patients will be enrolled (Figure). Patients (≥12 y) must present with at least a third pericarditis episode (all etiologies except infectious and malignant) characterized by a pain score ≥4 on the 11-point Numeric Rating Scale (NRS) and C-reactive protein (CRP) ≥1 mg/dL at screening. Patients may be receiving stable doses of analgesics, NSAIDs, colchicine, and/or CS. After a loading dose (320 mg SC in adults and 4.4 mg/kg SC in children), all patients will receive weekly rilonacept (160 mg SC in adults and 2.2 mg/kg SC in children) during the run-in period. Patients able to taper and discontinue concomitant pericarditis medications and achieve clinical response (mean daily NRS score ≤2.0 during the 7 days before randomization and CRP level ≤0.5 mg/dL) will be randomized 1:1 in a blinded fashion to continued rilonacept or matching placebo weekly SC injections. Investigators may choose different treatments for pericarditis recurrences based on patient clinical status, including bailout rilonacept, while maintaining the blind to prior treatment assignment. The primary efficacy endpoint is time to pericarditis recurrence (adjudicated by an independent committee) in the randomized-withdrawal portion of the study. Secondary efficacy endpoints are the proportion of patients maintaining a clinical response, percentage of days with NRS pain score ≤1, and percentage of patients with no-to-minimal pericarditis symptoms based on patient global assessment. Safety evaluations include adverse events monitoring, physical examinations, and laboratory tests. Figure 1 Conclusions RHAPSODY is a pivotal Phase 3 trial evaluating the efficacy and safety of rilonacept in patients with RP using a double-blind, placebo-controlled, randomized-withdrawal design. The results of this study may inform the management of RP. Acknowledgement/Funding This study is sponsored by Kiniksa Pharmaceuticals, Ltd.
The rapid growth and progression of breast tumors is driven by multiple oncogenic mutations. Of these genetic alterations, one of the most important is the increased activity of the human epidermal growth factor receptor 2 (HER2) which is present in a third of breast cancers and associated with aggressive disease and poor survival. Although new agents have improved outcomes in HER2+ breast cancer, many patients continue to progress, develop metastases and die of their disease. Novel and effective targeted therapies are urgently required to improve survival from this devastating cancer. HER2+ cancers consistently exhibit a high reliance on glycolysis to fuel their rapid growth and metastasis. The high glycolytic flux in these tumors is driven by HER2-mediated effectors including the PI3K/AKT and Ras/MAPK pathways and HIF-1α which increase glucose metabolism in part by increasing the activity of a family of enzymes termed the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4). The PFKFBs produce fructose-2,6-bisphosphate (F26BP) which regulates glycolysis by activating a key rate-limiting glycolytic enzyme, 6-phosphofructo-1-kinase (PFK1). In recent studies, we have found that the PFKFB4 family member is highly expressed in a series of HER2+ patient-derived breast tumors relative to normal breast tissue with markedly higher expression in their matched metastatic lymph nodes. We have determined that silencing PFKFB4 markedly reduced F26BP, glycolysis and cell survival in HER2+ breast cancer cells in vitro. We have now developeda novel and potent small molecule PFKFB4 inhibitor that selectively inhibits recombinant PFKFB4 activity, decreases glycolysis and proliferation in HER2+ breast cancer cells and limits their migration and invasion at concentrations that do not affect their viability and suppresses xenograft tumor growth in mice without systemic toxicity. During our studies, we observed that inhibition of a frequently co-expressed PFKFB family member, PFKFB3, increased PFKFB4 expression, indicating that PFKFB4 may compensate for decreased PFKFB3 expression. We now have also found that the simultaneous administration of PFKFB4 and PFKFB3 inhibitors synergistically and significantly decreases proliferation in HER2+ breast cancer cells. These observations carry additional relevance since a novel PFKFB3 inhibitor has recently completed Phase I clinical trial evaluation and compensation by PFKFB4 may limit the efficacy of this and other PFKFB3 inhibitors. Taken together, our current data indicate that targeting PFKFB4 may prove to be a successful treatment option against HER2+ breast tumors and strongly support the further exploration of co-targeting PFKFB4 and PFKFB3 as a potential therapeutic strategy to improve outcomes in this cancer.
