Combining Simvastatin with the Farnesyltransferase Inhibitor Tipifarnib Results in an Enhanced Cytotoxic Effect in a Subset of Primary CD34+ Acute Myeloid Leukemia Samples

Background: Tipifarnib (Zarnestra, Z) is a non-peptidomimetic farnesyltransferase inhibitor (FTI) with clinical activity in hematologic malignancies, including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and chronic myeloid leukemia. Preclinical data suggest that tipifarnib may be synergistic with some chemotherapeutic agents. Methods: We designed a phase I/II study in patients (pts) age 15–70 years, with previously untreated AML or high-risk MDS (blasts ≥ 10%), who received induction with idarubicin (Ida) 12 mg/m2/day on days 1–3, cytarabine (ara-C) 1.5 g/m2 IV over 24 hours daily on days 1–4 (days 1–3 only if age ≥ 60 years) and Z, with first cohort (n=6) receiving 200mg PO BID and all others 300 mg PO BID x 21 days every 28 days. Pts achieving a complete remission (CR) received consolidation (5 courses) with Ida 8 mg/m2/day on days 1–2, ara-C 0.75 g/m2/day on days 1–3, and Z 300 mg PO BID x 14 days every 4–6 weeks. Maintenance was with Z 300 mg PO BID x 21 days every 4–6 weeks for 6 months. Results: We treated 95 pts, median age 50 yrs (range, 17–61 yrs), and all are evaluable for response with a median followup of 61 weeks (range, 35–138). Seventy pts (73%) responded: 61 (64%) achieved a CR and 9 (9%) a CRp. Median CR duration was 72 weeks, (range, 4–121) with median OS 70 weeks (range, 1–138). Response by cytogenetics was: 34/41 (83%) for diploid, 13/19 (69%) with −5/−7, 1/2 (50%) with t(8;21), and 21/32 (65%) with other abnormalities. Response by age was 31/43 (72%) for < 50 yrs, 12/18 (67%) for ≥ 50 yrs with diploid karyotype, and 18/34 (53%) for ≥ 50 yrs with abnormal karyotype. Response by FLT3 status was 12/16 (75%) for mutated, 51/66 (78%) for unmutated. Overall response rate (CR+CRp) in a similar historical population treated with the same chemotherapy regimen, idarubicin/cytarabine (IA), without Z was 72% (p=0.847), median CR duration 52 weeks (range, 2–319) (p=0.493), median OS 65 weeks (range, 3–322) (p=0.698). The most common grade ≥ 3 adverse events have included diarrhea (39%), hypokalemia (27%), rash (21%), and hepatic dysfunction (18%). Fifty-three (56%) pts have required treatment dose reductions during induction, 21 pts (40%) during consolidation, and 3 pts (18%) during maintenance. Conclusion: We conclude that Z combined with IA induces a high rate of CR in high-risk MDS or AML, but the outcome may not be superior to what is obtained with IA alone.

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P2X7 Receptor Activation By ATP As Target of Novel Therapies in Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v126.23.3684.3684 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3684-3684

Author(s):

Valentina Salvestrini ◽

Stefania Orecchioni ◽

Francesca Reggiani ◽

Giovanna Talarico ◽

Elisa Orioli ◽

...

Keyword(s):

Cell Death ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Pore Formation ◽

Cytotoxic Effect ◽

Leukemic Cells ◽

Cell Compartment ◽

Hematopoietic Stem ◽

Direct Cytotoxicity ◽

Acute Myeloid

Abstract ATP is the key energy molecule as well as an ubiquitous extracellular messenger. Depending on its dose and the engaged purinergic P2 receptor (P2R) subtype, ATP can trigger many different cell responses, including proliferation and cell death. Recent studies have shown that high ATP level exhibits direct cytotoxicity on many tumor cell types. Among the receptors engaged by ATP, P2X7 is the most consistently expressed by tumor cells and its overexpression is related to tumor growth and progression. The P2X7 is an ATP-gated ion channel that, upon sustained stimulation with millimolar ATP concentrations, drives the opening of a non-selective large conductance pore, triggering cell-death signal. We previously demonstrated that ATP is a potent stimulator of normal hematopoietic stem cell compartment while inhibiting acute myeloid leukemia (AML) cells. Based on this observation, we studied AML samples (n=20) collected from the bone marrow or the peripheral blood of leukemic patients at diagnosis before treatment (percentage of circulating blasts >90%). In addition, normal hematopoietic stem cells (HSC) were isolated from leukapheresis products of 5 healthy donors receiving G-CSF. Our data demonstrate that AML cells express high level of P2X7 and that its activation with high dose of ATP reduces blast cell viability while is not effective on normal CD34+ cells. The cytotoxic effect is due to the induction of apoptosis, associated with reduction of mithocondrial membrane potential and activation of caspase cascade. Interestingly, P2X7 is also expressed by leukemic stem/progenitor cells (LSC) and ATP treatment exerts a direct cytotoxicity on different subsets of stem/progenitor cell compartment i.e. CD34- CD38-, CD34+ CD38-, CD34+ CD38+ and CD34- CD38+. Of note, this cytotoxic effect was not observed on HSC subpopulations. Furthermore, we transplanted 1x106 human AML cells into NSG immunodeficient mice followed by intraperitoneal administration of ATP every other day for thirty days post-transplantation. Our results show a 40% inhibition of AML engraftment in ATP-treated mice vs controls. Different P2X7 splice variants have been identified among which only two are functional: P2X7A, which shows both pro-apoptotic and trophic activity and P2X7B, which retains only the growth promoting phenotype. In order to explain ATP different effects on LSCs and normal HSCs, we assumed a different P2X7 isoforms expression on normal and leukemic cells. Preliminary results showed a reduced expression of both P2X7A and P2X7B on normal CD34+ compared to leukemic cells. In particular normal CD34+ express very low level of P2X7A, which is responsible for pore formation after ATP stimulation. Moreover, since P2X7 pore formation facilitates the passage of hydrophilic chemotherapeutic agents, we hypothesized that ATP may potentiate the cytotoxic effect of antineoplastic drugs. Our results showed that ATP potentiates the cytotoxic effect of ARA-C, by significantly reducing cell proliferation and increasing apoptosis of leukemia cell lines. In conclusion, overall survival of adult AML remains poor due to the lack of novel and effective therapies. Novel compounds that have the potential to improve the treatment efficacy with low toxicity are highly warranted. Overall, our results may provide the biological rationale to use P2X7 as a target for novel therapeutical approaches against AML. Disclosures Cavo: Janssen-Cilag, Celgene, Amgen, BMS: Honoraria.

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NSC348884 cytotoxicity is not mediated by inhibition of nucleophosmin oligomerization

10.1101/2020.02.06.936666 ◽

2020 ◽

Author(s):

Markéta Šašinková ◽

Petr Heřman ◽

Aleš Holoubek ◽

Dita Strachotová ◽

Petra Otevřelová ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Cytotoxic Effect ◽

Leukemia Cells ◽

Live Cells ◽

Wild Type ◽

C Terminus ◽

Interaction Partners ◽

And Function ◽

Acute Myeloid

AbstractOligomerization of the nucleolar phosphoprotein nucleophosmin (NPM) is mediated by its N-terminal domain. In acute myeloid leukemia, a frequent NPM mutation occurring at the C-terminus causes NPM delocalization to the cytoplasm. Due to formation of NPM heterooligomers, the wild-type NPM as well as many of NPM interaction partners are also delocalized. Proper localization and function of mislocalized proteins in the cells with mutated NPM may be restored by targeting NPM oligomerization. We introduce a reliable set of complementary methods for monitoring NPM oligomerization in both cell lysates and live cells. Using this methodological background we show that a putative inhibitor of NPM oligomerization, NSC348884, does not prevent formation of NPM oligomers in leukemia cells. Instead, we reveal that the observed cytotoxic effect of NSC348884 is associated with changes in cell adhesion signaling.

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Cytotoxic effect of CLL‑1 CAR‑T cell immunotherapy with PD‑1 silencing on relapsed/refractory acute myeloid leukemia

Molecular Medicine Reports ◽

10.3892/mmr.2021.11847 ◽

2021 ◽

Vol 23 (3) ◽

Author(s):

Guoqiang Lin ◽

Yanming Zhang ◽

Lei Yu ◽

Depei Wu

Keyword(s):

Acute Myeloid Leukemia ◽

T Cell ◽

Myeloid Leukemia ◽

Cytotoxic Effect ◽

Car T Cell ◽

Cell Immunotherapy ◽

Car T ◽

Refractory Acute Myeloid Leukemia ◽

T Cell Immunotherapy ◽

Acute Myeloid

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A phase 1-2 study of a farnesyltransferase inhibitor, tipifarnib, combined with idarubicin and cytarabine for patients with newly diagnosed acute myeloid leukemia and high-risk myelodysplastic syndrome

Cancer ◽

10.1002/cncr.25575 ◽

2010 ◽

Vol 117 (6) ◽

pp. 1236-1244 ◽

Cited By ~ 26

Author(s):

Elias Jabbour ◽

Hagop Kantarjian ◽

Farhad Ravandi ◽

Guillermo Garcia-Manero ◽

Zeev Estrov ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Myelodysplastic Syndrome ◽

Myeloid Leukemia ◽

Phase 1 ◽

Newly Diagnosed ◽

Farnesyltransferase Inhibitor ◽

Acute Myeloid

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The Hypomethylating Agent Decitabine Prior to Chemotherapy Improves the Therapy Efficacy in Refractory/Relapsed Acute Myeloid Leukemia Patients

Blood ◽

10.1182/blood.v126.23.4932.4932 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4932-4932

Author(s):

Xuejie Jiang ◽

Zhixiang Wang ◽

Changxin Yin ◽

Guopan Yu ◽

Jieyu Ye ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Western Blotting ◽

Myeloid Leukemia ◽

Cytotoxic Effect ◽

Disease Free Survival ◽

Platelet Recovery ◽

Hypomethylating Agent ◽

Significant Difference ◽

Acute Myeloid

Abstract Introduction. Most acute myeloid leukemia (AML) patients with adverse prognosis either fail to achieve complete remission (CR) or relapse after short-term remission, new strategies are needed to improve therapeutic effect in these patients. Gene silencing via DNA methylation are frequent and reversible in high-risk AML, it provides the possibility to treat AML patients with DNA-hypomethylating agent. Decitabine alone has limited anti-leukemia effect and minimal toxicity. Studies demonstrated that decitabine prior to chemotherapy was likely to increase efficacy in AML. In this study, we investigated the effect of decitabine on susceptibility to cytotoxic drugs in chemoresistant AML cells. Efficacy and safety of decitabine prior to HAA regimen was evaluated in refractory, relapsed and high-risk AML patients. Methods. HL60, HL60/ADR, Kasumi-1, and primary AML cells were pre-treated with 1.0 μM decitabine for 72 hours, Sensitivities to harringtonine, adriamycin, cytarabine and the combination was determined by MTT, apoptosis was analyzed by flow cytometry. Protein expression was detected by western blotting. In clinic, Twenty-three patients were enrolled in decitabine prior to HAA regimen, and twenty-four patients in HAA alone. CR ratio was used to evaluate efficacy. Durations of neutrocytopenia or thrombcytopemia and infection incidence were observed to assess the safety. All of patients were followed up to 36 monthes, overall survival (OS) and disease-free survival (DFS) were calculated. Result. Decitabine increased sensitivity and apoptosis induced by harringtonine in HL60/ADR, as well as adriamycin and cytarabine in HL60/ADR and Kasumi-1 cells. But no change in sensitivity to each drug was observed in HL60, and sensitivity to harringtonine in Kasumi-1. The similar changes in sensitivity to adriamycin and cytarabine were also observed in primary AML cells from refractory patients (n=6). Cytotoxic effect of HAA was alsoincreaed by decitabine in HL60/ADR and Kasumi-1 cells (p=0.004, 0.018). Western blotting showed that decitabine decreased expression of DNMT1, activation of p53 and inhibition of c-Myc, Survivin and Bcl-2. In clinic, 16 (69.6%) patients in decitabine plus HAA regimen responded to the first course of induction therapy: 14 CR (60.9%) and 2 PR (8.7%). 1 in 2 patients with PR achieved CR after second course induction. It brought the overall CR was 65.2%. Otherwise, 10 (45.8%) patients in HAA regimen alone responded to the first induction: 7 CR (29.2%) and 4 PR (16.7%), 3 in 4 patients with PR achieved CR after the second induction, and overall CR reached 41.7%. The first-cycle CR ratio in decitabine plus HAA was higher than that in HAA alone (p=0.041). Patients continued to receive chemotherapy alternatively combined with decitabine. The median OS was 14 months in chemotherapy plus decitabine, 6 months in chemotherapy alone, and median DFS were 18 and 5 months in the former and latter. No significant difference was observed in the time of neutrophil (p=0.832, 0.631) or platelet recovery (p=0.798, 0.544) after induction and intensification therapy. The incidences of infection were also similar (p=0.724, 0.697). The clinic data indicated that decitabine plus HAA regimenit was efficacy and well-tolerated to treat refractory AML patients. Conclusion. Our results demonstrated that decitabine increased cytotoxic effect against chemoresistant AML cells. Combination of decitabine and HAA was safe and efficacy to treat refractory/relapsed AML. These findings support clinic protocols based on decitabine prior to chemotherapy to overcome resistance and improve therapeutic efficacy in AML patients. Disclosures Carter: PrismBiolab: Research Funding.

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A phase 2 study of the oral farnesyltransferase inhibitor tipifarnib in patients with refractory or relapsed acute myeloid leukemia

Blood ◽

10.1182/blood-2006-09-046144 ◽

2007 ◽

Vol 109 (12) ◽

pp. 5151-5156 ◽

Cited By ~ 56

Author(s):

Jean-Luc Harousseau ◽

Jeffrey E. Lancet ◽

Josy Reiffers ◽

Bob Lowenberg ◽

Xavier Thomas ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Response Rate ◽

Phase 2 ◽

Farnesyltransferase Inhibitor ◽

Phase 2 Study ◽

Bone Marrow Blasts ◽

Relapsed Acute Myeloid Leukemia ◽

Acute Myeloid

AbstractThis phase 2 study evaluated the efficacy and safety of the oral farnesyltransferase inhibitor tipifarnib in adults with refractory or relapsed acute myeloid leukemia (AML). Patients (n = 252) received tipifarnib 600 mg twice a day for 21 days in 28-day cycles. Median age was 62 years; 99 (39%) patients were 65 years or older. Eleven (4%) of 252 patients achieved complete remission (CR) or complete remission with incomplete platelet recovery (CRp; 9 CR and 2 CRp). Nineteen patients (8%), including those who achieved CR/CRp, achieved a reduction in bone marrow blasts to less than 5% blasts. Bone marrow blasts were reduced more than 50% in an additional 8 patients (total = 27; 11%). Median survival was 369 days for patients who achieved CR/CRp. Myelosuppression was the most common adverse event. The most common nonhematologic toxicities were fever, nausea, and hypokalemia. Single-agent treatment with tipifarnib induced durable CR/CRp, which was associated with prolonged survival, in some patients with refractory or relapsed AML. The response rate observed in this heavily pretreated group of patients suggests the requirement to enhance the response rate either by combining tipifarnib with other active agents or determining factors that are predictive of response.

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