Regulation of transforming growth factor-β signaling as a therapeutic approach to treating colorectal cancer

Table 1 Characteristics of individual colorectal cancer subtypes

CMS1	CMS2	CMS3	CMS4
(MSI immune)	(Canonical)	(Metabolic)	(Mesenchymal)
CIMP high	CIN	CIN, CIMP low	CIN
Hypermethylation
SCNA-low	SCNA-high	SCNA-intermediate	SCNA-high
BRAF mutant		KRAS mutant
Activation of immune cells	WNT, MYC activation	Metabolic deregulation	TGF- activation
Worse survival after relapse	Superior survival after relapse		Worse relapse-free and overall survival

SCNA: Somatic copy number alteration; CIN: Chromosomal instability; CIMP: Methylation of the CpG island; TGF: Transforming growth factor.

Table 2 Roles of individual small mothers against decapentaplegic homolog proteins in the onset and progression of colorectal cancer

Type of SMAD	Role in colorectal cancer	References
SMAD1	Participates in the modification of cell growth, differentiation, apoptosis and other processes that are essential in the regulation of the body’s immune system	[39-42]
	Promotes epithelial-mesenchymal transition process
	By increasing the expression of ATG5 induces autophagy
SMAD2	Inhibits the expression of related functional genes, cell proliferation and regulates the transcriptional response that promotes cell apoptosis	[43,44]
	Expression of SMAD2 is correlated with patient survival
SMAD3	In the formation of a tumor, depending on the stage of the cancer, it plays the double role of an oncogene or a tumor suppressor gene	[45-48]
	Reduces its expression through mir-4429, and inhibits the appearance, development and metastasis of cancer cells
SMAD4	Plays a very important role in the transduction of the TGF-β signaling pathway	[32,49]
	Maintains the cell cycle in the G1 phase, which leads to abnormal tumor proliferation
	Is a tumor suppressor gene
	High mutation rate of SMAD4 in CRC patients was associated with poor prognosis, but not with clinical stage
SMAD5	Mediates TGF-β superfamily ligand signaling pathway and thus influences cancer progression	[50]
	No relevant studies on the role of SMAD5 in CRC patients have been found in the last 5 years
SMAD6	Regulates TGF-β signaling pathway, promotes angiogenesis, stimulates extracellular matrix, and inhibits immunity, thus contributing to tumor growth, diffusion, and metastasis	[51]
	No relevant studies on the role of SMAD6 in CRC patients have been found in the last 5 years
SMAD7	Plays a dual role in different tumor stages, acting as a tumor suppressor gene by inhibiting proliferation and promoting apoptosis in the early stage, and increasing invasion in the late stage, promoting epithelial-mesenchymal transition, which correlates with the degree of malignancy	[52,53]

SMAD: Small mothers against decapentaplegic homolog; ATG5: Autophagy-related gene 5; CRC: Colorectal cancer; TGF: Transforming growth factor.

Table 3 Clinical trials of drugs for the treatment of colorectal cancer (United States National Library of Medicine; ClinicalTrials.gov)

Clinical trials (phase)	Drug	Target	Mechanism of action
Antisense oligonucleotides
NCT00844064 (I)	AP12009 (trabedersen)	TGF-β2	By binding to TGF-βII mrna, its expression is reduced
Antibodies
NCT04952753 (II)	NIS793	TGF-β	Reduction of active cytokine, reduction of SMAD2/3 phosphorylation, and reduction of TGF-β target gene expression
NCT02947165 (I)	NIS793	TGF-β	Reduction of active cytokine, reduction of SMAD2/3 phosphorylation, and reduction of TGF-β target gene expression
NCT01646203(I)	IMC-TR1	TGF-βRII	Reduction of active cytokine, reduction of SMAD2/3 phosphorylation, and reduction of TGF-β target gene expression
Ligand traps
NCT03436563 (I/II)	M7824	TGF-βRII	Bifunctional anti-PD-L1/TGF-βRII trap fusion protein
NCT02517398(I)	Bintrafusp alfa	TGF-βRII and PD-L1	First-in-class bifunctional fusion protein composed of a mab against PD-L1 fused to the extracellular domain of the TGF-β receptor II
NCT04856787 (II/III)	SHR-1701	TGF-βRII	Bifunctional anti-PD-L1/TGF-βRII agent
Small molecule receptor kinase inhibitors
NCT04031872 (I/II)	LY3200882; capecitabine	TGF-βRI	By blocking ATP binding to TGF-βR, receptor kinase activity and signal transduction are reduced
NCT05400122 (I)	Vactosertib	TGF-βRI	Inhibits the activity of TGF-βR1
NCT03724851 (I/II)	Vactosertib + Pembroli-zumab	TGF-βRI	Inhibits the activity of TGF-βR1
NCT03470350 (I/II)	Galunisertib	TGF-βRI	Inhibits the activity of TGF-βR1
Immune checkpoints
NCT04540159		TGF-β1	Measuring the level Active TGF-β1 by flow-cytometric analysis in the intraabdominal ascites
Adoptive cell therapy
NCT03431311 (I/II)	ACT	TGF-βII	ACT with Radium-1 TCR + T cells transiently redirected against the TGF-βRII frameshift antigen which is expressed in MSI+ colon cancer.
NCT05040568 (I)	CB-NK-TGF-βR2-/NR3C1		Immunotherapy with ex vivo preactivated and expanded CB-NK cells in combination with cetuximab

ACT: Adoptive cell therapy; TGF: Transforming growth factor.