Multi-institutional phase 2 study of the farnesyltransferase inhibitor tipifarnib (R115777) in patients with relapsed and refractory lymphomas

Witzig, Thomas E.; Tang, Hui; Micallef, Ivana N.; Ansell, Stephen M.; Link, Brian K.; Inwards, David J.; Porrata, Luis F.; Johnston, Patrick B.; Colgan, Joseph P.; Markovic, Svetomir N.; Nowakowski, Grzegorz S.; Thompson, Carrie A.; Allmer, Cristine; Maurer, Mathew S.; Gupta, Mamta; Weiner, George J.; Hohl, R. J.; Kurtin, Paul J.; Ding, Husheng; Loegering, David A.; Schneider, Paula A.; Peterson, Kevin; Habermann, Thomas M.; Kaufmann, Scott H.

doi:10.1182/blood-2011-02-334904

Cited by 40 publications

(23 citation statements)

References 37 publications

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“…This drug is currently under evaluation in hematologic diseases with high rates of RAS mutation and activation. [35][36][37][38]53,54 A phase 1 study showed that tipifarnib was welltolerated by pediatric patients with resistant or refractory AML, although a poor clinical response was observed, partially due to the fact that RAS hyperactivation is not demonstrable in all AML variants. Support to the rationale of using tipifarnib is provided by the observation that apoptosis after drug exposure was enhanced in primary blasts carrying t(6;11), whereas blasts carrying other MLL rearrangement of childhood AML never showed relevant sensitivity to this drug.…”

Section: 46mentioning

confidence: 99%

“…Tipifarnib is a drug not currently used in the treatment of pediatric AML, and it is currently adopted in clinical trials for different diseases [35][36][37][38] for its ability to block the farnesyltransferase enzyme to inhibit targets among which there is Ras. 39,40 We treated t(6;11)-translocated cell lines, ML2 and SHI-1, as well as cell lines with different rearrangements of MLL (ie, THP1 and NOMO1), both MLL-AF9 translocated, by comparing increasing concentrations of different cytotoxic drugs currently used for AML treatment, such as doxorubicin (Doxo), cytarabine (Ara-C), and etoposide (VP16) with tipifarnib.…”

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confidence: 99%

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MLL-AF6 fusion oncogene sequesters AF6 into the nucleus to trigger RAS activation in myeloid leukemia

Manara

Baron

Tregnago

et al. 2014

Blood

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Key Points• MLL-AF6 leads to aberrant activation of RAS and its downstream targets.• RAS targeting is a novel potential therapeutic strategy in AML patients carrying t(6;11).A rare location, t(6;11)(q27;q23) (MLL-AF6), is associated with poor outcome in childhood acute myeloid leukemia (AML). The described mechanism by which MLL-AF6, through constitutive self-association and in cooperation with DOT-1L, activates aberrant gene expression does not explain the biological differences existing between t(6;11)-rearranged and other MLL-positive patients nor their different clinical outcome. Here, we show that AF6 is expressed in the cytoplasm of healthy bone marrow cells and controls rat sarcoma viral oncogene (RAS)-guanosine triphosphate (GTP) levels. By contrast, in MLL-AF6-rearranged cells, AF6 is found localized in the nucleus, leading to aberrant activation of RAS and of its downstream targets. Silencing MLL-AF6, we restored AF6 localization in the cytoplasm, thus mediating significant reduction of RAS-GTP levels and of cell clonogenic potential. The rescue of RAS-GTP levels after MLL-AF6 and AF6 co-silencing confirmed that MLL-AF6 oncoprotein potentiates the activity of the RAS pathway through retention of AF6 within the nucleus. Exposure of MLL-AF6-rearranged AML blasts to tipifarnib, a RAS inhibitor, leads to cell autophagy and apoptosis, thus supporting RAS targeting as a novel potential therapeutic strategy in patients carrying t(6;11). Altogether, these data point to a novel role of the MLL-AF6 chimera and show that its gene partner, AF6, is crucial in AML development. (Blood. 2014;124(2):263-272) IntroductionThe mixed lineage leukemia (MLL) protein is a histone H3 lysine 4-specific methyltransferase, commonly associated with transcriptional activation.1 MLL is essential for both embryonic development and normal hematopoiesis, mainly through transcriptional regulation of the homeobox (HOX) gene.2 Chromosome translocations involving MLL locus are 1 of the major genetic lesions leading to acute leukemia. MLL translocations are detected in up to 80% of infant acute leukemia and in approximately 10% to 15% of childhood acute myeloid leukemia (AML).3,4 Aberrant proteins resulting from translocations, duplications, or amplifications of the MLL gene cause alteration of the differentiation program with severe effects on leukemogenesis. 5,6 To date, more than 60 fusion partners of MLL have been described, which result in AML, acute lymphoid, and biphenotypic or chemotherapy-related leukemias. 7,8 The underlying mechanisms for MLL-mediated leukemogenesis have been extensively studied; however, they still remain elusive for many of the described translocations. MLL-rearranged AML is, in fact, a heterogeneous disease, which depends on the MLL partner gene for its biological and clinical features, such as gene expression and genomic imbalances. 4 Among diverse fusion genes, the 1 that has been consistently associated with the worst outcome both in adult and pediatric AML is MLL-AF6. 9The t(6;11)(q27;q23) translocatio...

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Section: 46mentioning

confidence: 99%

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confidence: 99%

MLL-AF6 fusion oncogene sequesters AF6 into the nucleus to trigger RAS activation in myeloid leukemia

Manara

Baron

Tregnago

et al. 2014

Blood

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“…However, subsequent studies revealed their activity in tumors with normal Ras that seems to result from inhibition of prosurvival signaling mediated by other prenylation-dependent pathways. Importantly, tipifarnib, a farnesyltransferase inhibitor, was recently shown to exert some therapeutic activity in patients with relapsed and refractory lymphomas (25). Therefore, we decided to investigate in more detail the influence of prenyltransferase inhibitors on antitumor activity of anti-CD20 mAbs.…”

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confidence: 99%

Prenyltransferases Regulate CD20 Protein Levels and Influence Anti-CD20 Monoclonal Antibody-mediated Activation of Complement-dependent Cytotoxicity

Winiarska

Nowis

Bil

et al. 2012

Journal of Biological Chemistry

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Background:The influence of farnesyltransferase inhibitors (FTIs) on CD20 levels is unknown. Results: FTIs increase CD20 expression and improve rituximab-mediated activation of complement-dependent cytotoxicity. Conclusion: FTIs sensitize tumor cells to anti-CD20 mAbs. Significance: The combination of FTIs with anti-CD20 mAbs seems to be a reasonable therapeutic approach worth to be tested in patients with B-cell tumors.

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“…FTIs can inhibit the Ras-ERK/MAPK signaling pathway, and thus inhibit the proliferation of tumor cells [4,5]. They have been widely studied in the molecular targeted treatment of cancer, and some FTIs have entered Phase I or Phase II clinical study [6,7].…”

Section: Introductionmentioning

confidence: 99%

A farnesyl transferase inhibitor induces apoptosis of insulinoma pancreatic β cells of mouse

Gao¹,

Fu²,

Liu³

et al. 2018

biomedicalresearch

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This study is to investigate the effect of a Farnesyl Transferase Inhibitor (FTI) R115777 on apoptosis of mouse insulinoma pancreatic β cells. MTT assay was used to investigate the proliferative inhibition of in vitro cultured mouse insulinoma pancreatic β cell lines by a FTI R115777. The morphological changes of the cells were observed using a fluorescence microscope by staining with Hoechst 33258 and propidium iodide after the treatment with FTI R115777. The apoptosis rate of R115777-treated beta-TC-6 cells was detected by flow cytometry. The expressions of caspase-3 and caspase-9 of the R115777-treated beta-TC-6 cells were assayed by spectrophotometry. In addition, the sub-cellular distribution of cytochrome c and the expressions of Bax and Bcl-2 proteins were detected by Western blot. After the treatment with FTI R115777, the proliferation of the mouse insulinoma pancreatic β cell lines was significantly inhibited. Significant apoptosis was observed in the treated beta-TC-6 cells. The effect of R115777 on the apoptosis of beta-TC-6 cells showed time-and dose-dependent manners. The expressions of caspase-3, caspase-9 and Bax in the R115777-treated beta-TC-6 cells increased, while the expression of Bcl-2 decreased. The sub-cellular distribution of cytochrome-c changed, with reduced cytochrome-c in mitochondria and increased cytochrome-c in cytoplasm. FTI R115777 can inhibit the proliferation of mouse insulinoma pancreatic β cell lines, and might induce cell apoptosis through the mitochondrionmediated pathway. R115777 could be further studied as a potential antitumor drug.

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Multi-institutional phase 2 study of the farnesyltransferase inhibitor tipifarnib (R115777) in patients with relapsed and refractory lymphomas

Cited by 40 publications

References 37 publications

MLL-AF6 fusion oncogene sequesters AF6 into the nucleus to trigger RAS activation in myeloid leukemia

MLL-AF6 fusion oncogene sequesters AF6 into the nucleus to trigger RAS activation in myeloid leukemia

Prenyltransferases Regulate CD20 Protein Levels and Influence Anti-CD20 Monoclonal Antibody-mediated Activation of Complement-dependent Cytotoxicity

A farnesyl transferase inhibitor induces apoptosis of insulinoma pancreatic β cells of mouse

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