Current and emerging therapeutic approaches for colorectal cancer: A comprehensive review

Table 1 Tyrosine kinase inhibitors, plant based drugs, and selected target specific agents against colorectal cancer

Agent	Type of agent	Target/mechanism	FDA approval date/trial number/status	Sources/interventions	Results
Sunitinib	TKI	VEGFR1-3	NCT00457691. Completed	Phase II study: FOLFIRI and sunitinib for mCRC	Sunitinib did not add to the antitumor activity of FOLFIRI
Axitinib	TKI	VEGFR1-3	NCT00460603. Completed	Phase II study: axitinib and/or bevacizumab with modified FOLFOX-6 as first-line therapy for mCRC	Neither the addition of continuous axitinib nor the axitinib/bevacizumab combination to FOLFOX-6 improved ORR, PFS, or OS compared with bevacizumab as first-line treatment of mCRC
Sorafenib	Kinase inhibitor	VEGFR	NCT00326495. Completed	Phase II study: cetuximab and sorafenib for the treatment of KRAS-mutated mCRC	No objective responses were observed
Regorafenib	Multikinase inhibitor	VEGFR1-3, TIE2, KIT, RET, RAF, PDGFR-B, FGFR	September 27, 2012	Approved for ACRC, mCRC	-
Encorafenib	Kinase inhibitor	BRAF-V600E as well as wildtype BRAF and CRAF	April 8, 2020	Approved for mCRC	-
Simtuzumab	Monoclonal antibody	LOXL2	NCT01479465. Completed	Phase II study: efficacy of simtuzumab with FOLFIRI as second line treatment in CRC	The addition of simtuzumab to FOLFIRI did not improve clinical outcomes in patients with metastatic KRAS-mutant CRC
Lenvatinib	TKI of VEGFR	VEGFR1-3, KIT, RET, PDGFR-alpha, FGFR	NCT04776148. Ongoing	Phase III study ongoing: lenvatinib in combination with pembrolizumab for mCRC	Ongoing
Tivozanib	TKI of VEGFR	VEGFR1-3	NCT01058655. Completed	Phase II study: everolimus (RAD001) and tivozanib (AV-951) in patients with refractory or mCRC	The oral combination of tivozanib and everolimus was well tolerated, with stable disease achieved in 50% of patients with refractory or mCRC
Tipifarnib	Farnesyltransferase inhibitor	Farnesyltransferase	NCT00005833. Completed	Phase II trial study: R-115777 given as a single agent	Ineffective in patients with mCRC
D-1553	Small molecule KRasG12C inhibitor	KRAS G12C	NCT04585035. Ongoing	Phase I study using D-1553 in CRC with KRAS G12C mutation	Ongoing
Aflibercept	Recombinant fusion protein	VEGF-A and VEGF-B, PGF	NCT02181556. Completed	Phase II study: aflibercept in combination with FOLFIRI as first-line chemotherapy in patients with mCRC	Although the primary objective was not met, first-line FOLFIRI + aflibercept for mCRC resulted in median PFS and OS close to those reported with traditional doublet and targeted therapies
Berberine	Alkaloid	Anti-proliferation, cell cycle arrest	In vitro study	Plant/berberine	Berberine inhibited telomerase activity and induced cell cycle arrest and telomere erosion in colorectal cancer cell Line, HCT 116[149]
Piper nigrum ethanolic extract	Alkaloid	Antioxidative activity	In vitro study	Plant/EEPN	Time- and dose-dependent increase in the cytotoxic efficacy of 50% EEPN against colorectal carcinoma cell lines were noted[150]
Fucoidan	Polysaccharide	Inhibit growth and angiogenesis	In vitro study	Brown seaweed/combination of fucoidan with vitamin C	The combination of fucoidan with vitamin C showed significant inhibitory effects on HCT-116 colon cell viability[151]
Curcumin	Polyphenol	Apoptosis, antiangiogenesis, and cell cycle arrest	NCT02439385. Completed	Plant/phase II study: bevacizumab/FOLFIRI with ginsenoside-modifies nanostructured lipid carrier containing curcumin (G-NLC) in patients with mCRC	Bevacizumab/FOLFIRI with G-NLC increased long-term survival. Further randomized control studies are needed
			NCT01490996. Completed	Phase I/II study: curcumin combined with FOLFOX	Curcumin with FOLFOX was safe and tolerable. The HR for PFS and OS was 0.57 and 0.34, respectively
Gingerol	Polyphenol	Antioxidative and anti-inflammatory	NCT01344538. Completed	Plants/phase II randomized control trial. Ginger for CRC prevention	Result suggested ginger may reduce proliferation and increase apoptosis
EPA	Polyunsaturated fatty acids	Inhibit angiogenic factors	NCT00398333. Terminated	Marine microalgae/phase IV	Due to small sample size further investigation needed
EGCG	Polyphenol	Apoptosis	NCT02891538. Ongoing	Plants/early phase 1 study: EGCG in CRC patients	Ongoing
PSK	Polysaccharide	Apoptosis and antiproliferative	NCT00497107. NA	Fungi/phase III study: oral tegafur/uracil plus PSK	Results suggested that there was reduction in recurrence and mortality by 43.6% and 40.2%, respectively in stage I and stage II
Resveratrol	Polyphenol	Apoptosis and antiproliferative	NCT00920803. Completed	Plants/phase I study: resveratrol for resectable CRC	Resveratrol was effective in treating CRC by modulating the Wnt pathway
Topotecan	Alkaloid	Antiproliferative	EORTC	Plants/phase II study: oral topotecan	Topotecan administered as a five times daily regimen has only minor activity as a single-agent therapy in colorectal cancer
Metformin	Alkaloid	Antiproliferative and antimetastatic	NCT03047837. NA	Plants/phase II study: using aspirin and metformin in stage I-II CRC	Result suggested that the given intervention delayed recurrence and improved prognosis
Everolimus	Macrolide	Antiproliferative and antimetastatic	NCT01387880. Completed	Bacterial/phase II study: irinotecan, cetuximab, and everolimus to patients with mCRC	Everolimus showed promising effects on CRC prognosis
			NCT01058655. Completed	Phase II study: tivozanib and everolimus for patients with refractory mCRC	Oral combination of tivozanib and everolimus was well tolerated in 50% of the patient
Andrographolide	Diterpenoid	Apoptosis, antiproliferative, and cell cycle arrest	In vitro study	In vitro study using 5-FU with andrographolide	Andrographolide enhanced 5-FU induced antitumor effect in CRC via inhibition of the c-MET pathway[152]
Silymarin	Flavnoid	Apoptosis, antiproliferative	NCT03130634. Completed	Plants/phase IV study using silymarin in patients treated with first-line treatment FOLFIRI	Silymarin is a potential supplement for reducing toxicities in mCRC patients undergoing FOLFIRI plus bevacizumab first-line treatment
MMC	Hyleneimines	Antiproliferative	NCT00643877. NA	Streptomyces/phase III study using PHARC with oxaliplatin, MMC FUDR	Addition of PHRAC improved DFS in patients with stage II and stage III CRC
			NCT03073694. Ongoing	Phase II study using MMC and melphalan	Ongoing

5-FU: 5-fluorouracil; ACRC: Advanced colorectal cancer; BRAF-V600E: BRAF protein coding gene; CRC: Colorectal cancer; DFS: Disease-free survival; EEPN: Ethanolic extract of Piper nigrum; EGCG: Epigallocatechin gallate; EORTC: European Organization for Research and Treatment of Cancer; EPA: Eicosapentaenoic acid; FDA: Food and Drug Administration; FGFR: Fibroblast growth factor receptor; FOLFIRI: 5-flurouracil, leucovorin, and irinotecan; FOLFOX-6: 5-flurouracil, leucovorin, and oxaliplatin-6; FUDR: Fluorodeoxyuridine; G-NLC: Genistein-nanostructured lipid carriers; HR: Hazard ratio; KIT: Proto-oncogene receptor tyrosine kinase; LOXL2: Lysyl oxidase-like 2; mCRC: Metastatic colorectal cancer; MMC: Mitomycin C; NA: Not available; ORR: Objective response rate; OS: Overall survival; PDGFR-B: Platelet-derived growth factor receptor B; PFS: Progression-free survival; PGF: Placental growth factor; PHARC: Preoperative hepatic and regional atrial chemotherapy; PSK: Polysaccharide krestin; RAF: Rapidly activated fibrosarcoma; RET: Ret proto-oncogene; TIE2: Tyrosine kinase with immunoglobin and epidermal growth factor 2; TKI: Tyrosine kinase inhibitor; VEGFR1-3: Vascular endothelial growth factor 1-3.