Phase I Clinical/Pharmacokinetic and Pharmacodynamic Trial of the c-<i>raf</i>-1 Antisense Oligonucleotide ISIS 5132 (CGP 69846A)

Stevenson, James P.; Yao, Kang; Gallagher, Maryann; Friedland, David; Mitchell, Edith P.; Cassella, Amy; Monia, Brett P.; Kwoh, T. Jesse; Yu, Rosie Z.; Holmlund, Jon; Dorr, F. Andrew; O’Dwyer, Peter J.

doi:10.1200/jco.1999.17.7.2227

Cited by 120 publications

(54 citation statements)

References 24 publications

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“…Although studies of Ras transformation using other cell types now indicate that Raf-independent effector function also contributes to Ras transformation (Shields et al 2000), Raf is still generally considered to form the backbone of Ras oncogenesis. The importance of this pathway in Ras transformation is reflected by the current evaluation of anti-Raf and anti-MEK strategies in preclinical and clinical studies (Monia et al 1996;SeboltLeopold et al 1999;Stevenson et al 1999;Cunningham et al 2000;Kloog and Cox 2000;Sebolt-Leopold 2000;Stein and Waterfield 2000). There is also strong evidence for an important supportive role for PI3-kinase in Ras transformation (Rodriguez-Viciana et al 1997;Tolkacheva and Chan 2000).…”

Section: Discussionmentioning

confidence: 99%

Distinct requirements for Ras oncogenesis in human versus mouse cells

Hamad¹,

Elconin²,

Karnoub³

et al. 2002

Genes Dev.

395

314

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The spectrum of tumors associated with oncogenic Ras in humans often differs from those in mice either treated with carcinogens or engineered to sporadically express oncogenic Ras, suggesting that the mechanism of Ras transformation may be different in humans. Ras stimulates primarily three main classes of effector proteins, Rafs, PI3-kinase, and RalGEFs, with Raf generally being the most potent at transforming murine cells. Using oncogenic Ras mutants that activate single effectors as well as constitutively active effectors, we find that the RalGEF, and not the Raf or PI3-kinase pathway, is sufficient for Ras transformation in human cells. Thus, oncogenic Ras may transform murine and human cells by distinct mechanisms, and the RalGEF pathway-previously deemed to play a secondary role in Ras transformation-could represent a new target for anti-cancer therapy. Extracellular signals detected by cell-surface receptors can be transmitted to the cell by stimulating the conversion of the Ras oncoprotein from an inactive GDP-bound to an active GTP-bound state. In the GTP-bound state, Ras stimulates downstream targets, or effectors, which, in turn, affect numerous activities of the cell, such as proliferation, apoptosis, and differentiation (Shields et al. 2000). Mutated and constitutively activated forms of Ras are found in 30% of all human cancers (Bos 1989). Significant experimental and epidemiological evidence supports that such aberrant Ras activation plays a critical role in human oncogenesis. Consequently, there is considerable effort to develop inhibitors of the Ras-signaling pathway for use as novel anticancer drugs (Kloog and Cox 2000;Shields et al. 2000).Ras transformation is mediated by interactions with multiple downstream effectors whose contribution to Ras transformation has been evaluated primarily in rodent fibroblast model cell systems. Substantial evidence from these studies supports the role of Raf serine/threonine kinases (c-Raf-1, A-Raf, and B-Raf) as key effectors and mediators of Ras-transforming activity. Raf kinases phosphorylate and activate the MEK1 and MEK2 dual specificity kinases, which, in turn, phosphorylate and activate the ERK1/p44 and ERK2/p42 mitogen-activated protein kinases (MAPKs) (Kyriakis et al. 1992). The critical contribution of the Raf/MEK/ERK pathway to Ras transformation is shown by the ability of constitutively activated mutants of Raf or MEK to cause tumorigenic transformation of NIH 3T3 cells (Bonner et al. 1985;Stanton et al. 1989;Leevers et al. 1994;Stokoe et al. 1994). Additionally, dominant-negative mutants of Raf-1, MEK, and ERK, as well as pharmacologic inhibitors of MEK, have been shown to effectively block Ras transformation in vitro or suppress tumorigenic growth of cancer cell lines in vivo (Kolch et al. 1991;Schaap et al. 1993;Cowley et al. 1994;Westwick et al. 1994;Khosravi-Far et al. 1995;Qiu et al. 1995;Monia et al. 1996;Sebolt-Leopold et al. 1999).Perhaps the second best-characterized effector important for Ras transformation is phosphatidylinositol 3-kina...

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Section: Discussionmentioning

confidence: 99%

Distinct requirements for Ras oncogenesis in human versus mouse cells

Hamad¹,

Elconin²,

Karnoub³

et al. 2002

Genes Dev.

395

314

View full text Add to dashboard Cite

show abstract

“…132 The antitumor activity of ISIS 5132, a 20-nucleotide phosphorothioate 2 0 deoxynucleotide targeting the 3 0 untranslated region of C-RAF mRNA, was very promising at the early preclinical stage. 133,134 However, no major clinical benefits were observed in several Phase I [135][136][137] or Phase II clinical trials. [138][139][140][141] In addition, the use of ISIS 13650, a second generation antisense oligonucleotide with further modifications in the sugar moiety targeting the same C-RAF sequence as ISIS 5132, has not been superior in certain preclinical settings.…”

Section: Raf Kinases and Cancer Drug Discoverymentioning

confidence: 99%

Raf kinases: Oncogenesis and drug discovery

Schreck

Rapp

2006

Intl Journal of Cancer

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Raf kinase signaling has been thoroughly investigated over the last 20 years. A-Raf, B-Raf and C-Raf, the 3 mammalian members of the Raf family, are involved in a variety of cellular processes such as growth, proliferation, survival, differentiation and transformation. The detection of B-RAF mutations in a wide variety of human cancers, the description of wildtype and mutant B-RAF as tumor antigens in melanoma and the promising outcome of clinical trials evaluating the Raf inhibitor Nexavar 1 (Sorafenib, BAY 43-9006) have sparked a broad interest in the scientific community. After a short historical detour and an introduction into Raf kinase signaling, we are going to discuss here recent outcomes of Raf kinase research with respect to tumor formation and give an overview on current efforts to develop anticancer therapies interfering with aberrant Raf kinase signaling. ' 2006 Wiley-Liss, Inc.Key words: cancer; clinical trials; transformation; drug delivery; signal transduction; mitogenic cascade; Raf kinases Raf kinases: The historyIn 1983, the cloning of the acutely transforming replication-defective mouse type C virus 3611-MSV and characterization of its acquired oncogene was reported. 1 Since 3611-MSV induces rapidly growing f ibrosarcoma in mice, the transduced oncogene was called v-raf, whereas its cellular homologue was named c-raf. 1 Shortly thereafter, Bister and coworkers described the cloning of the avian acute leukemia retrovirus Mil Hill No. 2 (MH2). 2 MH2 was found to carry a second potential oncogene in addition to vmyc, which was termed v-mil, whereas its cellular counterpart was called c-mil. 3 Already a hybridization analysis and the gross comparison of restriction maps of v-raf and v-mil pointed at sequence homologies between these 2 genes. 4 By direct sequencing of both genes it was finally proven that 3611-MSV and MH2 have integrated orthologues of the same gene into their genomes. 5 In the following we are going to use the nomenclature for Raf kinases as proposed in a recent review from Wellbrock et al. 6 In contrast to all other oncogene kinases known at that time, no tyrosine kinase activity was detected in C-Raf. 7 Indeed, it was found that C-Raf is a serine/threonine kinase. 8,9 This and the observation that Raf coexists with the Myc oncogene in retroviruses 10 led to two novel concepts: (i) There is a tyrosine to serine phosphorylation switch as the growth factor signal enters the cell, and (ii) the mechanistic basis for cooperation between nuclear and cytoplasmic oncogenes as well as for signal transduction from cell surface receptors to the nucleus is the phosphorylation of transcription factor class oncogenes such as Myc. 11-13 Growth factor abrogation and oncogene cooperation studies were performed to corroborate this signaling scheme. 14-17 Additional important early findings were (i) the cooperation between Raf and Myc in growth factor independent proliferation, immortalization and tumor induction, 14,18,19 leading to the Raf-Myc balance model, 20 and (ii) the cell lineage-switch ...

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“…49 Phase I studies in various advanced cancer patients with Raf antisense molecules demonstrated a few patients with prolonged stable disease and one patient with a significant response. [50][51][52] Unfortunately, two phase II studies in lung cancer (total of 26 patients) failed to demonstrate any significant anti-tumor activity. 53 A third set of studies targeted Bcl-2, an apoptotic inhibitor that is overexpressed by many tumors including 80-90% of SCLCs and is associated with increased resistance to chemotherapy.…”

Section: Anti-sense Therapymentioning

confidence: 99%

Gene therapy for lung neoplasms

Albelda

Wiewrodt

Sterman

2002

Clinics in Chest Medicine

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SYNOPSISBoth advanced stage lung cancer and malignant pleural mesothelioma are associated with a poor prognosis. Although there have been advances in treatment regimens for both diseases, these have had only a modest effect on their progressive course. Gene therapy for thoracic malignancies represents a novel therapeutic approach and has been evaluated in a number of clinical trials over the last two decades. Strategies have included induction of apoptosis, tumor suppressor gene replacement, suicide gene expression, cytokine based therapy, various vaccination approaches, and adoptive transfer of modified immune cells. This review will consider the clinical results, limitations, and future directions of gene therapy trials for thoracic malignancies.

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Phase I Clinical/Pharmacokinetic and Pharmacodynamic Trial of the c-raf-1 Antisense Oligonucleotide ISIS 5132 (CGP 69846A)

Abstract: ISIS 5132 is well tolerated at doses up to 6.0 mg/kg when administered as a thrice weekly 2-hour infusion for 3 consecutive weeks. The pharmacokinetic behavior of the drug is reproducible, and suppression of target gene expression is observed in circulating PBMCs.

Cited by 120 publications

References 24 publications

Distinct requirements for Ras oncogenesis in human versus mouse cells

Distinct requirements for Ras oncogenesis in human versus mouse cells

Raf kinases: Oncogenesis and drug discovery

Gene therapy for lung neoplasms

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