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Burzynski Research Institute, Inc. Announces the Launch of a New Clinical Trial in Diffuse Intrinsic Brainstem Glioma

On April 14, 2016 Burzynski Research Institute, Inc. (BRI) reported that it has begun patient enrollment into an FDA-reviewed and IRB-approved, open-label, single-arm phase 2 study of Antineoplastons A10 and AS2-1 in patients > 3 months of age with a diffuse intrinsic brainstem glioma (DIPG) (Press release, Burzynski Research Institute, APR 14, 2016, View Source [SID:1234510800]). Study subjects will be placed in one of five treatment groups based on their age and whether or not they have received prior treatment for DIPG. The primary study endpoint is a decrease in the size of the tumor, either a partial response (≥ 50% decrease in the size of the tumor) or a complete response (disappearance of the tumor).

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DIPG is primarily a disease of childhood, with the majority of patients being between 5 and 10 years of age. However, infants and adults can also be affected. It is the most common brainstem tumor in children, representing 75-80% of childhood brainstem tumors, and affecting an estimated 300 children in the U.S. each year. The prognosis for children with DIPG is significantly worse than that of other primary brainstem tumors. The standard of care for patients with newly-diagnosed DIPG is radiation therapy (RT), which appears to control tumor growth for a short period of time, prolonging survival by approximately 3 months. Within 3-8 months after completion of RT, most patients with DIPG will show progression of their disease. No chemotherapeutic agent has ever demonstrated a significant improvement in outcome beyond that achieved by RT alone. An original BRI paper, "The response and survival of children with recurrent intrinsic pontine glioma based on a phase II study of Antineoplastons A10 and AS2-1 in patients with brainstem glioma" was published in Child’s Nervous System in December 2014, Volume 30, Issue 12, pages 2051-2061 (DOI 10.1007/s00381-014-2401-z).

Causes of Cancer Death Among First-Degree Relatives in Japanese Families with Lynch Syndrome.

To elucidate the causes of cancer death in Japanese families with Lynch syndrome (LS).
The distributions of cancer deaths in 485 individuals from 67 families with LS (35, 30, and two families with MutL homologue 1 (MLH1), MSH2, and MSH6 gene mutations, respectively), obtained from the Registry of the Japanese Society for Cancer of the Colon and Rectum were analyzed.
Among 98 cancer deaths of first-degree relatives of unknown mutation status, 53%, 19%, 13% (among females), 7% (among females) and 5% were due to colorectal, gastric, uterine, ovarian, and hepatobiliary cancer, respectively. The proportion of deaths from extra-colonic cancer was significantly higher in families with MSH2 mutation than in those with MLH1 mutation (p=0.003).
In addition to colonic and uterine cancer, management and surveillance targeting gastric, ovarian and hepatobiliary cancer are considered important for Japanese families with LS. Extra-colonic cancer in families with MSH2 mutation might require for more intensive surveillance.
Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

A randomized, double-blind trial of pegfilgrastim versus filgrastim for the management of neutropenia during CHASE(R) chemotherapy for malignant lymphoma.

Pegfilgrastim is a pegylated form of the granulocyte-colony stimulating factor, filgrastim. Herein, we report the results of a multicentre, randomized, double-blind phase III trial comparing the efficacy and safety of pegfilgrastim with filgrastim in patients with malignant lymphoma. Patients were randomized to receive either a single subcutaneous dose of pegfilgrastim or daily subcutaneous doses of filgrastim on day 4 after the completion of cyclophosphamide, cytarabine, etoposide and dexamethasone ± rituximab (CHASE(R); day 1-3) chemotherapy. The primary endpoint was the duration of severe neutropenia (DSN), defined as the number of days with neutrophil count &lt;0·5 × 10(9) /l in the first cycle of chemotherapy. A total of 111 lymphoma patients were randomized to either the pegfilgrastim or filgrastim group. 109 patients received either pegfilgrastim (n = 54) or filgrastim (n = 55). Efficacy data were available for 107 patients (pegfilgrastim: n = 53, filgrastim: n = 54). Both groups were well balanced in terms of gender, age, performance status and other variables. The mean DSN (±S.D.) was 4·5 (±1·2) and 4·7 (±1·3) d in the pegfilgrastim and filgrastim groups. No significant difference in safety was observed. This trial verified the non-inferiority of a single subcutaneous dose of pegfilgrastim compared with daily subcutaneous doses of filgrastim, considering DSN as an indicator.
© 2016 The Authors. British Journal of Haematology published by John Wiley &amp; Sons Ltd.

Co-activation of AMPK and mTORC1 Induces Cytotoxicity in Acute Myeloid Leukemia.

AMPK is a master regulator of cellular metabolism that exerts either oncogenic or tumor suppressor activity depending on context. Here, we report that the specific AMPK agonist GSK621 selectively kills acute myeloid leukemia (AML) cells but spares normal hematopoietic progenitors. This differential sensitivity results from a unique synthetic lethal interaction involving concurrent activation of AMPK and mTORC1. Strikingly, the lethality of GSK621 in primary AML cells and AML cell lines is abrogated by chemical or genetic ablation of mTORC1 signaling. The same synthetic lethality between AMPK and mTORC1 activation is established in CD34-positive hematopoietic progenitors by constitutive activation of AKT or enhanced in AML cells by deletion of TSC2. Finally, cytotoxicity in AML cells from GSK621 involves the eIF2α/ATF4 signaling pathway that specifically results from mTORC1 activation. AMPK activation may represent a therapeutic opportunity in mTORC1-overactivated cancers.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Structure-Based Design of a Novel SMYD3 Inhibitor that Bridges the SAM-and MEKK2-Binding Pockets.

SMYD3 is a lysine methyltransferase overexpressed in colorectal, breast, prostate, and hepatocellular tumors, and has been implicated as an oncogene in human malignancies. Methylation of MEKK2 by SMYD3 is important for regulation of the MEK/ERK pathway, suggesting the possibility of selectively targeting SMYD3 in RAS-driven cancers. Structural and kinetic characterization of SMYD3 was undertaken leading to a co-crystal structure of SMYD3 with a MEKK2-peptide substrate bound, and the observation that SMYD3 follows a partially processive mechanism. These insights allowed for the design of GSK2807, a potent and selective, SAM-competitive inhibitor of SMYD3 (Ki = 14 nM). A high-resolution crystal structure reveals that GSK2807 bridges the gap between the SAM-binding pocket and the substrate lysine tunnel of SMYD3. Taken together, our data demonstrate that small-molecule inhibitors of SMYD3 can be designed to prevent methylation of MEKK2 and these could have potential use as anticancer therapeutics.
Copyright © 2016 Elsevier Ltd. All rights reserved.