GRN163L Inhibits Telomerase Activity in B-CLL Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5041-5041 ◽  
Author(s):  
Claudia Lin ◽  
Rajendra N. Damle ◽  
Nicholas Chiorazzi ◽  
Allison C. Chin
Keyword(s):  
Hematologic Malignancies ◽  
Telomerase Activity ◽  
Lymphocytic Leukemia ◽  
Telomerase Inhibition ◽  
Nuclear Compartments ◽  
Telomerase Inhibitor ◽  
Effective Inhibition ◽  
Xenograft Models

Abstract B-CLL cells, like many solid and hematologic malignancies, are characterized by short telomeres, suggesting that they would be acutely susceptible to telomerase inhibition. We and others have documented that CLL patients in poorer prognosis subsets, i.e., those without IgVH mutations, had shorter mean telomere lengths and higher telomerase levels than patients with IgVH mutations (Damle et al, 2004; Keating et al, 2003; Bechter et al 1998, Hultdin et al, 2003). Treatment with the telomerase inhibitor GRN163L, a lipid-conjugated 13-mer thio-phosphoramidate oligonucleotide (Geron Corporation), inhibits the growth of human hepatoma (Djojosubroto et al, 2005), ovarian carcinoma (Ertem et al, 2004, 2005), and multiple myeloma (CAG, MM.1S) cell lines in vitro and in vivo (AACR 2004 and 2005 Annual Meetings). Although no validated human B-CLL xenograft models exist, preliminary data indicate effective inhibition of telomerase in freshly thawed B-CLL cells upon exposure to GRN163L. We will present data demonstrating robust uptake of GRN163L into primary B-CLL patient cells, along with the subcellular distribution of the oligonucleotide into cytoplasmic and nuclear compartments. Comparison of the effect of GRN163L and a mismatch oligonucleotide control on telomerase inhibition will be described. Geron initiated a Phase I/II trial with GRN163L in chronic lymphocytic leukemia in July 2005.

scholarly journals The biochemical and clinical consequences of 2'-deoxycoformycin in refractory lymphoproliferative malignancy

Blood ◽  
1981 ◽  
Vol 57 (3) ◽  
pp. 406-417 ◽  
Author(s):  
MR Grever ◽  
MF Siaw ◽  
WF Jacob ◽  
JA Neidhart ◽  
JS Miser ◽  
...  
Keyword(s):  
Bone Marrow Cells ◽  
Severe Combined Immunodeficiency ◽  
Single Agent ◽  
Cell Mass ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Central Nervous System Toxicity ◽  
Marked Rise

Abstract A deficiency of adenosine deaminase, an enzyme important in purine nucleoside catabolism, is associated with a severe combined immunodeficiency disease in children. Inhibition of this enzyme in vitro and in vivo results in an impairment in lymphoblast proliferation. We have investigated the pharmacologic inhibition of this enzyme by 2′-deoxycoformycin in 15 patients with hematologic malignancies. Biochemical consequences of the administration of this agent were closely monitored in erythrocytes, nucleated peripheral blood and bone marrow cells, serum, and urine. A marked rise in erythrocyte dATP was accompanied by a depletion of ATP in those patients exhibiting toxicity. Most patients excreted large amounts of deoxyadenosine but not adenosine in the urine. Serum deoxyadenosine rose in patients demonstrating a marked decrease in cell mass. The biochemical disturbances and clinical toxicity, including hepatic, renal, and conjunctival abnormalities, were usually reversible. Central nervous system toxicity, which potentially was the most serious consequence, was associated with high erythrocyte dATP/ATP ratios and high levels of cerebrospinal fluid deoxyadenosine. In patients with lymphoma and leukemia, objective responses were observed but were short- lived. Patients with chronic lymphocytic leukemia receiving weekly low doses of the drug demonstrated minimal toxicity and some efficacy. The chemotherapeutic potential o 2′-deoxycoformycin, as either a single agent or in combination with Ara-A, merits further exploration.

scholarly journals Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia

Blood ◽  
2012 ◽  
Vol 120 (23) ◽  
pp. 4621-4634 ◽  
Author(s):  
Rosa Lapalombella ◽  
Qingxiang Sun ◽  
Katie Williams ◽  
Larissa Tangeman ◽  
Shruti Jha ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Nuclear Export ◽  
Therapeutic Index ◽  
Hematologic Malignancies ◽  
Cysteine Residue ◽  
Lymphocytic Leukemia ◽  
Selective Inhibitors ◽  
Multiple Tumor

Abstract The nuclear export protein XPO1 is overexpressed in cancer, leading to the cytoplasmic mislocalization of multiple tumor suppressor proteins. Existing XPO1-targeting agents lack selectivity and have been associated with significant toxicity. Small molecule selective inhibitors of nuclear export (SINEs) were designed that specifically inhibit XPO1. Genetic experiments and X-ray structures demonstrate that SINE covalently bind to a cysteine residue in the cargo-binding groove of XPO1, thereby inhibiting nuclear export of cargo proteins. The clinical relevance of SINEs was explored in chronic lymphocytic leukemia (CLL), a disease associated with recurrent XPO1 mutations. Evidence is presented that SINEs can restore normal regulation to the majority of the dysregulated pathways in CLL both in vitro and in vivo and induce apoptosis of CLL cells with a favorable therapeutic index, with enhanced killing of genomically high-risk CLL cells that are typically unresponsive to traditional therapies. More importantly, SINE slows disease progression, and improves overall survival in the Eμ-TCL1-SCID mouse model of CLL with minimal weight loss or other toxicities. Together, these findings demonstrate that XPO1 is a valid target in CLL with minimal effects on normal cells and provide a basis for the development of SINEs in CLL and related hematologic malignancies.

TSP-A74, a Novel Therapeutic Monoclonal Antibody Against TfR1 for Treatment of Hematologic Malignancies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5214-5214
Author(s):  
Lilin Zhang ◽  
Fumiko Nomura ◽  
Youichi Aikawa ◽  
Yukio Sudo ◽  
Kazuhiro Morishita ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Tumor Growth ◽  
Cell Lymphoma ◽  
Xenograft Model ◽  
Hematologic Malignancies ◽  
Tumor Growth Inhibition ◽  
Xenograft Models ◽  
Complete Tumor

Abstract Transferrin receptor 1(TfR1) is a type II transmembrane glycoprotein regulating the intracellular uptake of iron and is involved in cell growth, proliferation and survival. TfR1 is highly expressed on malignant cells, including those of hematologic malignancies. Therefore, TfR1 may be an attractive target for therapeutic monoclonal antibodies. We generated a panel of fully-human, anti-TfR1 monoclonal antibodies and evaluated the anti-tumor effects of these antibodies both in vitro and in vivo. The results led to the selection of TSP-A74, an antibody with potent in vitro and in vivo anti-tumor activity, for further evaluation in several hematologic malignancy models. First, the efficacy of TSP-A74 was evaluated in acute myeloid leukemia (AML) models. Two AML cell lines, Kasumi-1 and HL-60, were subcutaneously inoculated in severe combined immunodeficiency (SCID) mice. After the tumors were grown to a size of 150 mm3, TSP-A74 was administrated intravenously (IV) once weekly for 4 weeks at doses of 0.4, 2 and 10 mg/kg and 1, 3 and 10 mg/kg for the Kasumi and HL60 xenograft models, respectively. TSP-A74 demonstrated complete tumor regression in these two xenograft models at 10 mg/kg and complete tumor growth suppression in the Kasumi model at 2 mg/kg. Even at the low dose of 1 mg/kg, TSP-A74 demonstrated tumor growth inhibition (TGI) of 60% in the HL60 model. Next, the anti-tumor efficacy of TSP-A74 was assessed in an acute lymphoblastic leukemia (ALL) model. The ALL cell line, CCRF-CEM, was engrafted into SCID mice intravenously. After 3 days, TSP-A74 was administrated IV at a dose of 10 mg/kg once weekly for 4 weeks. The control mice (n=10) rapidly developed leukemia and none survived at 42 days after leukemia cell engraftment. However, 7 of 10 (70%) mice treated with TSP-A74 survived to 179 days after engraftment when the study was terminated. Finally, the efficacy of TSP-A74 was evaluated in non-Hodgkin's lymphoma subcutaneous xenograft models. TSP-A74 produced complete regression of established tumors in the SU-DHL-2 (diffuse large B-cell lymphoma) xenograft model at a dose of 3 mg/kg and tumor growth inhibition of 100 % in the HH (cutaneous T cell lymphoma) xenograft model at a dose of 10 mg/kg. These results indicate that the human anti-TfR1 monoclonal antibody, TSP-A74, could be a new therapeutic candidate for hematologic malignancies. Disclosures Zhang: Perseus Proteomics Inc.: Employment. Nomura:Perseus Proteomics Inc.: Employment. Aikawa:Perseus Proteomics Inc.: Employment. Sudo:Perseus Proteomics Inc.: Employment. Morishita:Perseus Proteomics Inc.: Research Funding.

scholarly journals Telomerase activity in normal leukocytes and in hematologic malignancies

Blood ◽  
1995 ◽  
Vol 85 (9) ◽  
pp. 2315-2320 ◽  
Author(s):  
CM Counter ◽  
J Gupta ◽  
CB Harley ◽  
B Leber ◽  
S Bacchetti
Keyword(s):  
Bone Marrow ◽  
Hematologic Malignancies ◽  
Telomerase Activity ◽  
Carcinoma Cells ◽  
Lymphocytic Leukemia ◽  
Telomere Maintenance ◽  
Telomeric Dna ◽  
Somatic Tissues ◽  
Low Levels

Telomeres are essential for function and stability of eukaryotic chromosomes. In the absence of telomerase, the enzyme that synthesizes telomeric DNA, telomeres shorten with cell division, a process thought to contribute to cell senescence and the proliferative crisis of transformed cells. We reported telomere stabilization concomitant with detection of telomerase activity in cells immortalized in vitro and in ovarian carcinoma cells, and suggested that telomerase is essential for unlimited cell proliferation. We have now examined the temporal pattern of telomerase expression in selected hematologic malignancies. We found that, unlike other somatic tissues, peripheral, cord blood, and bone marrow leukocytes from normal donors expressed low levels of telomerase activity. In leukocytes from chronic lymphocytic leukemia (CLL) patients, activity was lower than in controls in early disease, and comparable with controls in late disease. Relative to bone marrow, telomerase activity was enhanced in myelodysplastic syndrome (MDS) and more significantly so in acute myeloid leukemia (AML). Regardless of telomerase levels, telomeres shortened with progression of the diseases. Our results suggest that early CLL and MDS cells lack an efficient mechanism of telomere maintenance and that telomerase is activated late in the progression of these cancers, presumably when critical telomere loss generates selective pressure for cell immortality.

scholarly journals The biochemical and clinical consequences of 2'-deoxycoformycin in refractory lymphoproliferative malignancy

Blood ◽  
1981 ◽  
Vol 57 (3) ◽  
pp. 406-417 ◽  
Author(s):  
MR Grever ◽  
MF Siaw ◽  
WF Jacob ◽  
JA Neidhart ◽  
JS Miser ◽  
...  
Keyword(s):  
Bone Marrow Cells ◽  
Severe Combined Immunodeficiency ◽  
Single Agent ◽  
Cell Mass ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Central Nervous System Toxicity ◽  
Marked Rise

A deficiency of adenosine deaminase, an enzyme important in purine nucleoside catabolism, is associated with a severe combined immunodeficiency disease in children. Inhibition of this enzyme in vitro and in vivo results in an impairment in lymphoblast proliferation. We have investigated the pharmacologic inhibition of this enzyme by 2′-deoxycoformycin in 15 patients with hematologic malignancies. Biochemical consequences of the administration of this agent were closely monitored in erythrocytes, nucleated peripheral blood and bone marrow cells, serum, and urine. A marked rise in erythrocyte dATP was accompanied by a depletion of ATP in those patients exhibiting toxicity. Most patients excreted large amounts of deoxyadenosine but not adenosine in the urine. Serum deoxyadenosine rose in patients demonstrating a marked decrease in cell mass. The biochemical disturbances and clinical toxicity, including hepatic, renal, and conjunctival abnormalities, were usually reversible. Central nervous system toxicity, which potentially was the most serious consequence, was associated with high erythrocyte dATP/ATP ratios and high levels of cerebrospinal fluid deoxyadenosine. In patients with lymphoma and leukemia, objective responses were observed but were short- lived. Patients with chronic lymphocytic leukemia receiving weekly low doses of the drug demonstrated minimal toxicity and some efficacy. The chemotherapeutic potential o 2′-deoxycoformycin, as either a single agent or in combination with Ara-A, merits further exploration.

scholarly journals The BET Inhibitor JQ1 Augments the Antitumor Efficacy of Gemcitabine in Preclinical Models of Pancreatic Cancer

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3470
Author(s):  
Aubrey L. Miller ◽  
Patrick L. Garcia ◽  
Samuel C. Fehling ◽  
Tracy L. Gamblin ◽  
Rebecca B. Vance ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Dna Damage ◽  
Cholesterol Biosynthesis ◽  
Antitumor Efficacy ◽  
Rna Seq ◽  
Bet Inhibitor ◽  
Bet Inhibitors ◽  
Xenograft Models

Gemcitabine is used to treat pancreatic cancer (PC), but is not curative. We sought to determine whether gemcitabine + a BET bromodomain inhibitor was superior to gemcitabine, and identify proteins that may contribute to the efficacy of this combination. This study was based on observations that cell cycle dysregulation and DNA damage augment the efficacy of gemcitabine. BET inhibitors arrest cells in G1 and allow increases in DNA damage, likely due to inhibition of expression of DNA repair proteins Ku80 and RAD51. BET inhibitors (JQ1 or I-BET762) + gemcitabine were synergistic in vitro, in Panc1, MiaPaCa2 and Su86 PC cell lines. JQ1 + gemcitabine was more effective in vivo than either drug alone in patient-derived xenograft models (P < 0.01). Increases in the apoptosis marker cleaved caspase 3 and DNA damage marker γH2AX paralleled antitumor efficacy. Notably, RNA-seq data showed that JQ1 + gemcitabine selectively inhibited HMGCS2 and APOC1 ~6-fold, compared to controls. These proteins contribute to cholesterol biosynthesis and lipid metabolism, and their overexpression supports tumor cell proliferation. IPA data indicated that JQ1 + gemcitabine selectively inhibited the LXR/RXR activation pathway, suggesting the hypothesis that this inhibition may contribute to the observed in vivo efficacy of JQ1 + gemcitabine.

scholarly journals The loss of SHMT2 mediates 5-fluorouracil chemoresistance in colorectal cancer by upregulating autophagy

Oncogene ◽  
2021 ◽  
Author(s):  
Jian Chen ◽  
Risi Na ◽  
Chao Xiao ◽  
Xiao Wang ◽  
Yupeng Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Patient Survival ◽  
Serine Hydroxymethyltransferase ◽  
First Line ◽  
Xenograft Models ◽  
Potential Opportunity ◽  
First Line Treatment ◽  
Novel Therapeutic

Abstract5-Fluorouracil (5-FU)-based chemotherapy is the first-line treatment for colorectal cancer (CRC) but is hampered by chemoresistance. Despite its impact on patient survival, the mechanism underlying chemoresistance against 5-FU remains poorly understood. Here, we identified serine hydroxymethyltransferase-2 (SHMT2) as a critical regulator of 5-FU chemoresistance in CRC. SHMT2 inhibits autophagy by binding cytosolic p53 instead of metabolism. SHMT2 prevents cytosolic p53 degradation by inhibiting the binding of p53 and HDM2. Under 5-FU treatment, SHMT2 depletion promotes autophagy and inhibits apoptosis. Autophagy inhibitors decrease low SHMT2-induced 5-FU resistance in vitro and in vivo. Finally, the lethality of 5-FU treatment to CRC cells was enhanced by treatment with the autophagy inhibitor chloroquine in patient-derived and CRC cell xenograft models. Taken together, our findings indicate that autophagy induced by low SHMT2 levels mediates 5-FU resistance in CRC. These results reveal the SHMT2–p53 interaction as a novel therapeutic target and provide a potential opportunity to reduce chemoresistance.

Evaluation of vecabrutinib as a model for non-covalent BTK/ITK inhibition for treatment of chronic lymphocytic leukemia

Blood ◽  
2021 ◽  
Author(s):  
Billy Michael Chelliah Jebaraj ◽  
Annika Müller ◽  
Rashmi Priyadharshini Dheenadayalan ◽  
Sascha Endres ◽  
Philipp M. Roessner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Inhibitory Effect ◽  
Lymphocytic Leukemia ◽  
Transfer Model ◽  
Treatment Benefit ◽  
Btk Inhibitors

Covalent Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib have proven to be highly beneficial in the treatment of chronic lymphocytic leukemia (CLL). Interestingly, the off-target inhibition of IL-2-inducible T-cell kinase (ITK) by ibrutinib may also play a role in modulating the tumor microenvironment, potentially enhancing the treatment benefit. However, resistance to covalently binding BTK inhibitors can develop by a mutation in cysteine 481 of BTK (C481S), which prevents the irreversible binding of the drugs. In the present study we performed pre-clinical characterization of vecabrutinib, a next generation non-covalent BTK inhibitor, with ITK inhibitory properties similar to those of ibrutinib. Unlike ibrutinib and other covalent BTK inhibitors, vecabrutinib showed retention of the inhibitory effect on C481S BTK mutants in vitro, similar to that of wildtype BTK. In the murine Eµ-TCL1 adoptive transfer model, vecabrutinib reduced tumor burden and significantly improved survival. Vecabrutinib treatment led to a decrease in CD8+ effector and memory T-cell populations, while the naïve populations were increased. Of importance, vecabrutinib treatment significantly reduced frequency of regulatory CD4+ T-cells (Tregs) in vivo. Unlike ibrutinib, vecabrutinib treatment showed minimal adverse impact on activation and proliferation of isolated T-cells. Lastly, combination treatment of vecabrutinib with venetoclax was found to augment treatment efficacy, significantly improve survival and lead to favourable reprogramming of the microenvironment in the murine Eµ-TCL1 model. Thus, non-covalent BTK/ITK inhibitors such as vecabrutinib may be efficacious in C481S BTK mutant CLL, while preserving the T-cell immunomodulatory function of ibrutinib.

Chronic lymphocytic leukemia: revelations from the B-cell receptor

Blood ◽  
2004 ◽  
Vol 103 (12) ◽  
pp. 4389-4395 ◽  
Author(s):  
Freda K. Stevenson ◽  
Federico Caligaris-Cappio
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Cell Of Origin ◽  
Regulatory B Cell ◽  
V Genes

Abstract The finding that chronic lymphocytic leukemia (CLL) consists of 2 clinical subsets, distinguished by the incidence of somatic mutations in the immunoglobulin (Ig) variable region (V) genes, has clearly linked prognosis to biology. Antigen encounter by the cell of origin is indicated in both subsets by selective but distinct expression of V genes, with evidence for continuing stimulation after transformation. The key to distinctive tumor behavior likely relates to the differential ability of the B-cell receptor (BCR) to respond. Both subsets may be undergoing low-level signaling in vivo, although analysis of blood cells limits knowledge of critical events in the tissue microenvironment. Analysis of signal competence in vitro reveals that unmutated CLL generally continues to respond, whereas mutated CLL is anergized. Differential responsiveness may reflect the increased ability of post-germinal center B cells to be triggered by antigen, leading to long-term anergy. This could minimize cell division in mutated CLL and account for prognostic differences. Unifying features of CLL include low responsiveness, expression of CD25, and production of immunosuppressive cytokines. These properties are reminiscent of regulatory T cells and suggest that the cell of origin of CLL might be a regulatory B cell. Continuing regulatory activity, mediated via autoantigen, could suppress Ig production and lead to disease-associated hypogammaglobulinemia. (Blood. 2004;103:4389-4395)

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