Inhibition of ALK1 signaling with dalantercept combined with VEGFR TKI leads to tumor stasis in renal cell carcinoma

Abstract

Treatment of metastatic renal cell carcinoma (mRCC) with agents that block signaling through vascular endothelial growth factor receptor 2 (VEGFR2) induces disease regression or stabilization in some patients; however, these responses tend to be short-lived. Therefore, development of combination therapies that can extend the efficacy of VEGFR antagonists in mRCC remains a priority.We studied murine xenograft models of RCC that become refractory to treatment with the VEGFR tyrosine kinase inhibitor (TKI) sunitinib. Dalantercept is a novel antagonist of Activin receptor-like kinase 1 (ALK1)/Bone morphogenetic protein (BMP) 9 signaling. Dalantercept inhibited growth in the murine A498 xenograft model which correlated with hyperdilation of the tumor vasculature and an increase in tumor hypoxia. When combined with sunitinib, dalantercept induced tumor necrosis and prevented tumor regrowth and revascularization typically seen with sunitinib monotherapy in two RCC models. Combination therapy led to significant downregulation of angiogenic genes as well as downregulation of endothelial specific gene expression particularly of the Notch signaling pathway.We demonstrate that simultaneous targeting of molecules that control distinct phases of angiogenesis, such as ALK1 and VEGFR, is a valid strategy for treatment of mRCC. At the molecular level, combination therapy leads to downregulation of Notch signaling.

A Phase Ib, Open-Label Study of Dalantercept, an Activin Receptor-Like Kinase 1 Ligand Trap, plus Sorafenib in Advanced Hepatocellular Carcinoma

“…Preclinical and early clinical studies suggest that dalantercept in combination with VEGF pathway inhibitors may maximize growth inhibition in tumors that are sensitive to antiangiogenic agents . This phase Ib study was designed to determine the maximum tolerated dose of dalantercept in combination with sorafenib for phase II studies.…”

“…In addition, the BMP9/BMP10/ALK1 pathway regulates development of lymphatic vessels , which has implications for metastatic spread of tumor cells through lymphatic vasculature . Preclinical and early clinical studies suggest that dalantercept in combination with VEGF pathway inhibitors may maximize growth inhibition in tumors that are sensitive to antiangiogenic agents . Further, the safety profile of dalantercept is distinct from that of VEGF tyrosine kinase inhibitors (TKIs), which include fatigue, weight loss, rash/desquamation, hand‐foot skin reaction, alopecia, diarrhea, anorexia, nausea, and abdominal pain .…”

ALK1 signaling in development and disease: new paradigms

“…Phase I clinical trials demonstrated reasonable drug tolerance and some anti-tumor efficacy [238], but a monotherapy phase II trial for endometrial cancer was unsuccessful [239]. Combination therapies may hold more promise: dalantercept plus sunitinib, a receptor tyrosine kinase (RTK) inhibitor, was more effective in a mouse model of renal cell carcinoma than either drug alone [240], and dalantercept plus axitinib, another RTK inhibitor, showed promise in a renal cell carcinoma phase I clinical trial [241]. Interestingly, although most studies have reported decreased tumor angiogenesis in response to dalantercept, others have reported dilated tumor vessels and increased blood flow [240].…”

“…Combination therapies may hold more promise: dalantercept plus sunitinib, a receptor tyrosine kinase (RTK) inhibitor, was more effective in a mouse model of renal cell carcinoma than either drug alone [240], and dalantercept plus axitinib, another RTK inhibitor, showed promise in a renal cell carcinoma phase I clinical trial [241]. Interestingly, although most studies have reported decreased tumor angiogenesis in response to dalantercept, others have reported dilated tumor vessels and increased blood flow [240]. These observations are in line with effects of ALK1 loss in humans and animal models and suggest that ALK1 inhibition may actually prove most useful in increasing tumor blood flow and thus enhancing delivery of other chemotherapeutic drugs.…”

Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment

“…PR and SD were observed in portions of patients who still had lesions and cancer progression following VEGFR tyrosine kinase inhibitor (TKI) treatment. The combination of VEGFR TKI and ACE-041 results in a promising antiangiogenesis effect with marked tumor vascular disruption in xenograft models (118).…”