Targeting the TGFβ pathway for cancer therapy

Introduction: The transforming growth factor-β (TGF-β) signaling pathway has a pivotal role in tumor suppression and yet, paradoxically, in tumor promotion. Functional context dependent insights into the TGF-β pathway are crucial in developing TGF-β-based therapeutics for cancer. Areas covered: This review discusses the molecular mechanism of the TGF-β pathway and describes the different ways of tumor suppression by TGF-β. It is then explained how tumors can evade these effects and how TGF-β contributes to further growing and spreading of some of the tumors. In the last part of the review, the data on targeting TGF-β pathway for cancer treatment is assessed. This review focuses on anti-TGF-β based treatment and other options targeting activated pathways in tumors where the TGF-β tumor suppressor pathway is lost. Pre-clinical as well up to date results of the most recent clinical trials are given. Expert opinion: Targeting the TGF-β pathway can be a promising direction in cancer treatment. However, several...

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Targeting TGF-β signaling in cancer

ALK1 as an emerging target for antiangiogenic therapy of cancer

Transforming growth factor-β (TGF-β) mediates numerous biological processes, including embryonic development and the maintenance of cellular homeostasis in a context-dependent manner. Consistent with its central role in maintaining cellular homeostasis, inhibition of TGF-β signaling results in disruption of normal homeostatic processes and subsequent carcinogenesis, defining the TGF-β signaling pathway as a tumor suppressor. However, once carcinogenesis is initiated, the TGF-β signaling pathway promotes cancer progression. This dichotomous function of the TGF-β signaling pathway is mediated through altering effects on both the cancer cells, by inducing apoptosis and inhibiting proliferation, and the tumor microenvironment, by promoting angiogenesis and inhibiting immunosurveillance. Current studies support inhibition of TGF-β signaling either alone, or in conjunction with anti-angiogenic therapy or immunotherapy as a promising strategy for the treatment of human cancers.

/pdf/dichotomous-roles-of-tgf-b-in-human-cancer-2d05hj7bb0.pdf

Dichotomous roles of TGF-β in human cancer

Endoglin is a homodimeric cell membrane glycoprotein receptor for transforming growth factor β and bone morphogenetic proteins. Endoglin is essential for angiogenesis, being densely expressed on proliferating endothelial cells and upregulated during hypoxia. Its expression is implicated in development of resistance to vascular endothelial growth factor (VEGF) inhibition. TRC105 is an antibody that binds endoglin and prevents endothelial cell activation. Targeting endoglin and the VEGF pathway concurrently improves treatment in vitro and appears to reverse resistance to bevacizumab in some refractory cancer patients. Randomized trials are under way to assess the clinical benefit of adding TRC105 therapy to bevacizumab therapy. Further trials are under way to assess the activity of TRC105 with small-molecule inhibitors of the VEGF pathway in renal cell carcinoma, hepatocellular carcinoma, and soft tissue sarcoma. Stratification of soft tissue sarcomas based on endoglin expression levels is proposed to identify patients most likely to benefit from TRC105 treatment. The development of a TRC105 antibody–drug conjugate is also described.

Endoglin for Targeted Cancer Treatment

3034 Background: Transforming growth factor β (TGF β) is a cytokine able to regulate many biological processes, including tissue development and remodeling, cellular proliferation and survival. At the vascular level, the activity of TGFβ is exerted by selectively binding to its receptor, activin receptor like kinase 1 (ALK-1), through TGFβRII, which triggers a downstream signaling involving intracellular and nuclear proteins (SMADs and Id1) and leading to transcriptional upregulation of pro-angiogenic factors. PF-03446962 is a fully human mAb against ALK-1 with dose dependent antiangiogenic activity as demonstrated in nonclinical studies in a chimera mouse model bearing human tumors xenograft. Methods: A phase 1 trial in patients with solid tumors is ongoing. Primary objective is to identify the MTD; secondary end points include safety profile, PK, antitumor activity, circulating endothelial cells (CEC), soluble proteins related to TGFβ and blood flow evaluation by contrast enhanced ultrasound (CE-US). Re...

Phase I study of PF-03446962, a fully human mAb against ALK 1, a TGF{beta} receptor involved in tumor angiogenesis.

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Phase I study of PF-03446962, a fully human mAb against ALK 1, a TGF{beta} receptor involved in tumor angiogenesis.