EXTH-55. TARGETING RECURRENT IDH MUTANT GLIOMA WITH CDK4/6 INHIBITION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi175-vi175
Author(s):  
Julie Miller ◽  
Daniel Cahill ◽  
Lisa Melamed ◽  
Hiroaki Nagashima
Keyword(s):  
Gene Deletion ◽  
Homozygous Deletion ◽  
Therapeutic Strategies ◽  
Enhanced Sensitivity ◽  
Rb Pathway ◽  
Cancer Types ◽  
Xenograft Models ◽  
The Relationship ◽  
Inhibitor Treatment

Abstract Despite initial responsiveness to standard treatments like radiation and chemotherapy, IDH mutant gliomas inevitably recur, become more clinically aggressively and lead to untimely death. Recurrent IDH mutant tumors are less responsive to conventional treatments, highlighting the need for improved therapeutic strategies at this stage of the disease. At least 20% of recurrent IDH mutant gliomas exhibit homozygous loss of CDKN2A, which results in aberrant signaling through the CDK-RB pathway. We hypothesized that CDKN2A loss leads to enhanced sensitivity to CDK4/6 inhibitors, which are approved for use in a variety of other cancer types. We examined the relationship between CDK4/6 inhibitor sensitivity and CDKN2A loss using patient-derived models of IDH mutant glioma with endogenous CDKN2A homozygous deletion as well as with CRIPSR-mediated gene deletion. We observed enhanced cytotoxicity in glioma models with CDKN2A loss in vitro. Studies to examine the efficacy of CDK4/6 inhibitor treatment on slowing tumor growth in patient-derived xenograft models are ongoing. These preclinical results provide foundational data for design of a biomarker-driven clinical trial of CDK4/6 inhibitors in patients with recurrent IDH mutant glioma.

scholarly journals Pan-cancer Analysis Identifies LMNB1 as a Target to Redress Th1/Th2 Imbalance and Enhance PARP Inhibitor Response in Human Cancers

2021 ◽  
Author(s):  
Haixiang Qin ◽  
Yingqiang Lu ◽  
Lin Du ◽  
Jingyan Shi ◽  
Haoli Yin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parp Inhibitor ◽  
Homologous Recombination Repair ◽  
Human Cancers ◽  
Th2 Cell ◽  
Recombination Repair ◽  
Cancer Types ◽  
Pan Cancer ◽  
Inhibitor Treatment

Abstract Background: Emerging evidence suggests that LMNB1 is involved in the development of multiple cancer types. However, there is no study reporting the potential role of LMNB1 in a systematic pan-cancer manner.Methods: The gene expression level and potential oncogenic roles of LMNB1 in The Cancer Genome Atlas (TCGA) database were analyzed with Tumor Immune Estimation Resource version 2 (TIMER2.0), Gene Expression Profiling Interactive Analysis version 2 (GEPIA2), UALCAN and Sangerbox tools. Pathway enrichment analysis was carried out to explore the possible mechanism of LMNB1 on tumorigenesis and tumor progression. The therapeutic effects of LMNB1 knockdown combined with PARP inhibition on human cancers were further investigated in vitro. Results: LMNB1 upregulation is generally observed in the tumor tissues of most TCGA cancer types, and is verified in kidney renal clear cell carcinoma using clinical specimens of our institute. High level of LMNB1 expression usually predicts poor overall survival and disease free survival for patients with tumors. Mechanically, LMNB1 level is positively correlated with CD4+ Th2 cell infiltration and DNA homologous recombination repair gene expression. In vitro experiments reveal that targeting LMNB1 has a synergistic effect on prostate cancer with PARP inhibitor treatment. Conclusions: LMNB1 is a biomarker of CD4+ Th2 cell infiltration and DNA homologous recombination repair in human cancers. Blockage of LMNB1 combined with PARP inhibitor treatment could be a promising therapeutic strategy for patients with cancers.

scholarly journals SH-1028, An Irreversible Third-Generation EGFR TKI, Overcomes T790M-Mediated Resistance in Non-Small Cell Lung Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Luwei Han ◽  
Xiaomeng Zhang ◽  
Zhiqiang Wang ◽  
Xian Zhang ◽  
Liwen Zhao ◽  
...  
Keyword(s):  
Third Generation ◽  
Wild Type ◽  
Egfr Inhibition ◽  
Erk Phosphorylation ◽  
Xenograft Models ◽  
The Relationship ◽  
Egfr Tki ◽  
Resistant Mutation

SH-1028 is an irreversible third-generation EGFR TKI. Both SH-1028 and osimertinib have a pyrimidine structure (a typical mutant-selective EGFR TKI structure). Compared with osimertinib, SH-1028 is modified on the indole ring, thus resulting in a more stable 6,7,8,9-tetrahydro-pyrrolo [1, 2-a] indol structure. In this study, we explored the anti-tumor effect of SH-1028 in vitro and in vivo, the inhibition of cell signal, such as EGFR and ERK phosphorylation, and verified the relationship between the pharmacokinetics and pharmacodynamic responses. Firstly, SH-1028 selectively inhibited EGFR sensitive and resistant mutations, with up to 198-fold more effective compared with wild-type EGFR cells. Then, in mouse xenograft models, oral administration of SH-1028 at a daily dose of 5 mg/kg significantly inhibited proliferation of tumor cells with EGFR sensitive mutation (exon 19 del) and resistant mutation (T790 M) for consecutive 14 days, with no TKI-induced weight loss. Moreover, SH-1028 exhibited good bioavailability, and was distributed extensively from the plasma to the tissues. The main metabolite of SH-1028, Imp3, was tested and showed no wild-type EGFR inhibition or off-target effects. In conclusion, SH-1028 is a new third-generation EGFR inhibitor that exhibits potent activity against EGFR sensitive and resistant (T790 M) mutations.

scholarly journals Bcl-2 Targeted Overexpression Into the Erythroid Lineage of Transgenic Mice Delays But Does Not Prevent the Apoptosis of Erythropoietin-Deprived Erythroid Progenitors

Blood ◽  
1997 ◽  
Vol 90 (8) ◽  
pp. 3050-3056 ◽  
Author(s):  
V. Lacronique ◽  
P. Varlet ◽  
P. Mayeux ◽  
A. Porteu ◽  
S. Gisselbrecht ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Transgenic Animals ◽  
Erythroid Differentiation ◽  
Erythroid Progenitors ◽  
Enhanced Sensitivity ◽  
Maturation In Vitro ◽  
Low Levels ◽  
The Relationship

Abstract Erythropoietin (Epo) is known to control the erythroid developmental program through various biologic activities including maintenance of viability, cell proliferation, and/or cell maturation. In vitro experiments showed massive apoptosis in cultures of Epo-deprived colony-forming unit-erythroid (CFU-E) progenitors, demonstrating the Epo requirement of late-stage erythroid progenitors for survival. Based on these data, a model has been proposed whereby from CFU-E to proerythroblast stages, Epo acts rather as a survival factor than a proliferating factor. To investigate the relationship between Epo dependence and apoptotic mechanisms, we generated transgenic mice expressing the antiapoptotic human bcl-2 gene product in erythroid progenitors. Transgenic animals developed without any evidence of erythropoietic disorders. In vitro studies showed that overexpression of bcl-2 in erythroid progenitors delayed, but did not prevent the loss of CFU-E from Epo-deprivation. By measuring burst-forming unit-erythroid (BFU-E) and CFU-E–derived colonies, an enhanced sensitivity to low levels of Epo was demonstrated in adult bone marrow of transgenic mice with respect to nontransgenic animals. No spontaneous erythroid colonies were, however, observed in vitro in the absence of the cytokine, indicating that overexpression of bcl-2 is not sufficient to induce by itself a complete erythroid differentiation. Taken together, our data indicate that targeted erythroid overexpression of bcl-2 fails to alter the normal erythropoietic development in vivo and that erythroid progenitors remain strictly dependent on Epo for their survival.

scholarly journals Histone N-terminal acetyltransferase NAA40 links one-carbon metabolism to chemoresistance

Oncogene ◽  
2021 ◽  
Author(s):  
Christina Demetriadou ◽  
Anastasia Raoukka ◽  
Evelina Charidemou ◽  
Constantine Mylonas ◽  
Christina Michael ◽  
...  
Keyword(s):  
Nuclear Periphery ◽  
Metabolic Genes ◽  
Epigenetic Modifiers ◽  
Regulatory Link ◽  
Cancer Types ◽  
Xenograft Models ◽  
One Carbon Metabolism ◽  
The One

AbstractAberrant function of epigenetic modifiers plays an important role not only in the progression of cancer but also the development of drug resistance. N-alpha-acetyltransferase 40 (NAA40) is a highly specific epigenetic enzyme catalyzing the transfer of an acetyl moiety at the N-terminal end of histones H4 and H2A. Recent studies have illustrated the essential oncogenic role of NAA40 in various cancer types but its role in chemoresistance remains unclear. Here, using transcriptomic followed by metabolomic analysis in colorectal cancer (CRC) cells, we demonstrate that NAA40 controls key one-carbon metabolic genes and corresponding metabolites. In particular, through its acetyltransferase activity NAA40 regulates the methionine cycle thereby affecting global histone methylation and CRC cell survival. Importantly, NAA40-mediated metabolic rewiring promotes resistance of CRC cells to antimetabolite chemotherapy in vitro and in xenograft models. Specifically, NAA40 stimulates transcription of the one-carbon metabolic gene thymidylate synthase (TYMS), whose product is targeted by 5-fluorouracil (5-FU) and accordingly in primary CRC tumours NAA40 expression associates with TYMS levels and poorer 5-FU response. Mechanistically, NAA40 activates TYMS by preventing enrichment of repressive H2A/H4S1ph at the nuclear periphery. Overall, these findings define a novel regulatory link between epigenetics and cellular metabolism mediated by NAA40, which is harnessed by cancer cells to evade chemotherapy.

scholarly journals Blocking TNF and IL-1 Sensitizes AML Stem Cells to NF-κB Inhibitor Treatment

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2302-2302
Author(s):  
Volk Andrew ◽  
Jing Li ◽  
Jun Zhang ◽  
Joseph Cannova ◽  
Caiqin Hao ◽  
...  
Keyword(s):  
Stem Cells ◽  
In Vitro Culture ◽  
Conflicts Of Interest ◽  
In Vivo Models ◽  
Hematopoietic Stem ◽  
Enhanced Sensitivity ◽  
Repressive Effect ◽  
Inhibitor Treatment

Abstract Background: NF-κB inhibition selectively eliminates leukemia stem cells (LSCs) but has less effect on healthy hematopoietic stem cells (HSCs), suggesting an advantageous target for leukemia therapy. However, NF-κB inhibition alone does not have a significant effect on in vivo models of leukemia. We have reported that many types of AML cells produce tumor necrosis factor-α (TNF) which appears to protect LSCs from NF-κB inhibition by stimulating JNK-AP1 survival/proliferative signaling parallel to NF-κB. Complete inactivation of TNF signaling cannot fully reproduce the effects of JNK-AP1 inhibition, suggesting that some other inflammatory cytokine(s) might also compensate for NF-κB inhibition through activation of JNK-AP1. We found that IL-1α and β (IL-1) is such a cytokine. Methods: TNF and IL-1 expression was examined in 430 AML samples by microarray and verified by qRT-PCR. IL-1α and β protein levels in the sera of AML patients and medium from cultured AML cells were examined by ELISA. MLL-AF9-transduced murine AML cells, human AML cell lines and primary patient samples were used in this study. TNF signal was blocked by genetic deletion of receptors Tnfr1 and 2, or treatment with a TNF-specific monoclonal antibody. IL-1 signal was blocked by shRNA knockdown of IL-1R or treatment with an IL-1R antagonist. The effects of IL-1 and TNF signal co-inactivation on growth and response to NF-κB inhibition in AML cells were evaluated by in vitro culture and colony-forming assay, and in vivo transplantation/leukemogenesis assays. Results: We found that most types of human AML cells both express and produce TNF and IL-1. Treatment with these cytokines stimulated the growth and colony-forming ability of AML cells but repressed the growth of normal HSPC in in vitro culture. Inactivation of either the TNF or IL-1 signaling axes suppressed the growth of and significantly sensitized AML stem cells to NF-κB inhibition both in vitro by targeting clonogenic AML progenitor cells, and in vivo through compromising leukemogenesis. Simultaneous inactivation of both TNF and IL-1 resulted in an enhanced repressive effect on AML cells compared to inactivation of either individual cytokine’s receptors alone. AML cells with inactivation of both TNF and IL-1 signals showed significantly lower clonogenic ability in vitro, further reduced leukemogenic capacity in vivo and enhanced sensitivity to NF-kB inhibitor treatment both in vitro and in vivo. Mechanistically, we found that both TNF and IL-1 stimulate JNK-AP1 and NF-κB, two parallel survival signaling pathways in AML cells, but induce JNK-mediated death signaling in normal HSPCs. Conclusion: Both TNF and IL-1 provide protection to LSCs from the effects of NF-κB inhibitor treatment in an autocrine manner and contribute to repression of normal hematopoiesis in a paracrine fashion. This protection is mediated by JNK-AP1. Our studies show inhibiting both TNF and IL-1 inflammatory signals can block this effect, and may be a better strategy to successfully treat AML when combined with NF-κB inhibitors. Disclosures No relevant conflicts of interest to declare.

Ultrastructural Correlations between Clonal Human Tumor Colonies and in Vivo Neoplasms

1982 ◽  
Vol 40 ◽  
pp. 210-211
Author(s):  
M.J. Murphy ◽  
R.R. Price ◽  
J.C. Sloman
Keyword(s):  
Cultured Cells ◽  
Human Tumor ◽  
Cell Type ◽  
Tumor Mass ◽  
Initial Cell ◽  
Cloning Assay ◽  
Human Tumor Cloning ◽  
The Relationship

The in vitro human tumor cloning assay originally described by Salmon and Hamburger has been applied recently to the investigation of differential anti-tumor drug sensitivities over a broad range of human neoplasms. A major problem in the acceptance of this technique has been the question of the relationship between the cultured cells and the original patient tumor, i.e., whether the colonies that develop derive from the neoplasm or from some other cell type within the initial cell population. A study of the ultrastructural morphology of the cultured cells vs. patient tumor has therefore been undertaken to resolve this question. Direct correlation was assured by division of a common tumor mass at surgical resection, one biopsy being fixed for TEM studies, the second being rapidly transported to the laboratory for culture.

Plasminogen Depletion during Streptokinase Treatment or Two-Chain Urokinase Incubation Correlates with Decreased Clot Lysability Ex Vivo and In Vitro

1993 ◽  
Vol 70 (06) ◽  
pp. 0998-1004 ◽  
Author(s):  
Páll T Önundarson ◽  
H Magnús Haraldsson ◽  
Lena Bergmann ◽  
Charles W Francis ◽  
Victor J Marder
Keyword(s):  
Myocardial Infarction ◽  
Ex Vivo ◽  
Time Dependent ◽  
State Variables ◽  
Thrombolytic Treatment ◽  
Direct Proportion ◽  
Plasmin Activity ◽  
Plasma Exposure ◽  
The Relationship

SummaryThe relationship between lytic state variables and ex vivo clot lysability was investigated in blood drawn from patients during streptokinase administration for acute myocardial infarction. A lytic state was already evident after 5 min of treatment and after 20 min the plasminogen concentration had decreased to 24%, antiplasmin to 7% and fibrinogen 0.2 g/1. Lysis of radiolabeled retracted clots in the patient plasmas decreased from 37 ± 8% after 5 min to 21 ± 8% at 10 min and was significantly lower (8 ± 9%, p <0.005) in samples drawn at 20, 40 and 80 min. Clot lysability correlated positively with the plasminogen concentration (r = 0.78, p = 0.003), but not with plasmin activity. Suspension of radiolabeled clots in normal plasma pre-exposed to 250 U/ml two-chain urokinase for varying time to induce an in vitro lytic state was also associated with decreasing clot lysability in direct proportion with the duration of prior plasma exposure to urokinase. The decreased lysability correlated with the time-dependent reduction in plasminogen concentration (r = 0.88, p <0.0005). Thus, clot lysability decreases in conjunction with the development of the lytic state and the associated plasminogen depletion. The lytic state may therefore limit reperfusion during thrombolytic treatment.

Monitoring Anticoagulant Therapy by Activated Partial Thromboplastin Time: Hirudin Assessment

1994 ◽  
Vol 72 (05) ◽  
pp. 685-692 ◽  
Author(s):  
Michael T Nurmohamed ◽  
René J Berckmans ◽  
Willy M Morriën-Salomons ◽  
Fenny Berends ◽  
Daan W Hommes ◽  
...  
Keyword(s):  
Whole Blood ◽  
Partial Thromboplastin Time ◽  
Ex Vivo ◽  
Fold Increase ◽  
Heparin Therapy ◽  
Activated Partial Thromboplastin Time ◽  
Recombinant Hirudin ◽  
Interindividual Differences ◽  
The Relationship

SummaryBackground. Recombinant hirudin (RH) is a new anticoagulant for prophylaxis and treatment of venous and arterial thrombosis. To which extent the activated partial thromboplastin time (APTT) is suitable for monitoring of RH has not been properly evaluated. Recently, a capillary whole blood device was developed for bed-side monitoring of the APTT and it was demonstrated that this device was suitable to monitor heparin therapy. However, monitoring of RH was not evaluated.Study Objectives. To evaluate in vitro and ex vivo the responsiveness and reproducibility for hirudin monitoring of the whole blood monitor and of plasma APTT assays, which were performed with several reagents and two conventional coagulometers.Results. Large interindividual differences in hirudin responsiveness were noted in both the in vitro and the ex vivo experiments. The relationship between the APTT, expressed as clotting time or ratio of initial and prolonged APTT, and the hirudin concentration was nonlinear. A 1.5-fold increase of the clotting times was obtained at 150-200 ng/ml plasma. However, only a 2-fold increase was obtained at hirudin levels varying from 300 ng to more than 750 ng RH/ml plasma regardless of the assays. The relationship linearized upon logarithmic conversion of the ratio and the hirudin concentration. Disregarding the interindividual differences, and presuming full linearity of the relationship, all combinations were equally responsive to hirudin.Conclusions. All assays were equally responsive to hirudin. Levels up to 300 ng/ml plasma can be reliably estimated with each assay. The manual device may be preferable in situations where rapid availability of test results is necessary.

Thickness of endometrium: predictor of the effectiveness of IVF/ICSI programs (literature review)

GYNECOLOGY ◽  
2018 ◽  
Vol 20 (1) ◽  
pp. 113-116
Author(s):  
L A Bagdasaryan ◽  
I E Korneyeva
Keyword(s):  
Assisted Reproductive Technologies ◽  
Endometrial Thickness ◽  
Molecular Genetic ◽  
Uterine Cavity ◽  
Reproductive Technologies ◽  
Genetic Characteristics ◽  
Vitro Fertilization ◽  
Need To Evaluate ◽  
The Relationship

The aim of the study is to systematically analyze the data available in the modern literature on the relationship between endometrial thickness and the frequency of pregnancy in the program of assisted reproductive technologies (ART). Materials and methods. The review includes data from foreign and domestic articles found in PubMed on this topic. Results. The article presents data on the relationship between the thickness of the endometrium and the frequency of pregnancy in ART programs. The greatest number of studies is devoted to the evaluation of the relationship between the thickness of the endometrium and the frequency of pregnancy on the day of the ovulation trigger. Data are presented on the existence of a correlation between the thickness of the endometrium measured on the day of the ovulation trigger and the frequency of clinical pregnancy, as well as data on the need to evaluate the structure of the endometrium and the state of subendometric blood flow. The importance of multilayered (three-layered) endometrium as a prognostic marker of success in in vitro fertilization/intracytoplasmic sperm injection programs in the ovum is emphasized. The conclusion. The thickness of the endometrium can not be used as an argument for canceling the cycle or abolishing embryo transfer to the uterine cavity. Further studies in this direction are needed with a study of the morphological and molecular genetic characteristics of the endometrium, which in the future will allow us to evaluate the relationship between the thickness of the endometrium and the probability of pregnancy.

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