DNA methyltransferase inhibitor / Quimatryx - LARVOL DELTA

Resistance to SL-401 in AML and BPDCN Is Associated with Loss of the Diphthamide Synthesis Pathway Enzyme DPH1 and Is Reversible By Azacitidine (ASH 2017) - P1; "...Therefore, we tested the DNA methyltransferase inhibitor azacitidine in combination with SL-401 and observed synergistic cytotoxicity, in naïve (combination index (CI) = 0.45; <1 indicates synergy) and SL-401 resistant (CI = 0.55) cells...In summary, we found that DPH1 is a biomarker of SL-401 activity and acquired resistance, and resistance is reversible by azacitidine. Based on these data, we have initiated a multicenter phase 1 trial of the combination of SL-401 and azacitidine in patients with AML or MDS (NCT03113643), with correlative laboratory studies designed to explore these hypotheses."

Acute Myelogenous Leukemia • Biosimilar • Immunology • Myelodysplastic Syndrome

A Phase I, Open-Label, Multicenter Trial of Oral Azacitidine (CC-486) Plus R-CHOP in Patients with High-Risk, Previously Untreated Diffuse Large B-Cell Lymphoma, Grade 3B Follicular Lymphoma, or Transformed Lymphoma (ASH 2017) - P1; "...Preclinical data show low doses of DNA methyltransferase inhibitors, such as azacitidine, suppress DLBCL tumor growth, while causing minimal DNA damage and enhancing chemosensitivity... CC-486 combined with R-CHOP showed promising preliminary efficacy in pts with high-risk, previously untreated DLBCL or grade 3B FL. Results from this study identified a RP2D of 300 mg for future studies of CC-486 plus R-CHOP in DLBCL pts. Adverse events were generally consistent with the known safety profile of azacitidine and toxicities associated with R-CHOP."

Adverse events • Acute Myelogenous Leukemia • Biosimilar • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Indolent Lymphoma • Myelodysplastic Syndrome

Phase 3, randomized, double-blind, placebo-controlled study of venetoclax combined with azacitidine versus azacitidine in treatment-naïve patients with acute myeloid leukemia. (ASCO 2017) - P1b,P3; "In preclinical models, venetoclax has been shown to kill AML cells as a single agent with demonstrated synergistic activity in combination with the DNA methyltransferase inhibitor azacitidine (AZA). Patients on arm B will receive once daily placebo orally on days 1–28 plus daily 75 mg/m2 SC or IV AZA for 7 days on a 28-day cycle. Study recruitment began in February 2017, with target enrollment of 400 patients."

Head-to-Head • HEOR • P3 data • Acute Myelogenous Leukemia • Biosimilar

Phenotypic human tumor cell line profiling and predictive biomarker analysis for epigenetic inhibitors (AACR 2017) - "We have tested decitabine, a DNA methyltransferase inhibitor, panobinostat, a histone deacteylase inhibitor, GSK-343, an EZH2 inhibitor, GSK-J4, a JMJD3/UTX inhibitor, and JQ1, a BRD2/3/4 inhibitor in OncoPanel LT™. These inhibition data, as well as the genomic features of the cell lines, were utilized to perform univariate genomic analysis to identify predictive biomarkers of response. We will discuss the activity of compounds against this cell line panel, as well as statistically significant biomarkers of response, based on the univariate genomic analysis."

Biosimilar • Oncology

Targeting epigenetics for treatment of BRAF mutated metastatic melanoma with decitabine in combination with vemurafenib: A phase lb study. (PubMed, Oncotarget) - "...Therefore, we hypothesized that the action of vemurafenib (BRAF inhibitor) can be made more effective by combining with low dose decitabine (a DNA methyltransferase inhibitor)...The combination of oral vemurafenib with subcutaneous decitabine is safe and showed activity in V600EBRAF positive metastatic melanoma. Since most responses were seen in cohort 1, which utilized low-dose, long-term decitabine, future studies of this combination treatment should utilize longer duration of decitabine, at the lowest dose of 0.1 mg/kg."

Journal • Biosimilar • Melanoma • Oncology • Renal Disease

Effect of DNA methyltransferase inhibitor 5-azacitidine on 3D chromatin structure measured by Hi-C (AACR 2017) - "Our findings using Hi-C were found to be in agreement with previous results using alternative experimental methods, which identified Aza and CTCF as the top upstream regulators of these genes. Our data also suggests that overall changes in 3D chromatin activities measured by Hi-C could be a better predictor of transcriptional regulation compared to H2K27me3 and H3K4me3 alone, particularly in situations where there are no significant changes in those marks but where changes in gene expression exist."

Biomarker • Biosimilar • Colorectal Cancer • Gastrointestinal Cancer • Hematological Malignancies • Leukemia • Microsatellite Instability • Oncology

Mechanism of Pax5 Down-Regulation and Its Function in Primary Effusion Lymphoma (ASH 2017) - "The DNA methyltransferase inhibitor, 5-Azacytidine, was used for demethylation of Pax5 promoter. Pax5 is silenced in PEL cells via the methylation of Pax5 promoter region. Pax5 regulates cell cycle and causes growth inhibition. Reduction of Pax5 has a critical role in the development of PEL and Pax5 is a tumor suppressor in PEL."

Polymerase Chain Reaction • Biosimilar • Non-Hodgkin’s Lymphoma • Sarcoma

Characterization of Cytosine Methylation and the DNA Methyltransferases of Toxoplasma gondii. (PubMed) - Int J Biol Sci - "Tachyzoite proliferation in parasitophorous vacuoles (PV) can be inhibited by the DNA methyltransferase inhibitor 5-azacytidine, a chemical analogue of the nucleotide cytosine that can inactivate DNA methyltransferases. These findings provide the first confirmation of DNA methylation in T. gondii."

Journal • Biosimilar • Immunology

Azacitidine in combination with intensive induction chemotherapy in older patients with acute myeloid leukemia: The AML-AZA trial of the study alliance leukemia. (PubMed) - "Azacitidine added to standard chemotherapy increases toxicity in older patients with AML, but provides no additional benefit for unselected patients.Leukemia accepted article preview online, 02 November 2015. doi:10.1038/leu.2015.306."

Journal • Acute Myelogenous Leukemia • Biosimilar • Hematological Malignancies • Leukemia • Oncology

Epigenetic Induction of Definitive and Pancreatic Endoderm Cell Fate in Human Fibroblasts. (PubMed) - Stem Cells Int - "Our findings underscore the role epigenetic modification in transdifferentiation of one somatic cell into another. However, full reprogramming of fibroblasts to β-cells will require combination of this approach with TF overexpression and/or culture of the partially reprogrammed cells under β-cell specific conditions."

Journal • Biosimilar

Genetic correlations with clinical response to ASTX727 in patients with myelodysplastic syndromes (MDS) (AACR 2017) - "DNA methyltransferase inhibitors (DNMTis) have been shown to alter the natural history of MDS and reduce related complications; however, many patients do not respond to DNMTi therapy or progress with limited effective secondary options...Treatment with the DNMTi decitabine (DAC) requires 5 daily parenteral doses every month administered in the clinic...This work shows preliminary effects on mutational burden and allele frequency concurrent with activity of ASTX727. Further analyses of patients treated at the RP2D in the Phase 2 trial are ongoing."

Biosimilar • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

Aberrant Hypomethylation of Solute Carrier Family 6 Member 12 Promoter Induces Metastasis of Ovarian Cancer. (PubMed) - Yonsei Med J - "Our findings provide novel evidence for the biological and clinical significance of SLC6A12 as a metastasis-promoting gene."

Journal • Biosimilar • Oncology • Ovarian Cancer

Aberrant Methylation-mediated Silencing of lncRNA MEG3 Functions as a ceRNA in Esophageal Cancer. (PubMed) - Mol Cancer Res - "MEG3 functions as a tumor-suppressive lncRNA and aberrant promoter hypermethylation is critical for MEG3 gene silencing in ESCC. In addition, MEG3 acts as a ceRNA to regulate expression of E-cadherin and FOXO1 by competitively binding miR-9 and may be used as a potential biomarker in predicting ESCC patients' progression and prognosis."

Biomarker • Journal • Biosimilar • Esophageal Cancer • Gastrointestinal Cancer • Oncology

Hypermethylation of the Keap1 gene inactivates its function, promotes Nrf2 nuclear accumulation, and is involved in arsenite-induced human keratinocyte transformation. (PubMed) - "Results showed that enhancement of Keap1 expression by 5-Aza-dC significantly reduced Nrf2 and its target antioxidant enzyme levels, and that in turn suppressed cell proliferation and colony formation of the transformed cells. Taken together, the present study strongly suggests that loss of Keap1 function by hypermethylation of its promoter region leading to Nrf2 nuclear accumulation appears to play a role in arsenite-induced human keratinocyte transformation."

Journal • Biosimilar • Oncology

Methylation of Septin9 Mediated by DNMT3a Enhances Hepatic Stellate Cells Activation and Liver Fibrogenesis. (PubMed) - Toxicol Appl Pharmacol - "Nevertheless, the suppression of Sept9 could be blocked by DNMT3a-siRNA and DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (5-azadC). These observations suggested that Sept9 contributed to alleviate liver fibrosis might partially through promoting activated HSCs apoptosis and this anti-fibrogenesis effect might be blocked by DNMT-3a mediated methylation of Sept9. Therefore, pharmacological agents that inhibit Sept9 methylation and increase its expression could be considered as valuable treatments for liver fibrosis."

Journal • Biosimilar • Fibrosis • Gastrointestinal Cancer • Graft versus Host Disease • Hepatocellular Cancer • Immunology • Oncology

Lack of ADAM2, CALR3 and SAGE1 Cancer/Testis Antigen Expression in Lung and Breast Cancer. (PubMed) - "Treatment with DNA methyltransferase inhibitors has been proposed as an attractive strategy to increase the expression of cancer/testis antigens in tumors before immunotargeting; however, neither ADAM2, CALR3 nor SAGE1 could be significantly induced in lung and breast cancer cell lines using this strategy. Our results suggest that ADAM2, CALR3 and SAGE1 cancer/testis antigens are not promising targets for immunotherapy of breast and lung cancer."

Journal • Biosimilar • Breast Cancer • Non Small Cell Lung Cancer • Oncology • Triple Negative Breast Cancer

The Role of DNA Methylation in ST6Gal1 Expression in Gliomas. (PubMed) - Glycobiology - "Focused glycotranscriptomic analyses of three invasive glioma cell lines following 5-aza-dC treatment demonstrated the modulation of select glycogene transcripts. Taken together, these results demonstrate that epigenetic modulation of ST6Gal1 expression plays a key role in the glioma phenotype in vitro and that that therapeutic approaches targeting elements of the epigenetic machinery for the treatment of human glioblastoma are warranted."

Journal • Biosimilar • Oncology

Airway Epithelial Cell IL-22R1 Expression is Attenuated in the Infant Nonhuman Primate Lung. (PubMed) - "IL-22R1 mRNA in adult cultures was not altered by 5-aza-2'-deoxycytidine or Trichostatin A. IL-22R1 mRNA in infant cultures showed no change with 5-aza-2'-deoxycytidine, but was significantly increased following Trichostatin A treatment; however, IL-22R1 protein did not increase concurrently. These data suggest that IL-22R1 in airway epithelium is regulated, in part, by epigenetic mechanisms that are dependent upon chronologic age."

Journal • Biosimilar • Immunology