A phase I trial of palbociclib in combination with dexamethasone in relapsed or refractory adult B-cell acute lymphoblastic leukemia (ALL).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS7065-TPS7065 ◽  
Author(s):  
Margaret T. Kasner ◽  
Lindsay Wilde ◽  
Gina Keiffer ◽  
Neil David Palmisiano ◽  
Bruno Calabretta
Keyword(s):  
Cell Cycle ◽  
Phase I ◽  
B Cell ◽  
Cell Cycle Arrest ◽  
Lymphoblastic Leukemia ◽  
Ectopic Expression ◽  
Maximum Tolerated Dose ◽  
Cyclin D3 ◽  
Cycle Arrest ◽  
Dose Limiting Toxicity

TPS7065 Background: c-Myb is a DNA-binding transcription factor that is highly expressed in immature hematopoietic cells. c-Myb and its products are essential in regulating normal hematopoiesis and influencing leukemogenesis. Knockdown of c-Myb causes cell cycle arrest and apoptosis in pre-B-ALL cells. The effects of c-Myb depend on transcriptional regulation of CDK6 and Bcl-2. c-Myb-silenced Ph+ ALL cells exhibit Rb-dependent cell cycle arrest and apoptosis, both of which are rescued by ectopic expression of cyclin D3, CDK6, and Bcl-2 expression. Preclinical studies suggest that the cytotoxic activity of dexamethasone in ALL cells may be due to decreased c-Myb expression and reduced Bcl-2 levels. Thus, the novel combination of palbociclib, a small molecule CDK4/6 inhibitor, and dexamethasone is a logical approach for the treatment of B-cell ALL. Methods: This is a single arm, phase I, dose escalation study with a traditional 3+3 design. Adult patients with relapsed or refractory B-cell ALL are eligible. Patients with Ph+ ALL must be refractory to or intolerant of standard tyrosine kinase inhibitor therapy. Patients receive a 1-week lead-in of palbociclib alone followed by induction with 4 weeks of palbociclib and dexamethasone. If an adequate response is seen, patients move to maintenance therapy, which consists of 1 week of palbociclib plus dexamethasone followed by 3 weeks of palbociclib alone. Treatment continues until disease progression, dose limiting toxicity, or availability of an alternative therapy. The primary endpoints are dose limiting toxicity and maximum tolerated dose of palbociclib and dexamethasone. Correlative studies, which are performed on pretreatment, day +1 and day +8 samples, include RB phosphorylation and FOXM1 expression as measures of palbociclib activity; CD19+ cell gene expression profiling of (1) p21 expression as an indicator of cell cycle activity, (2) S-Phase, Annexin V/Caspase 3 activation as indicators of proliferation and apoptosis and (3) Myb and Bcl-2 expression as indicators of dexamethasone sensitivity. Cohort 1 is currently enrolling. Once a maximum tolerated dose is established, an expansion cohort is planned. Clinical trial information: NCT03472573.

scholarly journals Pre–B cell receptor–mediated cell cycle arrest in Philadelphia chromosome–positive acute lymphoblastic leukemia requires IKAROS function

2009 ◽  
Vol 206 (8) ◽  
pp. 1739-1753 ◽  
Author(s):  
Daniel Trageser ◽  
Ilaria Iacobucci ◽  
Rahul Nahar ◽  
Cihangir Duy ◽  
Gregor von Levetzow ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Acute Lymphoblastic Leukemia ◽  
Tumor Suppressor ◽  
B Cell ◽  
Cell Cycle Arrest ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Cycle Arrest

B cell lineage acute lymphoblastic leukemia (ALL) arises in virtually all cases from B cell precursors that are arrested at pre–B cell receptor–dependent stages. The Philadelphia chromosome–positive (Ph+) subtype of ALL accounts for 25–30% of cases of adult ALL, has the most unfavorable clinical outcome among all ALL subtypes and is defined by the oncogenic BCR-ABL1 kinase and deletions of the IKAROS gene in >80% of cases. Here, we demonstrate that the pre–B cell receptor functions as a tumor suppressor upstream of IKAROS through induction of cell cycle arrest in Ph+ ALL cells. Pre–B cell receptor–mediated cell cycle arrest in Ph+ ALL cells critically depends on IKAROS function, and is reversed by coexpression of the dominant-negative IKAROS splice variant IK6. IKAROS also promotes tumor suppression through cooperation with downstream molecules of the pre–B cell receptor signaling pathway, even if expression of the pre–B cell receptor itself is compromised. In this case, IKAROS redirects oncogenic BCR-ABL1 tyrosine kinase signaling from SRC kinase-activation to SLP65, which functions as a critical tumor suppressor downstream of the pre–B cell receptor. These findings provide a rationale for the surprisingly high frequency of IKAROS deletions in Ph+ ALL and identify IKAROS-mediated cell cycle exit as the endpoint of an emerging pathway of pre–B cell receptor–mediated tumor suppression.

scholarly journals BLNK suppresses pre–B-cell leukemogenesis through inhibition of JAK3

Blood ◽  
2009 ◽  
Vol 113 (7) ◽  
pp. 1483-1492 ◽  
Author(s):  
Joji Nakayama ◽  
Mutsumi Yamamoto ◽  
Katsuhiko Hayashi ◽  
Hitoshi Satoh ◽  
Kenji Bundo ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cell ◽  
Cell Cycle Arrest ◽  
Lymphoblastic Leukemia ◽  
Genetic Alterations ◽  
Leukemia Cells ◽  
Cell Leukemia ◽  
Cycle Arrest ◽  
B Cell Leukemia

Abstract Pre–B-cell leukemia spontaneously develops in BLNK-deficient mice, and pre–B-cell acute lymphoblastic leukemia cells in children often lack BLNK protein expression, demonstrating that BLNK functions as a tumor suppressor. However, the mechanism by which BLNK suppresses pre–B-cell leukemia, as well as the identification of other genetic alterations that collaborate with BLNK deficiency to cause leukemogenesis, are still unknown. Here, we demonstrate that the JAK3/STAT5 signaling pathway is constitutively activated in pre-B leukemia cells derived from BLNK−/− mice, mostly due to autocrine production of IL-7. Inhibition of IL-7R signaling or JAK3/STAT5 activity resulted in the induction of p27kip1 expression and cell-cycle arrest, accompanied by apoptosis in the leukemia cells. Transgene-derived constitutively active STAT5 (STAT5b-CA) strongly synergized with the loss of BLNK to initiate leukemia in vivo. In the leukemia cells, exogenously expressed BLNK inhibited autocrine JAK3/STAT5 signaling, resulting in p27kip1 induction, cell-cycle arrest, and apoptosis. BLNK-inhibition of JAK3 was dependent on the binding of BLNK to JAK3. These data indicate that BLNK normally regulates IL-7–dependent proliferation and survival of pre–B cells through direct inhibition of JAK3. Thus, somatic loss of BLNK and concomitant mutations leading to constitutive activation of Jak/STAT5 pathway result in the generation of pre–B-cell leukemia.

scholarly journals p21WAF1 modulates drug-induced apoptosis and cell cycle arrest in B-cell precursor acute lymphoblastic leukemia

Cell Cycle ◽  
2015 ◽  
Vol 14 (22) ◽  
pp. 3602-3612 ◽  
Author(s):  
Carwyn Davies ◽  
Linda A Hogarth ◽  
Karen L Mackenzie ◽  
Andrew G Hall ◽  
Richard B Lock
Keyword(s):  
Cell Cycle ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Cell Cycle Arrest ◽  
Lymphoblastic Leukemia ◽  
Cell Precursor ◽  
Drug Induced ◽  
Cycle Arrest ◽  
Induced Apoptosis

scholarly journals Synergistic Drug Combinations with a CDK4/6 Inhibitor in T-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2488-2488 ◽  
Author(s):  
Yana Pikman ◽  
Andrew Furman ◽  
Emily S. Lee ◽  
Andrew E. Place ◽  
Gabriela Alexe ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Acute Lymphoblastic Leukemia ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Cyclin D3 ◽  
Cycle Arrest ◽  
Cell Acute Lymphoblastic Leukemia

Abstract While significant progress has been made in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), approximately 10-20% of newly diagnosed patients will experience either induction failure or relapse. Additionally, fewer than 50% of T-ALL patients who experience a relapse are long-term survivors. New targeted therapies are needed for the treatment of this disease. Multiple lines of evidence point to Cyclin D3/CDK4/6 as a potential therapeutic target in T-ALL. Cyclin D3 (CCND3), a direct target of activated NOTCH1, is upregulated in T-ALL, and CCND3 null animals are refractory to NOTCH1 driven T-ALL. CCND3 binds and activates CDK4/6, and the CCND3-CDK complex phosphorylates the tumor suppressor RB leading to cell cycle progression. Previous studies have demonstrated that CDK4/6 small-molecule inhibition is an effective therapeutic strategy for the treatment of NOTCH1-driven T-ALL mouse models. Using the publicly available Genomics of Drug Sensitivity in Cancer data set, we identified NOTCH1 mutations as a biomarker of response and RB mutations as a biomarker of resistance to the CDK4/6 inhibitor palbociclib. We validated that RB null status predicts resistance to the Novartis CDK4/6 inhibitor LEE011 in a panel of T-ALL cell lines. Interestingly, we identified both NOTCH1 mutant, as well as NOTCH1 wildtype, T-ALL cell lines that were sensitive to LEE011 treatment. Mining of publicly available data revealed that CDK6 is consistently marked by a super-enhancer in T-ALL cell lines, both NOTCH1 mutant and wildtype, suggesting another potential reason for sensitivity to CDK4/6 inhibition in this lineage. Treatment with LEE011 also led to a dose-dependent cell cycle arrest and cell death in T-ALL cells, including MOLT4 (NOTCH1 mutant) and MOLT16 (NOTCH1 wildtype). Combinations of drugs with CDK4/6 inhibitors will likely be critical for the successful translation of this drug class because they generally do not induce cell death. Combinations with cytotoxic chemotherapy are predicted to be antagonistic, however, as most of these drugs rely on rapidly proliferating cells, and CDK4/6 inhibition induces cell cycle arrest. To discover effective, and immediately translatable combination therapies with LEE011 in T-ALL, we performed combination studies of LEE011 with agents standardly used for T-ALL treatment, including corticosteroids, methotrexate, mercaptopurine, asparaginase, vincristine and doxorubicin. Combinations of LEE011 with methotrexate, mercaptopurine, vincristine or asparaginase were antagonistic in T-ALL cell lines while the combination with doxorubicin was additive. Combination treatment of LEE011 with corticosteroids had a synergistic effect on cell viability in MOLT4 and MOLT16 cell lines as measured by excess over Bliss additive and isobologram analyses. This combination also decreased phospho RB signaling, increased cell cycle arrest and induced cell death to a greater degree than either drug alone. LEE011 treatment increased CCND3 protein levels, an effect mitigated by glucocorticoid treatment, one possible mechanism contributing to the observed synergy. Additionally, the combination of LEE011 with everolimus, an mTOR inhibitor, was synergistic in these cell lines. We next extended testing to in vivo models of T-ALL. In a MOLT16 orthotopic mouse model, the combination of LEE011 and everolimus significantly prolonged mouse survival compared to treatment with each individual drug alone. The combination of LEE011 with dexamethasone did not extend survival over treatment with LEE011 alone and dexamethasone was inactive in vivo. Both LEE011 and everolimus had on-target activity in the treated mice as measured by inhibition of peripheral blood phospho-RB and phospho-4EBP1. We then tested the combination of LEE011 with dexamethasone in a second mouse model, a MOLT4 orthotopic model. Here, the combination of LEE011 with dexamethasone was more effective in prolonging survival compared to each treatment alone, supporting a heterogeneous response to the combination of LEE011 with dexamethasone in vivo. We conclude that LEE011 is active in T-ALL, and that combination therapy with corticosteroids and/or mTOR inhibitors warrants further investigation in the clinical setting. Disclosures Kim: Novartis Pharmaceuticals: Employment. Stegmaier:Novartis Pharmaceuticals: Consultancy.

scholarly journals Growth Suppression by Acute PromyelocyticLeukemia-Associated Protein PLZF Is Mediated by Repression ofc-mycExpression

2003 ◽  
Vol 23 (24) ◽  
pp. 9375-9388 ◽  
Author(s):  
Melanie J. McConnell ◽  
Nathalie Chevallier ◽  
Windy Berkofsky-Fessler ◽  
Jena M. Giltnane ◽  
Rupal B. Malani ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Cell Cycle Arrest ◽  
Target Genes ◽  
Ectopic Expression ◽  
Growth Suppression ◽  
Quiescent State ◽  
Cycle Arrest

ABSTRACT The transcriptional repressor PLZF was identified by its translocation with retinoic acid receptor alpha in t(11;17) acute promyelocytic leukemia (APL). Ectopic expression of PLZF leads to cell cycle arrest and growth suppression, while disruption of normal PLZF function is implicated in the development of APL. To clarify the function of PLZF in cell growth and survival, we used an inducible PLZF cell line in a microarray analysis to identify the target genes repressed by PLZF. One prominent gene identified was c-myc. The array analysis demonstrated that repression of c-myc by PLZF led to a reduction in c-myc-activated transcripts and an increase in c-myc-repressed transcripts. Regulation of c-myc by PLZF was shown to be both direct and reversible. An interaction between PLZF and the c-myc promoter could be detected both in vitro and in vivo. PLZF repressed the wild-type c-myc promoter in a reporter assay, dependent on the integrity of the binding site identified in vitro. PLZF binding in vivo was coincident with a decrease in RNA polymerase occupation of the c-myc promoter, indicating that repression occurred via a reduction in the initiation of transcription. Finally, expression of c-myc reversed the cell cycle arrest induced by PLZF. These data suggest that PLZF expression maintains a cell in a quiescent state by repressing c-myc expression and preventing cell cycle progression. Loss of this repression through the translocation that occurs in t(11;17) would have serious consequences for cell growth control.

scholarly journals Anti-CD19 inhibits the growth of human B-cell tumor lines in vitro and of Daudi cells in SCID mice by inducing cell cycle arrest

Blood ◽  
1994 ◽  
Vol 83 (5) ◽  
pp. 1329-1336 ◽  
Author(s):  
MA Ghetie ◽  
LJ Picker ◽  
JA Richardson ◽  
K Tucker ◽  
JW Uhr ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cell ◽  
Cell Cycle Arrest ◽  
Inhibitory Effect ◽  
Scid Mice ◽  
Cell Tumor ◽  
Cycle Arrest ◽  
A Chain

Abstract In this report, we extend our previous findings that IgG or F(ab′)2 fragments of HD37 anti-CD19 antibody (Ab) in combination with the immunotoxin (IT), RFB4-anti-CD22-deglycosylated ricin A chain (dgA) (but neither reagent alone), prolonged the survival of SCID mice with disseminated human Daudi lymphoma (SCID/Daudi mice) to 1 year at which time they still remained tumor-free. We explored the mechanisms by which the HD37 Ab exerts antitumor activity in vivo by studying its activity in vitro. We found that it has antiproliferative activity (IC50 = 5.2 - 9.8 x 10(-7) mol/L) on three CD19+ Burkitt's lymphoma cell lines (Daudi, Raji, and Namalwa) but not on a weakly CD19-positive (CD19lo) pre-B cell tumor (Nalm-6). The inhibitory effect was manifested by cell cycle arrest, but not apoptosis. Results using three additional anti-CD19 Abs, suggest that the affinity of the antibody and possibly the epitope which it recognizes may effect its capacity to transmit a signal that induces cell cycle arrest. Hence, therapeutically useful Abs may exert anti-tumor activity by a variety of mechanisms, each of which should be evaluated before undertaking clinical trials in humans.

scholarly journals Jianpi Huayu Decoction Inhibits Proliferation in Human Colorectal Cancer Cells (SW480) by Inducing G0/G1-Phase Cell Cycle Arrest and Apoptosis

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Song-yang Xi ◽  
Yu-hao Teng ◽  
Yan Chen ◽  
Jie-ping Li ◽  
Ying-ying Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Caspase 3 ◽  
Cyclin D3 ◽  
Phase Cell ◽  
G1 Phase ◽  
Dependent Manner ◽  
Cycle Arrest ◽  
Sw480 Cells

Jianpi Huayu Decoction (JHD), a Chinese medicine formula, is a typical prescription against multiple tumors in the clinical treatment, which can raise quality of life and decrease complications. The aim of this study is to assess the efficacy of JHD against human colorectal carcinoma cells (SW480) and explore its mechanism. MTT assay showed that JHD decreased the cellular viability of SW480 cells in dose-dependent and time-dependent manner. Flow cytometry analysis revealed that JHD induced G0/G1-phase cell cycle arrest in SW480 cells and had a strong apoptosis-inducing effect on SW480 cells. Meanwhile it enhanced the expression of p27, cleaved PARP, cleaved caspase-3, and Bax and decreased the levels of PARP, caspase-3, Bcl-2, CDK2, CDK4, CDK6, cyclin D1, cyclin D2, cyclin D3, and cyclin E1, which was evidenced by RT-qPCR and Western blot analysis. In conclusion, these results indicated that JHD inhibited proliferation in SW480 cells by inducing G0/G1-phase cell cycle arrest and apoptosis, providing a practicaltherapeutic strategy against colorectal cancer.

scholarly journals Synergistic activity of rapamycin and dexamethasone in vitro and in vivo in acute lymphoblastic leukemia via cell-cycle arrest and apoptosis

2012 ◽  
Vol 36 (3) ◽  
pp. 342-349 ◽  
Author(s):  
Chong Zhang ◽  
Yong-Ku Ryu ◽  
Taylor Z. Chen ◽  
Connor P. Hall ◽  
Daniel R. Webster ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Acute Lymphoblastic Leukemia ◽  
Cell Cycle Arrest ◽  
Lymphoblastic Leukemia ◽  
Synergistic Activity ◽  
Cycle Arrest
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