Cyclin-Dependent KinasesInitial Approaches to Exploit a Novel Therapeutic Target

Sausville, Edward A.; Zaharevitz, Daniel; Gussio, Robert; Meijer, Laurent; Louarn-Leost, Maryse; Kunick, Conrad; Schultz, Robert J.; Lahusen, Tyler; Headlee, Donna; Stinson, Sherman F.

doi:10.1016/s0163-7258(98)00062-x

Cited by 114 publications

(68 citation statements)

References 23 publications

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“…Compounds much more selective for CDK inhibition versus other kinases include flavopiridol that inhibits all CDKs, however, buty-rolactone I, olomucine and roscovitine, purvanolol and paullone derivatives are relatively selective for CDK1(CDC2) and CDK2, but spare CDK4 and CDK6. The antiproliferative effects of these compounds on the growth of several human cell lines has been well documented (Sausville et al, 1999;Meijer et al, 1999). The effects in vivo of these compounds paralleled the in vitro efficiency and were further confirmed with the use of dominant negatives, the overexpression of natural CKIs and the microinjection of inactivating antibodies or antisense technologies (van den Heuvel and Harlow, 1993).…”

Section: Chemical Inhibitors Of Cdkmentioning

confidence: 86%

Targeting the cell cycle for cancer therapy

Carnero

2002

Br J Cancer

134

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Most if not all neoplasias show a directly or indirectly deregulated cell cycle. Targeting its regulatory molecules, the cyclindependent kinases, as a therapeutic mode to develop new anticancer drugs, is being currently explored in both academia and pharmaceutical companies. The development of new compounds is being focused on the many features of the cell cycle with promising preclinical data in most fields. Moreover, a few compounds have entered clinical trials with excellent results maintaining the high hopes. Thus, although too early to provide a cell cycle target based new commercial drug, there is no doubt that it will be an excellent source of new anticancer compounds.

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Section: Chemical Inhibitors Of Cdkmentioning

confidence: 86%

Targeting the cell cycle for cancer therapy

Carnero

2002

Br J Cancer

134

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“…As predicted, the preliminary results of experimental studies in our laboratory indicate that breast cancer cell lines with PTEN mutations are extraordinarily sensitive to rapamycin (Hidalgo M, personal communication). In addition to increased sensitivity to rapamycin conferred by mutations of the PTEN suppressor oncogene, abnormalities of regulators of the G 1 checkpoint such as pRB, p16, p27, and cyclin D1 may also increase the sensitivity of tumors to rapamycin and may predict for drug e cacy (Sausville et al, 1999). It is clear that de®ning the molecular characteristics of tumors of patients enrolled in clinical trials of CCI-779 may help to identify which patients may bene®t from treatment.…”

Section: Clinical Developmentmentioning

confidence: 99%

The rapamycin-sensitive signal transduction pathway as a target for cancer therapy

2000

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“…This does not exclude the possibility that abnormalities in G 1 checkpoint regulators known to occur in ES cells (Deneen and Denny, 2001) may also contribute to, and most likely increase their sensitivity to rapamycin. In this regard, the presence in ES cells of altered pRB, p16, p27 or cyclin D1 may be predictors of enhanced rapamycin efficacy (Sausville et al, 1999). As EWS/FLI-1 is the main determinant of the malignancy of ES tumors (Arvand and Denny, 2001), rapamycin treatment may have a dual effect as a cytostatic agent and suppressor of the neoplastic phenotype of ES cells.…”

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confidence: 99%

Rapamycin induces the fusion-type independent downregulation of the EWS/FLI-1 proteins and inhibits Ewing's sarcoma cell proliferation

Tirado

Notario

2003

Oncogene

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Ewing's sarcoma (ES) is the prototype of a family of tumors (ESFT) of neuroectodermal origin formed by small, round cells with limited neural differentiation, which arise most frequently within bones in children or adolescents. The proliferation of ESFT cells is highly dependent on the establishment of, and signaling through several growth factor-mediated autocrine loops. The mammalian target of rapamycin (mTOR) is a central regulator of translation and cell proliferation, involved in the cellular response to various nutritional, stress and mitogenic effectors. As mTOR has recently been associated with certain human cancers, we investigated the possibility that mTOR played a role in the regulation of ES cell proliferation. Results showed that ES cell lines carrying EWS/FLI-1 alleles of different types expressed different levels of total and phosphorylated mTOR protein. We demonstrate that rapamycin, an mTOR inhibitor, efficiently blocked the proliferation of all cell lines by promoting cell cycle arrest at the G 1 phase. This was paralleled by the downregulation of the levels of the EWS/FLI-1 proteins, regardless of their fusion type, and the concomitant restoration of the expression of the TGFb type 2 receptor (TGFb RII), which is known to be repressed by several EWS-ETS fusion proteins. The expression of a rapamycin-resistant mTOR construct prevented both the proliferation blockade and the EWS/ FLI-1 downregulation. These data demonstrate that mTOR signaling plays a central role in ES cell pathobiology and strongly suggest that the use of rapamycin as a cytostatic agent may be an efficient tool for the treatment of ES patients. Oncogene (2003) 22, 9282-9287. doi:10.1038/sj.onc.1207081Keywords: mTOR; rapamycin; EWS/FLI-1; Ewing's sarcoma Ewing's sarcoma (ES) and primitive neuroectodermal tumors (PNET) are characterized by the presence of a specific chromosomal translocation leading to the fusion of the 5 0 end of the EWS gene and the 3 0 end of various genes encoding transcription factors of the ETS family, usually FLI-1 and ERG. The most frequent fusion, resulting from a t(11;22)(q24;q12) translocation, involves EWS and FLI-1 and is found in about 90-95% of the cases (Arvand and Denny, 2001). Identification of several breakpoints for both EWS and FLI-1 demonstrated that EWS/FLI-1 fusion genes are heterogeneous. Breakpoints of type 1 (exon 7 of EWS/exon 6 of FLI-1), type 2 (exon 7 of EWS/exon 5 of FLI-1) and type 3

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Cyclin-Dependent KinasesInitial Approaches to Exploit a Novel Therapeutic Target

Cited by 114 publications

References 23 publications

Targeting the cell cycle for cancer therapy

Targeting the cell cycle for cancer therapy

The rapamycin-sensitive signal transduction pathway as a target for cancer therapy

Rapamycin induces the fusion-type independent downregulation of the EWS/FLI-1 proteins and inhibits Ewing's sarcoma cell proliferation

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