CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma

Trudel, Suzanne; Li, Zhi Hua; Wei, Ellen; Wiesmann, Marion; Chang, Hong; Chen, Christine; Reece, Donna; Heise, Carla; Stewart, A. Keith

doi:10.1182/blood-2004-10-3913

Cited by 262 publications

(206 citation statements)

References 42 publications

(76 reference statements)

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“…Inhibition of wild-type and constitutively activated FGFR-3 autophosphorylation in human MM cell lines by the FGFR-specific tyrosine kinase inhibitors SU5402, SU10991, PD173074 or CHIR258 is associated with decreased viability and tumor cell growth arrest, both in vitro and in vivo in a murine model (Grand et al, 2004;Trudel et al, 2004Trudel et al, , 2005.…”

Section: Matrix Metalloproteinasesmentioning

confidence: 99%

Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma

2006

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Tumor microenvironment is essential for tumor cell proliferation, angiogenesis, invasion and metastasis through its provision of survival signals, secretion of growth and pro-angiogenic factors, and direct adhesion molecule interactions. This review examines its importance in the induction of an angiogenic response in multiple myeloma (MM). The encouraging results of preclinical and clinical trials in which MM has been treated by targeting the tumor microenvironment are also discussed.

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Section: Matrix Metalloproteinasesmentioning

confidence: 99%

Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma

2006

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“…For some patients, the presence of specific genetic markers may lend themselves to clinical trials of targeted therapies, for example FGFR3 kinase inhibitors. 85,86 …”

Section: The Arrival Of Targeted Therapiesmentioning

confidence: 99%

A practical guide to defining high-risk myeloma for clinical trials, patient counseling and choice of therapy

et al. 2007

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Clinical outcomes for multiple myeloma (MM) are highly heterogeneous and it is now clear that pivotal genetic events are the primary harbingers of such variation. These findings have broad implications for counseling, choice of therapy and the design and interpretation of clinical investigation. Indeed, as in acute leukemias and non-hodgkins lymphoma, we believe it is no longer acceptable to consider MM a single disease entity. As such, the accurate diagnosis of MM subtypes and the adoption of common criteria for the identification and stratification of MM patients has become critical. Herein, we provide a consensus high-risk definition and offer practical guidelines for the adoption of routine diagnostic testing. Although acknowledging that more refined classifications will continue to be developed, we propose that the definition of high-risk disease (any of the t(4;14), t(14;16), t(14;20), deletion 17q13, aneuploidy or deletion chromosome 13 by metaphase cytogenetics, or plasma cell labeling index 43.0) be adopted. This classification will identify most of the 25% of MM patients for whom current therapies are inadequate and for whom investigational regimens should be vigorously pursued. Conversely, the 75% of patients remaining have more favorable outcomes using existing -albeit non-curative -therapeutic options.

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“…For comparison, the in vitro kinase and cellular activities of 4 other multitargeted TKIs that have been reported to have anti-FGFR activity (and whose structures were published at the time of these studies), dovitinib, cediranib, BIBF 1120, and brivanib (29)(30)(31)(32)(33)(34)(35), were also examined. By both measures, ponatinib was found to be the most potent inhibitor of each of the 4 FGFRs ( Fig.…”

Section: Activitymentioning

confidence: 99%

“…Brivanib (BMS-540215) targets FGFR1 (32) and selectively inhibits growth of breast cancer cell lines with FGFR1 gene amplification (33). Finally, dovitinib (TKI258) inhibits the kinase activity of FGFR1, FGFR2, and FGFR3 and the cellular activity of FGFR3 in models of multiple myeloma (34,35). Ponatinib (AP24534) is an oral multitargeted kinase inhibitor that potently inhibits native and mutant forms of BCR-ABL (36)(37)(38) and is currently being investigated in a phase II pivotal trial in patients with chronic myelogenous leukemia (CML; Clinicaltrials.gov: NCT01207440).…”

Section: Introductionmentioning

confidence: 99%

Ponatinib (AP24534), a Multitargeted Pan-FGFR Inhibitor with Activity in Multiple FGFR-Amplified or Mutated Cancer Models

Gozgit¹,

Wong²,

Moran³

et al. 2012

Molecular Cancer Therapeutics

289

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Members of the fibroblast growth factor receptor family of kinases (FGFR1-4) are dysregulated in multiple cancers. Ponatinib (AP24534) is an oral multitargeted tyrosine kinase inhibitor being explored in a pivotal phase II trial in patients with chronic myelogenous leukemia due to its potent activity against BCR-ABL. Ponatinib has also been shown to inhibit the in vitro kinase activity of all four FGFRs, prompting us to examine its potential as an FGFR inhibitor. In Ba/F3 cells engineered to express activated FGFR1-4, ponatinib potently inhibited FGFR-mediated signaling and viability with IC 50 values <40 nmol/L, with substantial selectivity over parental Ba/F3 cells. In a panel of 14 cell lines representing multiple tumor types (endometrial, bladder, gastric, breast, lung, and colon) and containing FGFRs dysregulated by a variety of mechanisms, ponatinib inhibited FGFR-mediated signaling with IC 50 values <40 nmol/L and inhibited cell growth with GI 50 (concentration needed to reduce the growth of treated cells to half that of untreated cells) values of 7 to 181 nmol/L. Daily oral dosing of ponatinib (10-30 mg/kg) to mice reduced tumor growth and inhibited signaling in all three tumor models examined. Importantly, the potency of ponatinib in these models is similar to that previously observed in BCR-ABL-driven models and plasma levels of ponatinib that exceed the IC 50 values for FGFR1-4 inhibition can be sustained in patients. These results show that ponatinib is a potent pan-FGFR inhibitor and provide strong rationale for its evaluation in patients with FGFR-driven cancers.

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CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma

Cited by 262 publications

References 42 publications

Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma

Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma

A practical guide to defining high-risk myeloma for clinical trials, patient counseling and choice of therapy

Ponatinib (AP24534), a Multitargeted Pan-FGFR Inhibitor with Activity in Multiple FGFR-Amplified or Mutated Cancer Models

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