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Evaluation of ALK-1 expression in circulating endothelial cells (CECs) as an exploratory biomarker for PF-03446962 undergoing phase I trial in cancer patients
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2009
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Endothelial CellsHuman MabImmunologyPathologyCancer PatientsCancer BiologyTumor BiologyAngiogenesisTumor ImmunityCancer Cell BiologyAnti-cancer AgentMolecular OncologyCancer ResearchMedicineBiomarker TargetVascular BiologyCec ViabilityCancer TreatmentCell BiologyTumor MicroenvironmentPrognostic BiomarkersTβri FamilyEndothelial DysfunctionAlk-1 ExpressionOncologyCancer Growth
3573 Background: ALK-1 is a member of the TβRI family & a novel target for antiangiogenic therapy (Rx). PF- 03446962 (PF) is a fully human mAB (IgG2, κ) generated against ALK-1 with dose-dependent preclinical antiangiogenic activities (Hu-Lowe et al, Proc AACR, 2009). This study's objectives were to determine whether: 1) CECs in cancer patients express ALK-1; and 2) whether therapy with PF against ALK-1 will modulate ALK-1 expression or CEC function in an ongoing Ph I trial. Methods: The human mAb was conjugated with alexa fluor 647. ALK-1 expression was assayed by a standardized multicolor flow cytometry assay (Mancuso et al, CCR 2009). Results: ALK-1 expression was characterized on human vascular (HUVEC) & lymphatic (HDLC) endothelial cells; HUVEC & HDLC cells highly express ALK-1 (>99% of these cells are ALK- 1 + ). ALK-1 expression was assessed in healthy controls (n=17) & cancer patients after normalizing for CEC viability. Patients with advanced malignancies had increased numbers of ALK-1 + CECs: Patients with breast ca (n=12), melanoma (n=8), NSCLC (n=11), & CRC (n=4) had 16±12, 39±23, 50±30, & 62±25 ALK-1 + CECs/mL, respectively, vs 7±6 ALK-1 + CECs/mL in controls. In contrast, ALK-1 expression was minimally or not expressed in pts with hematologic malignancies; ALK-1 was absent in CD117 + or CD34 + bone marrow cells. In the Ph I trial, preliminary evidence suggests that PF may alter CEC function; ALK-1 + CECs were markedly reduced in the 1 st two pts studied at EIO after 22 days on Rx. Conclusions: ALK-1 is expressed in CECs. Flow cytometry enables rapid assay of ALK-1 expression in cancer patient blood. ALK-1 is expressed in an increased number of CECs/mL in cancer pts with solid malignancies vs controls. ALK-1 expression in CECs in pts with NSCLC & CRC may correspond to high ALK-1 expression observed in corresponding nonmatched tumor microarrays in addition to other malignancies such as sarcoma, SCLC & neuroendrocine pancreatic ca (Fiedler, Proc ASCO, 2009). Additional preliminary Ph I results will be reported as part of assessing whether CECs may have any role as biomarkers to potentially detect patients with ALK-1 + solid malignancies or monitor anti-ALK-1 therapy. [Table: see text]