Clinical relevance of VEGF receptors 1 and 2 in patients with chronic myelogenous leukemia

Verstovšek, Srđan; Lunin, Scott D.; Kantarjian, Hagop M.; Manshouri, Taghi; Faderl, Stefan; Cortes, Jorge; Giles, Francis J.; Albitar, Mäher

doi:10.1016/s0145-2126(02)00275-8

Cited by 36 publications

(11 citation statements)

References 49 publications

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“…VEGFR-2 appears to be required for the proliferation and migration of leukemic cells (13,57). Significantly, although both VEGFR-1 and VEGFR-2 are expressed at high levels in bone marrow from patients with CML, it is VEGFR-2 expression that correlates with decreased patient survival (73). Our results suggest that PRH levels play a central role in influencing the survival and growth of K562 leukemic cells.…”

Section: Discussionmentioning

confidence: 65%

PRH/Hhex Controls Cell Survival through Coordinate Transcriptional Regulation of Vascular Endothelial Growth Factor Signaling

Noy

Williams

Sawasdichai

et al. 2010

Molecular and Cellular Biology

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The proline-rich homeodomain protein (PRH) plays multiple roles in the control of gene expression during embryonic development and in the adult. Vascular endothelial growth factor (VEGF) is a mitogen that stimulates cell proliferation and survival via cell surface receptors including VEGFR-1 and VEGFR-2. VEGF signaling is of critical importance in angiogenesis and hematopoiesis and is elevated in many tumors. Here we show that PRH binds directly to the promoter regions of the Vegf, Vegfr-1, and Vegfr-2 genes and that in each case PRH represses transcription. We demonstrate that overexpression or knockdown of PRH directly impinges on the survival of both leukemic and tumor cells and that the modulation of VEGF and VEGF receptor signaling by PRH mediates these effects. Our findings demonstrate that PRH is a key regulator of the VEGF signaling pathway and describe a mechanism whereby PRH plays an important role in tumorigenesis and leukemogenesis.

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Section: Discussionmentioning

confidence: 65%

PRH/Hhex Controls Cell Survival through Coordinate Transcriptional Regulation of Vascular Endothelial Growth Factor Signaling

Noy

Williams

Sawasdichai

et al. 2010

Molecular and Cellular Biology

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“…sVEGFR-2 was previously found to be elevated in patients with certain types of cancer (26,28,29). We investigated whether sVEGFR-2 may serve as a marker of activity of SU11248.…”

Section: Discussionmentioning

confidence: 99%

Blood-Based Biomarkers of SU11248 Activity and Clinical Outcome in Patients with Metastatic Imatinib-Resistant Gastrointestinal Stromal Tumor

Norden-Zfoni

Desai

Manola

et al. 2007

Clinical Cancer Research

193

126

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Purpose: There is an unmet need for noninvasive markers to measure the biological effects of targeted agents, particularly those inhibiting the vascular endothelial growth factor (VEGF) receptor (VEGFR) pathway, and identify patients most likely to benefit from treatment. In this study, we investigated potential blood-based biomarkers for SU11248 (sunitinib malate), a multitargeted tyrosine kinase inhibitor, in patients with metastatic imatinib-refractory gastrointestinal stromal tumors. Experimental Design: Patients (n = 73) enrolled in a phase I/II trial received SU11248 daily for 14 or 28 days followed by 14 days without treatment per cycle. Clinical benefit was defined as progression-free survival of >6 months. We assessed plasma markers, including VEGF and soluble VEGFR-2 (sVEGFR-2), and two cellular populations bearing VEGF receptors: monocytes and, in a subset of patients, mature circulating endothelial cells (CEC). Results: Compared to patients with progressive disease, patients with clinical benefit had significantly greater increases in CECs (0.52 versus −−0.01 CEC/μL/d, P = 0.03) and smaller decreases in monocyte levels (47% versus 60%, P = 0.007) during cycle 1. VEGF increased by 2.2-fold and sVEGFR-2 decreased 25% during the first 2 weeks of treatment. Neither plasma marker correlated with clinical outcome although a modest inverse correlation was observed between sVEGFR-2 changes and plasma drug levels. Monocytes, VEGF, and sVEGFR-2 all rebounded towards baseline off treatment. Conclusions: Monocytes, VEGF, and sVEGFR-2 were consistently modulated by treatment, suggesting that they may serve as pharmacodynamic markers for SU11248. Changes in CECs and monocytes, but not the plasma markers, differed between the patients with clinical benefit and those with progressive disease. These end points merit further investigation in future trials to determine their utility as markers of SU11248 activity and clinical benefit in gastrointestinal stromal tumors and other tumor types.

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“…Expression of pKDR was also observed in the cytoplasm and nuclei of endometrial cancer cells in The existence of such an autocrine mechanism has been also suggested previously in a number of studies. [26][27][28][29] Whether such an autocrine loop functions as a stimulus for cancer cell proliferation, resistance to apoptotic stimuli or through some other process remains obscure. [30][31][32][33] Nevertheless, expression of pKDR was associated significantly with poor prognosis of stage I patients.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylated KDR expression in endometrial cancer cells relates to HIF1α/VEGF pathway and unfavourable prognosis

et al. 2006

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Clinical relevance of VEGF receptors 1 and 2 in patients with chronic myelogenous leukemia

Cited by 36 publications

References 49 publications

PRH/Hhex Controls Cell Survival through Coordinate Transcriptional Regulation of Vascular Endothelial Growth Factor Signaling

PRH/Hhex Controls Cell Survival through Coordinate Transcriptional Regulation of Vascular Endothelial Growth Factor Signaling

Blood-Based Biomarkers of SU11248 Activity and Clinical Outcome in Patients with Metastatic Imatinib-Resistant Gastrointestinal Stromal Tumor

Phosphorylated KDR expression in endometrial cancer cells relates to HIF1α/VEGF pathway and unfavourable prognosis

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