Phase I study of intermittent dosing of OSI-906, a dual tyrosine kinase inhibitor of insulin-like growth factor-1 receptor (IGF- 1R) and insulin receptor (IR) in patients with advanced solid tumors.

Carden, Craig P.; Kim, E. S.; Jones, R. L.; Alam, Salma; Johnson, Fred M.; Stephens, Andrew; Poondru, Srinivasu; Gedrich, Richard; Lippman, S. M.; Kaye, SB

doi:10.1200/jco.2010.28.15_suppl.2530

Cited by 31 publications

(31 citation statements)

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“…Although hyperglycemia is evident in mice treated with OSI-906, at maximum tolerated dose, OSI-906 is able to chronically suppress both IGF-1R and IR phosphorylation in tumor tissue, translating to effects on AKT signaling and TGI (44,45). In the clinic, hyperinsulinemia has been observed in select patients treated with either IGF-1R-specific antibodies or small-molecule IGF-1R/IR TKIs including OSI-906 (56)(57)(58). However, in phase I clinical studies, hyperglycemia was transient and reversible, and OSI-906 was well tolerated with an acceptable safety profile and plasma pharmacokinetic profile that correlates with inhibition of IGF-1R and IR targets in blood.…”

Section: Discussionmentioning

confidence: 99%

Compensatory Insulin Receptor (IR) Activation on Inhibition of Insulin-Like Growth Factor-1 Receptor (IGF-1R): Rationale for Cotargeting IGF-1R and IR in Cancer

Buck

Gokhale

Koujak

et al. 2010

Molecular Cancer Therapeutics

197

187

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Insulin-like growth factor-1 receptor (IGF-1R) is a receptor tyrosine kinase (RTK) and critical activator of the phosphatidylinositol 3-kinase-AKT pathway. IGF-1R is required for oncogenic transformation and tumorigenesis. These observations have spurred anticancer drug discovery and development efforts for both biological and small-molecule IGF-1R inhibitors. The ability for one RTK to compensate for another to maintain tumor cell viability is emerging as a common resistance mechanism to antitumor agents targeting individual RTKs. As IGF-1R is structurally and functionally related to the insulin receptor (IR), we asked whether IR is tumorigenic and whether IR-AKT signaling contributes to resistance to IGF-1R inhibition. Both IGF-1R and IR(A) are tumorigenic in a mouse mammary tumor model. In human tumor cells coexpressing IGF-1R and IR, bidirectional cross talk was observed following either knockdown of IR expression or treatment with a selective anti-IGF-1R antibody, MAB391. MAB391 treatment resulted in a compensatory increase in phospho-IR, which was associated with resistance to inhibition of IRS1 and AKT. In contrast, treatment with OSI-906, a small-molecule dual inhibitor of IGF-1R/IR, resulted in enhanced reduction in phospho-IRS1/phospho-AKT relative to MAB391. Insulin or IGF-2 activated the IR-AKT pathway and decreased sensitivity to MAB391 but not to OSI-906. In tumor cells with an autocrine IGF-2 loop, both OSI-906 and an anti-IGF-2 antibody reduced phospho-IR/phospho-AKT, whereas MAB391 was ineffective. Finally, OSI-906 showed superior efficacy compared with MAB391 in human tumor xenograft models in which both IGF-1R and IR were phosphorylated. Collectively, these data indicate that cotargeting IGF-1R and IR may provide superior antitumor efficacy compared with targeting IGF-1R alone. Mol Cancer Ther; 9(10); 2652-64. ©2010 AACR.

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Section: Discussionmentioning

confidence: 99%

Compensatory Insulin Receptor (IR) Activation on Inhibition of Insulin-Like Growth Factor-1 Receptor (IGF-1R): Rationale for Cotargeting IGF-1R and IR in Cancer

Buck

Gokhale

Koujak

et al. 2010

Molecular Cancer Therapeutics

197

187

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“…En 5 de 16 pacientes, se logró estabilización de la progresión del carcinoma, durante más de 12 semanas, incluyendo un paciente con una reducción de más del 80% de la masa tumoral. Un ensayo fase III de este medicamento, como terapia de segunda o tercera línea se está corriendo en varios países (53).…”

Section: Enfermedad Avanzadaunclassified

Carcinoma corticoadrenal. Revisión de tema

Polanía¹,

Linares²,

Linares³

et al. 2011

Rev. Med.

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IntroducciónLos adenomas son los tumores corticoadrenales más comunes, con una prevalencia del 4%, siendo los carcinomas corticoadrenales raros, con una incidencia de 1 caso por millón de habitantes. La mitad de estos carcinomas son funcionales con diagnósticos más tempranos por los síndromes de exceso de hormonas que producen, a diferencia del restante 50% que es silente, con hallazgo de metástasis al momento del diagnostico en más de la mitad de ellos. Pueden tener una presentación esporádica o hacer parte de síndromes de cáncer familiar con anormalidades en genes que resultan en un imbalance entre oncogenes y genes supresores de tumor; además de constituirse como potenciales marcadores diagnósticos, pronósticos y terapéuticos de esta enfermedad. Ante la sospecha de carcinoma de corteza suprarrenal, deben tenerse en cuenta criterios clínicos, bioquímicos y radiológicos para establecer adecuadamente el diagnóstico, el cual debe confirmarse por histología.

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“…Whether IGF-IR blockade clinically also results in raised IGF-II levels requires further investigation. It is noteworthy that preliminary clinical data in adrenocortical patients suggests that figitumumab monotherapy shows no significant activity in this disease, whereas the IGF-IR and IR small-molecule TKI OSI-906 has resulted in tumor responses (15,16), supporting further investigation of this combined IGF-IR and IR blockade strategy. It is hypothesized that this finding in adrenocortical cancer may be a result of increased expression of IGF-II due to loss of imprinting; such a combination targeting strategy may also be critically important in other tumors with aberrant expression of IGF-II, including Wilms' tumors, hepatocellular cancers, and rhabdomyosarcomas (17).…”

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confidence: 99%