Transforming growth factor-beta signaling in cancer: therapeutic implications, challenges, and pathways to progress

This study is led by Faizah Alabi and Izuchukwu Okpalanwaka (Texas Tech University Health Sciences Center) with Sikiru Imodoye (Huntsman Cancer Institute, University of Utah) serving as the article co-correspondent with Faizah Alabi. This review critically examines the challenges encountered in the clinical development of anti-TGFβ therapies for cancer treatment, despite significant advancements in preclinical research. It posits that targeting specific epitopes to modulate the tumorigenic activity of TGF-β could mitigate off-target toxicity while preserving its physiological homeostatic functions. Furthermore, the review suggests that implementing intermittent dosing schedules or optimally timed therapeutic interventions, particularly during early or precancerous stages when TGF-β's suppressive properties remain active, may help alleviate toxicity without compromising efficacy.

The limitations of preclinical models are also addressed, notably their potential failure to fully replicate the complex biological effects of TGF-β. This includes issues such as the loss of fidelity in cancer cell lines used in preclinical studies, especially patient-derived xenografts (PDXs), which often undergo selection processes—such as the accumulation of copy number alterations (CNAs)—that diverge from tumor evolution in patients. The review emphasizes the critical role of the tumor-immune microenvironment (TiME) in mediating TGF-β's anti-tumor effects, suggesting that models lacking this component, like PDXs, may not be ideal for evaluating anti-TGFβ therapies.

Additionally, the review discusses the activation of redundant and compensatory signaling pathways as key resistance mechanisms to anti-TGFβ therapies. Given the complexity of TGF-β signaling, multiple pathways can compensate for its inhibition at both receptor and downstream levels. This is particularly relevant considering most therapies target TGF-β receptors, especially TβRI.

The researchers also highlighted the importance of patient selection criteria, as molecular and cellular tumor characteristics significantly influence therapeutic response. For instance, tumors with extensive stromal support and mesenchymal phenotypes often exhibit high expression of TGF-β-related genes, potentially correlating with better treatment responses with anti-TGFβ therapies. This review critically examines the existing challenges encountered in the clinical development of anti-TGFβ therapies for cancer treatment, despite significant advancements in preclinical research. It posits that targeting specific epitopes to modulate the tumorigenic activity of TGF-β could mitigate off-target toxicity while preserving its physiological homeostatic functions. Furthermore, the review suggests that implementing intermittent dosing schedules or optimally timed therapeutic interventions, particularly during early or precancerous stages when TGF-β's suppressive properties remain active, may help alleviate toxicity without compromising efficacy.

The limitations of preclinical models are also addressed, particularly their potential failure to fully mimic the complex biological effects of TGF-β. This includes issues such as the loss of accuracy in cancer cell lines used in preclinical studies, especially patient-derived xenografts (PDXs), which often experience selection processes—such as the buildup of copy number alterations (CNAs)—that differ from tumor development in patients. The review highlights the essential role of the tumor-immune microenvironment (TiME) in mediating TGF-β's anti-tumor effects, suggesting that models without this component, like PDXs, may not be ideal for testing anti-TGFβ therapies.

Finally, the review delineates current strategies for targeting TGF-β, including small-molecule kinase inhibitors, neutralizing antibodies, ligand traps, integrin-mediated TGF-β signaling inhibitors, vaccine-based therapies, antisense oligonucleotides, and approaches targeting both canonical and non-canonical pathways. It emphasizes the pro-tumorigenic roles of TGF-β in promoting angiogenesis, epithelial-mesenchymal transition (EMT), immune evasion mechanisms affecting T and B lymphocytes, and antigen-presenting cells (APCs), and natural killer (NK) cells. The discussion concludes with an overview of combination strategies to overcome therapeutic resistance.

See the article:

Transforming Growth Factor-Beta Signaling in Cancer: Therapeutic Implications, Challenges, and Pathways to Progress

https://doi.org/10.1002/mog2.70027