Targeting the Transforming Growth Factor-beta Signaling Pathway in the Treatment of Gynecologic Cancer.

The transforming growth factor-beta (TGF-ß) signaling pathway has been reported to be dysregulated in the pathogenesis of several malignancies, including gynecologic cancers. This provides proof of concept of its potential value as a therapeutic target and prognostic biomarker in cervical cancer. Here we provide an overview of the biological role and clinical impact of TGF-ß inhibitors either as a single agent or as a combinatorial therapy in gynecological cancers, concentrating on phase I to phase II/III clinical trials. Aberrant TGF-ß signaling may lead to carcinogenesis. Inhibition of TGF-ß represents an interesting area of focus for the treatment of gynecological cancer. Several TGF-ß inhibitors are potential anticancer agents and are undergoing clinical trials in cancer, including galunisertib, dalantercept, and vigil. There is a growing body of data showing the potential therapeutic impact of targeting the TGF-ß pathway in different cancer types, although further studies are still warranted to explore the value of this strategy and finding the most appropriate patients who could most benefit from therapy.

Roles of TGF-ß signaling pathway in tumor microenvirionment and cancer therapy.

Transforming growth factor ß (TGF- ß) signaling pathway has pleiotropic effects on cell proliferation, differentiation, adhesion, senescence, and apoptosis. TGF-ß can be widely produced by various immune or non-immune cells and regulate cell behaviors through autocrine and paracrine. It plays essential roles in biological processes including embryological development, immune response, and tumor progression. Few cell signalings can contribute to so many pleiotropic functions as the TGF- ß signaling pathway in mammals. The significant function of TGF-ß signaling in tumor progression and evasion leading it to draw great attention in scientific and clinical research. Understanding the mechanism of TGF- ß signaling provides us with chances to potentiate the effectiveness and selectivity of this therapeutic method. Herein, we review the molecular and cellular mechanisms of TGF-ß signaling in carcinomas and tumor microenvironment. Then, we enumerate main achievements of TGF-ß blockades used or being evaluated in cancer therapy, providing us opportunities to improve therapeutical approaches in the tumor which thrive in a TGF-ß-rich environment.

Hitting More Birds with a Stone: Impact of TGF-ß on ILC Activity in Cancer.

Transforming growth factor (TGF)-ß is a central immunosuppressive cytokine within tumor microenvironment inhibiting the expansion and function of major cellular components of adaptive and innate immune system. Among them, compelling evidence has demonstrated that TGF-ß is a key regulator of natural killer (NK) cells, innate lymphoid cells (ILCs) with a critical role in immunosurveillance against different kinds of cancer cells. A TGF-ß rich tumor microenvironment blocks NK cell activity at multiple levels. This immunosuppressive factor exerts direct regulatory effects on NK cells including inhibition of cytokine production, alteration of activating/inhibitory receptor expression, and promotion of the conversion into non cytotoxic group I ILC (ILC1). Concomitantly, TGF-ß can render tumor cells less susceptible to NK cell-mediated recognition and lysis. Indeed, accumulating evidence suggest that changes in levels of NKG2D ligands, mainly MICA, as well as an increase of immune checkpoint inhibitors (e.g., PD-L1) and other inhibitory ligands on cancer cells significantly contribute to TGF-ß-mediated suppression of NK cell activity. Here, we will take into consideration two major mechanisms underlying the negative regulation of ILC function by TGF-ß in cancer. First, we will address how TGF-ß impacts the balance of signals governing NK cell activity. Second, we will review recent advances on the role of this cytokine in driving ILC plasticity in cancer. Finally, we will discuss how the development of therapeutic approaches blocking TGF-ß may reverse the suppression of host immune surveillance and improve anti-tumor NK cell response in the clinic.

Therapeutic Potential of Targeting Transforming Growth Factor-beta in Colorectal Cancer: Rational and Progress.

BACKGROUND: Colorectal cancer (CRC) is one of the most common types of cancer and is associated with an increasing rate of mortality. Transforming Growth Factor-Beta (TGF-ß) is often upregulated in CRC, and appears to play an important role in regulating cell proliferation, migration, immune surveillance, apoptosis, cell differentiation, drug-resistance and many cellular processes that may be involved in CRC, and therefore underscores its potential value as a therapeutic target in the treatment of CRC. An increased expression of the TGF- ß pathway has been associated with poor prognosis in several cancer types, including CRC. METHODS: Here, we describe the critical role of the TGF-ß pathway in CRC as well as the preclinical and clinical investigations on TGF-ß inhibitors, with particular emphasis on recent findings with small-molecule inhibitors in CRC. Several TGF-ß inhibitors (e.g., Trabedersen, Galunisertib, Gradalis, PF-03446962, NIS793) have been generated over the past decade for targeting this pathway. RESULTS: There is accumulating evidence of the therapeutic potential of this and other TGF-ß inhibitors for the treatment of other malignancies. These inhibitors might be used in combination with chemotherapy as well as with other biological agents, in order to overcome different resistance mechanisms. However, further studies are needed to identify determinants of the activity of TGF-ß inhibitors, through the analysis of genetic and environmental alterations affecting TGF-ß and parallel pro-cancer pathways. CONCLUSION: These studies will be critical to improving the efficacy and selectivity of current and future anticancer strategies targeting TGF-ß.

Safer approaches to therapeutic modulation of TGF-ß signaling for respiratory disease.

The transforming growth factor (TGF)-ß cytokines play a central role in development and progression of chronic respiratory diseases. TGF-ß overexpression in chronic inflammation, remodeling, fibrotic process and susceptibility to viral infection is established in the most prevalent chronic respiratory diseases including asthma, COPD, lung cancer and idiopathic pulmonary fibrosis. Despite the overwhelming burden of respiratory diseases in the world, new pharmacological therapies have been limited in impact. Although TGF-ß inhibition as a therapeutic strategy carries great expectations, the constraints in avoiding compromising the beneficial pleiotropic effects of TGF-ß, including the anti-proliferative and immune suppressive effects, have limited the development of effective pharmacological modulators. In this review, we focus on the pathways subserving deleterious and beneficial TGF-ß effects to identify strategies for selective modulation of more distal signaling pathways that may result in agents with improved safety/efficacy profiles. Adverse effects of TGF-ß inhibitors in respiratory clinical trials are comprehensively reviewed, including those of the marketed TGF-ß modulators, pirfenidone and nintedanib. Precise modulation of TGF-ß signaling may result in new safer therapies for chronic respiratory diseases.

A targeted transforming growth factor-beta (TGF-ß) blocker, TTB, inhibits tumor growth and metastasis.

Transforming growth factor beta (TGF-ß) promotes cancer growth in late stage cancers. To inhibit the TGF-ß pathway, we investigated a tumor-targeting TGF-ß receptor blocker, TTB, and its role in tumor progress. The targeted TTB comprised of the extracellular domain of the TGF-ß receptor II, the endoglin domain of TGF-ß receptor III, and the human immuno-globin IgG1 constant fragment (Fc). To enhance tumor microenvironment targeting, a RGD peptide was fused at the N-terminal of TTB. The targeted TTB exhibited potent TGF-ß neutralization activities, and inhibited cancer cell migration and invasion as well as colony formation. In xenograft models, the TTB had potent tumor inhibition activities. The TTB also attenuated the TGF-ß1-induced Smad2 phosphorylation and epithelial to mesenchymal transformation (EMT), and suppressed breast cancer metastasis. Thus, the TTB is an effective TGF-ß blocker with a potential for blocking excessive TGF-ß induced pathogenesis in vivo.

Design, 3D QSAR modeling and docking of TGF-ß type I inhibitors to target cancer.

Transforming growth factor-ß (TGF-ß) family members plays a vital role in regulating hormonal function, bone formation, tissue remodeling, and erythropoiesis, cell growth and apoptosis. TGF-ß super-family members mediate signal transduction via serine/threonine kinase receptors located on the cell membrane. Variation in expression of the TGF-ß type I and II receptors in the cancer cells compromise its tumor suppressor activities which direct to oncogenic functions. The present study was aimed to screen the potent TGF-ß type I inhibitors through atom based 3D-QSAR and pharmacophore modelling. For this purpose, we have chosen known TGF-ß type I inhibitors from the binding database. The PHASE module of Schrodinger identified the best Pharmacophore model which includes three hydrogen bond acceptors (A), one hydrophobic region (H), and one ring (R) as the structural features. The top pharmacophore model AAAHR.27 was chosen with the R2 value of 0.94 and validated externally using molecules of the test set. Moreover the AAAHR.27 model underwent virtual screening using the molecules from the NCI, ZINC and Maybridge database. The screened molecules were further filtered using molecular docking and ADME properties prediction. Additionally, the 7 lead molecules were compared with a newly identified compound "SB431542" (well known TGF-ß type I receptor inhibitor) and Galunisertib, a small molecule inhibitor of TGF-ß type I, under clinical development (phase II trials) using the docking score and other binding properties. Also a top scored screened molecule from our study has been compared and confirmed using molecular dynamic simulation studies. By this way, we have obtained 7 distinct drug-like TGF-ß type I inhibitors which can be beneficial in suppressing cancers reported with up-regulation of TGF-ß type I. This result highlights the guidelines for designing molecules with TGF-ß Type I inhibitory properties.