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Recent Advances in TGF-β Inhibitors for the Therapeutic Management of Cancer and Fibrosis

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: 20 February 2025 | Viewed by 30763

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Special Issue Editor

Dr. David Danielpour

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Guest Editor

Case Western Reserve University
Interests: Function and regulation of TGF-beta expression and signaling in prostate and renal cancers; androgen receptor signaling; cross-talk of TGF-beta with IGF-I, AKT, mTOR, androgen receptor, and Hic-5; survivin in cancer; Notch/Jagged1 signaling; drug discovery; YM155; mTOR inhibitors; TGF-beta signaling inhibitors; apoptosis; hypoxia and hypoxia-inducible pathways; AMPKs; chemoprevention; polyphenols

Special Issue Information

Dear Colleagues,

TGF-βs are highly conserved 25 kDa secretory proteins that signal through binding to and activating transmembrane serine-threonine kinase receptors. TGF-βs control many vital normal cellular and physiological processes such as apoptosis, growth control, differentiation, extracellular matrix production, epithelial-mesenchymal transition, angiogenesis, wound-healing, development and immune regulation. There are three TGF-β isoforms in mammals, namely TGF-β1, TGF-β2 and TGF-β3, each of which has a unique tissue expression profile, and their normal functions are both cell-type and context-dependent. Despite the well-documented tumor suppressor function of TGF-βs, TGF-β signaling has a dark side in cancer as it drives the growth, aggressiveness, and therapeutic resistance of many cancers. Another major dark side of TGF-β signaling is in driving fibrosis associated with many pathologies, and TGF-βs thus likely contribute to liver cirrhosis, chronic kidney disease, aortic stenosis, gastrointestinal strictures, cardiomyopathy, and pulmonary fibrosis. It is thus without surprise that major efforts have been taken to develop therapeutic inhibitors targeting TGF-βs and various components of TGF-β pathways. Although many TGF-β inhibitors have failed in clinical trials due to dose-limiting toxicities or inadequate responses, some of them are gaining enthusiastic support with potential to improving patient outcome, particularly in the setting of immune checkpoint inhibitors in cancer. This Special Issue is focused on summarizing the state-of-the-art findings, current research and future trends in the development and use of TGF-β pathway inhibitors for the therapeutic management of cancers and fibrosis.

Prof. Dr. David Danielpour
Guest Editor

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Keywords

TGF-β
metastasis
EMT
immunotherapy
fibrosis
Smad2
Smad3
angiogenesis
ligand traps
soluble receptors

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Published Papers (8 papers)

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Research

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22 pages, 7664 KiB

Open AccessArticle

Alvespimycin Exhibits Potential Anti-TGF-β Signaling in the Setting of a Proteasome Activator in Rats with Bleomycin-Induced Pulmonary Fibrosis: A Promising Novel Approach

by Osama A. Mohammed, Mustafa Ahmed Abdel-Reheim, Lobna A. Saleh, Mohannad Mohammad S. Alamri, Jaber Alfaifi, Masoud I. E. Adam, Alshaimaa A. Farrag, AbdulElah Al Jarallah AlQahtani, Waad Fuad BinAfif, Abdullah A. Hashish, Sameh Abdel-Ghany, Elsayed A. Elmorsy, Hend S. El-wakeel, Ahmed S. Doghish, Rabab S. Hamad and Sameh Saber

Pharmaceuticals 2023, 16(8), 1123; https://doi.org/10.3390/ph16081123 - 9 Aug 2023

Cited by 26 | Viewed by 2326

Abstract

Idiopathic pulmonary fibrosis (IPF) is an irreversible and life-threatening lung disease of unknown etiology presenting only a few treatment options. TGF-β signaling orchestrates a cascade of events driving pulmonary fibrosis (PF). Notably, recent research has affirmed the augmentation of TGF-β receptor (TβR) signaling via HSP90 activation. HSP90, a molecular chaperone, adeptly stabilizes and folds TβRs, thus intricately regulating TGF-β1 signaling. Our investigation illuminated the impact of alvespimycin, an HSP90 inhibitor, on TGF-β-mediated transcriptional responses by inducing destabilization of TβRs. This outcome stems from the explicit interaction of TβR subtypes I and II with HSP90, where they are clients of this cellular chaperone. It is worth noting that regulation of proteasome-dependent degradation of TβRs is a critical standpoint in the termination of TGF-β signal transduction. Oleuropein, the principal bioactive compound found in Olea europaea, is acknowledged for its role as a proteasome activator. In this study, our aim was to explore the efficacy of a combined therapy involving oleuropein and alvespimycin for the treatment of PF. We employed a PF rat model that was induced by intratracheal bleomycin infusion. The application of this dual therapy yielded a noteworthy impediment to the undesired activation of TGF-β/mothers against decapentaplegic homologs 2 and 3 (SMAD2/3) signaling. Consequently, this novel combination showcased improvements in both lung tissue structure and function while also effectively restraining key fibrosis markers such as PDGF-BB, TIMP-1, ACTA2, col1a1, and hydroxyproline. On a mechanistic level, our findings unveiled that the antifibrotic impact of this combination therapy likely stemmed from the enhanced degradation of both TβRI and TβRII. In conclusion, the utilization of proteasomal activators in conjunction with HSP90 inhibitors ushers in a promising frontier for the management of PF. Full article

(This article belongs to the Special Issue Recent Advances in TGF-β Inhibitors for the Therapeutic Management of Cancer and Fibrosis)

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25 pages, 3796 KiB

Open AccessArticle

STA9090 as a Potential Therapeutic Agent for Liver Fibrosis by Modulating the HSP90/TβRII/Proteasome Interplay: Novel Insights from In Vitro and In Vivo Investigations

by Osama A. Mohammed, Mustafa Ahmed Abdel-Reheim, Mohannad Mohammad S. Alamri, Jaber Alfaifi, Masoud I. E. Adam, Lobna A. Saleh, Alshaimaa A. Farrag, Amar Ibrahim Omer Yahia, Sameh Abdel-Ghany, AbdulElah Al Jarallah AlQahtani, Emad Bahashwan, Hanan B. Eltahir, Nahid A. Mohammed, Hend S. El-wakeel, Sara H. Hazem and Sameh Saber

Pharmaceuticals 2023, 16(8), 1080; https://doi.org/10.3390/ph16081080 - 28 Jul 2023

Cited by 9 | Viewed by 1845

Abstract

Liver fibrosis is a progressive condition characterized by the build-up of fibrous tissue resulting from long-term liver injury. Although there have been advancements in research and treatment, there is still a need for effective antifibrotic medication. HSP90 plays a crucial role in the development of fibrosis. It acts as a molecular chaperone that assists in the proper folding and stability of TβRII, potentially regulating the signaling of TGF-β1. It has been established that TβRII can be degraded through the proteasome degradation system, either via ubiquitination-dependent or -independent pathways. In the present study, STA9090 demonstrated promising effects in both in vitro and in vivo models. It reduced LDH leakage, prolonged the survival rate of hepatocytes in rats with liver fibrosis, and improved liver function. Importantly, STA9090 exerted pleiotropic effects by targeting proteins involved in limiting collagen production, which resulted in improved microscopic features of the rat livers. Our findings suggest that STA9090-induced inhibition of HSP90 leads to the degradation of TβRII, a fibrogenic client protein of HSP90, through the activation of the 20S proteasomal degradation system. We also revealed that this degradation mechanism is not dependent on the autophagy–lysosomal pathway. Additionally, STA9090 was found to destabilize HIF-1α and facilitate its degradation, leading to the reduced transcription of VEGF. Moreover, STA9090’s ability to deactivate the NFκB signaling pathway highlights its potential as an anti-inflammatory and antifibrotic agent. However, further research is necessary to fully elucidate the underlying mechanisms and fully capitalize on the therapeutic benefits of targeting HSP90 and associated pathways. Full article

(This article belongs to the Special Issue Recent Advances in TGF-β Inhibitors for the Therapeutic Management of Cancer and Fibrosis)

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15 pages, 2372 KiB

Open AccessArticle

HSPB5 Inhibition by NCI-41356 Reduces Experimental Lung Fibrosis by Blocking TGF-β1 Signaling

by Julie Tanguy, Pierre-Marie Boutanquoi, Olivier Burgy, Lucile Dondaine, Guillaume Beltramo, Burhan Uyanik, Carmen Garrido, Philippe Bonniaud, Pierre-Simon Bellaye and Françoise Goirand

Pharmaceuticals 2023, 16(2), 177; https://doi.org/10.3390/ph16020177 - 24 Jan 2023

Cited by 3 | Viewed by 2193

Abstract

Idiopathic pulmonary fibrosis is a chronic, progressive and lethal disease of unknown etiology that ranks among the most frequent interstitial lung diseases. Idiopathic pulmonary fibrosis is characterized by dysregulated healing mechanisms that lead to the accumulation of large amounts of collagen in the lung tissue that disrupts the alveolar architecture. The two currently available treatments, nintedanib and pirfenidone, are only able to slow down the disease without being curative. We demonstrated in the past that HSPB5, a low molecular weight heat shock protein, was involved in the development of fibrosis and therefore was a potential therapeutic target. Here, we have explored whether NCI-41356, a chemical inhibitor of HSPB5, can limit the development of pulmonary fibrosis. In vivo, we used a mouse model in which fibrosis was induced by intratracheal injection of bleomycin. Mice were treated with NaCl or NCI-41356 (six times intravenously or three times intratracheally). Fibrosis was evaluated by collagen quantification, immunofluorescence and TGF-β gene expression. In vitro, we studied the specific role of NCI-41356 on the chaperone function of HSPB5 and the inhibitory properties of NCI-41356 on HSPB5 interaction with its partner SMAD4 during fibrosis. TGF-β1 signaling was evaluated by immunofluorescence and Western Blot in epithelial cells treated with TGF-β1 with or without NCI-41356. In vivo, NCI-41356 reduced the accumulation of collagen, the expression of TGF-β1 and pro-fibrotic markers (PAI-1, α-SMA). In vitro, NCI-41356 decreased the interaction between HSPB5 and SMAD4 and thus modulated the SMAD4 canonical nuclear translocation involved in TGF-β1 signaling, which may explain NCI-41356 anti-fibrotic properties. In this study, we determined that inhibition of HSPB5 by NCI-41356 could limit pulmonary fibrosis in mice by limiting the synthesis of collagen and pro-fibrotic markers. At the molecular level, this outcome may be explained by the effect of NCI-41356 inhibiting HSPB5/SMAD4 interaction, thus modulating SMAD4 and TGF-β1 signaling. Further investigations are needed to determine whether these results can be transposed to humans. Full article

(This article belongs to the Special Issue Recent Advances in TGF-β Inhibitors for the Therapeutic Management of Cancer and Fibrosis)

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18 pages, 3134 KiB

Open AccessArticle

Oxy210, a Semi-Synthetic Oxysterol, Inhibits Profibrotic Signaling in Cellular Models of Lung and Kidney Fibrosis

by Feng Wang, Frank Stappenbeck and Farhad Parhami

Pharmaceuticals 2023, 16(1), 114; https://doi.org/10.3390/ph16010114 - 12 Jan 2023

Cited by 3 | Viewed by 2776

Abstract

Oxy210, a semi-synthetic oxysterol derivative, displays cell-selective inhibition of Hedgehog (Hh) and transforming growth factor beta (TGF-β) signaling in epithelial cells, fibroblasts, and macrophages as well as antifibrotic and anti-inflammatory efficacy in models of liver fibrosis. In the present report, we examine the effects of Oxy210 in cellular models of lung and kidney fibrosis, such as human lung fibroblast cell lines IMR-90, derived from healthy lung tissue, and LL97A, derived from an idiopathic pulmonary fibrosis (IPF) patient. In addition, we examine the effects of Oxy210 in primary human renal fibroblasts, pericytes, mesangial cells, and renal tubular epithelial cells, known for their involvement in chronic kidney disease (CKD) and kidney fibrosis. We demonstrate in fibroblasts that the expression of several profibrotic TGF-β target genes, including fibronectin (FN), collagen 1A1 (COL1A1), and connective tissue growth factor (CTGF) are inhibited by Oxy210, both at the basal level and following TGF-β stimulation in a statistically significant manner. The inhibition of COL1A1 gene expression translated directly to significantly reduced COL1A1 protein expression. In human primary small airway epithelial cells (HSAECs) and renal tubular epithelial cells, Oxy210 significantly inhibited TGF-β target gene expression associated with epithelial–mesenchymal transition (EMT). Oxy210 also inhibited the proliferation of fibroblasts, pericytes, and mesangial cells in a dose-dependent and statistically significant manner. Full article

(This article belongs to the Special Issue Recent Advances in TGF-β Inhibitors for the Therapeutic Management of Cancer and Fibrosis)

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Review

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73 pages, 4574 KiB

Open AccessReview

Advances and Challenges in Targeting TGF-β Isoforms for Therapeutic Intervention of Cancer: A Mechanism-Based Perspective

by David Danielpour

Pharmaceuticals 2024, 17(4), 533; https://doi.org/10.3390/ph17040533 - 20 Apr 2024

Cited by 9 | Viewed by 3171

Abstract

The TGF-β family is a group of 25 kDa secretory cytokines, in mammals consisting of three dimeric isoforms (TGF-βs 1, 2, and 3), each encoded on a separate gene with unique regulatory elements. Each isoform plays unique, diverse, and pivotal roles in cell growth, survival, immune response, and differentiation. However, many researchers in the TGF-β field often mistakenly assume a uniform functionality among all three isoforms. Although TGF-βs are essential for normal development and many cellular and physiological processes, their dysregulated expression contributes significantly to various diseases. Notably, they drive conditions like fibrosis and tumor metastasis/progression. To counter these pathologies, extensive efforts have been directed towards targeting TGF-βs, resulting in the development of a range of TGF-β inhibitors. Despite some clinical success, these agents have yet to reach their full potential in the treatment of cancers. A significant challenge rests in effectively targeting TGF-βs’ pathological functions while preserving their physiological roles. Many existing approaches collectively target all three isoforms, failing to target just the specific deregulated ones. Additionally, most strategies tackle the entire TGF-β signaling pathway instead of focusing on disease-specific components or preferentially targeting tumors. This review gives a unique historical overview of the TGF-β field often missed in other reviews and provides a current landscape of TGF-β research, emphasizing isoform-specific functions and disease implications. The review then delves into ongoing therapeutic strategies in cancer, stressing the need for more tools that target specific isoforms and disease-related pathway components, advocating mechanism-based and refined approaches to enhance the effectiveness of TGF-β-targeted cancer therapies. Full article

(This article belongs to the Special Issue Recent Advances in TGF-β Inhibitors for the Therapeutic Management of Cancer and Fibrosis)

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49 pages, 4386 KiB

Open AccessReview

Targeting SMAD-Dependent Signaling: Considerations in Epithelial and Mesenchymal Solid Tumors

by Farhana Runa, Gabriela Ortiz-Soto, Natan Roberto de Barros and Jonathan A. Kelber

Pharmaceuticals 2024, 17(3), 326; https://doi.org/10.3390/ph17030326 - 1 Mar 2024

Cited by 1 | Viewed by 6093

Abstract

SMADs are the canonical intracellular effector proteins of the TGF-β (transforming growth factor-β). SMADs translocate from plasma membrane receptors to the nucleus regulated by many SMAD-interacting proteins through phosphorylation and other post-translational modifications that govern their nucleocytoplasmic shuttling and subsequent transcriptional activity. The signaling pathway of TGF-β/SMAD exhibits both tumor-suppressing and tumor-promoting phenotypes in epithelial-derived solid tumors. Collectively, the pleiotropic nature of TGF-β/SMAD signaling presents significant challenges for the development of effective cancer therapies. Here, we review preclinical studies that evaluate the efficacy of inhibitors targeting major SMAD-regulating and/or -interacting proteins, particularly enzymes that may play important roles in epithelial or mesenchymal compartments within solid tumors. Full article

(This article belongs to the Special Issue Recent Advances in TGF-β Inhibitors for the Therapeutic Management of Cancer and Fibrosis)

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16 pages, 911 KiB

Open AccessReview

Hitting the Target! Challenges and Opportunities for TGF-β Inhibition for the Treatment of Cardiac fibrosis

by Maria Vistnes

Pharmaceuticals 2024, 17(3), 267; https://doi.org/10.3390/ph17030267 - 20 Feb 2024

Cited by 4 | Viewed by 5202

Abstract

Developing effective anti-fibrotic therapies for heart diseases holds the potential to address unmet needs in several cardiac conditions, including heart failure with preserved ejection fraction, hypertrophic cardiomyopathy, and cardiotoxicity induced by cancer therapy. The inhibition of the primary fibrotic regulator, transforming growth factor (TGF) β, represents an efficient strategy for mitigating fibrosis in preclinical models. However, translating these findings into clinical benefits faces challenges due to potential adverse effects stemming from TGF-β’s physiological actions in inflammation and tissue homeostasis. Various strategies exist for inhibiting TGF-β, each associated with a distinct risk of adverse effects. Targeting TGF-β directly or through its signaling pathway proves efficient in reducing fibrosis. However, direct TGF-β blockade may lead to uncontrolled inflammation, especially following myocardial infarction, while interference with the signaling pathway may compromise structural integrity, resulting in issues like insufficient wound healing or ventricular dilatation. Influencing TGF-β activity through interacting signaling pathways, for instance by inhibitors of the renin–angiotensin–aldosterone-system, is insufficiently potent in reducing fibrosis. Targeting activators of latent TGF-β, including ADAMTS enzymes, thrombospondin, and integrins, emerges as a potentially safer strategy to reduce TGF-β-induced fibrosis but it requires the identification of appropriate targets. Encouragement is drawn from promising agents developed for fibrosis in other organs, fueling hope for similar breakthroughs in treating cardiac fibrosis. Such advances depend on overcoming obstacles for the implementation of anti-fibrotic strategies in patients with heart disease, including fibrosis quantification. In this review, insights garnered from interventional and mechanistic studies, obtained through a non-systemic search spanning preclinical and clinical evidence, are summarized to pinpoint the most promising targets for further exploration and development. Full article

(This article belongs to the Special Issue Recent Advances in TGF-β Inhibitors for the Therapeutic Management of Cancer and Fibrosis)

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17 pages, 1326 KiB

Open AccessReview

TGF-β Inhibitors for Therapeutic Management of Kidney Fibrosis

by Cheol Ho Park and Tae-Hyun Yoo

Pharmaceuticals 2022, 15(12), 1485; https://doi.org/10.3390/ph15121485 - 29 Nov 2022

Cited by 21 | Viewed by 4847

Abstract

Kidney fibrosis is a common pathophysiological mechanism of chronic kidney disease (CKD) progression caused by several underlying kidney diseases. Among various contributors to kidney fibrosis, transforming growth factor-β1 (TGF-β1) is the major factor driving fibrosis. TGF-β1 exerts its profibrotic attributes via the activation of canonical and non-canonical signaling pathways, which induce proliferation and activation of myofibroblasts and subsequent accumulation of extracellular matrix. Over the past few decades, studies have determined the TGF-β1 signaling pathway inhibitors and evaluated whether they could ameliorate the progression of CKD by hindering kidney fibrosis. However, therapeutic strategies that block TGF-β1 signaling have usually demonstrated unsatisfactory results. Herein, we discuss the therapeutic concepts of the TGF-β1 signaling pathway and its inhibitors and review the current state of the art regarding regarding TGF-β1 inhibitors in CKD management. Full article

(This article belongs to the Special Issue Recent Advances in TGF-β Inhibitors for the Therapeutic Management of Cancer and Fibrosis)

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