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.

Table 2 Immunotherapeutic agents and vaccines against colorectal cancer

Antibodies/antigenic composition	Origin	Target/CRC stage	Approval date/trial number/yr	Description/interventions	Inference
Monoclonal antibodies
Cetuximab	Chimeric	EGFR	February 12, 2004	Cetuximab alone for mCRC	Adding cetuximab to first-line chemotherapy in patients with WT KRAS mCRC was statistically beneficial for OS and PFS[153]
			July 6, 2012	For mCRC cetuximab + FOLFIRI
Panitumumab	Humanized	EGFR	September 27, 2006	For mCRC panitumumab + FOLFOX for WT KRAS mCRC. For WT RAS mutation mCRC	In WT KRAS mCRC, PFS was improved, objective response was higher, and there was a trend toward improved OS with panitumumab-FOLFOX4[42,43,154]
			May 23, 2014
			June 29, 2017
Nimotuzumab	Humanized	EGFR	NCT05278728. Completed	Phase II study nimotuzumab along with radiotherapy and concurrent capecitabine	No significant outcomes
			NCT05278728. Completed	Phase IIa study of nimotuzumab to treat CRC	Ongoing
Necitumumab	Human	Cetuximab-resistant EGFR	NCT00835185. Completed	Phase II study necitumumab plus modified FOLFOX6 for locally advanced and mCRC	First-line necitumumab + mFOLFOX6 was active with manageable toxicity in locally advanced or mCRC
Bevacizumab	Humanized	VEGF	February 26, 2004	For mCRC	The addition of bevacizumab to 5-fluorouracil-based combination significantly increased patient survival[155,156]
Ramucirumab	Human	VEGFR-2	April 24, 2015	Ramucirumab with FOLFIRI as second-line treatment for mCRC	The addition of ramucirumab to FOLFIRI improved patient outcomes in the RAISE trial[157]
Nivolumab	Human	PD-1	August 1, 2017	Nivolumab approved for MSI-H/dMMR mCRC	Nivolumab provided durable responses and disease control in pre-treated patients with dMMR/MSI-H mCRC[51]
Ipilimumab	Human	CTLA-4	July 11, 2018	Nivolumab plus low dose ipilimumab approved for previously treated MSI-H/dMMR mCRC	Clinical effect with nivolumab + low-dose ipilimumab was significant and long-lasting for MSI-H/dMMR mCRC[57]
Cemiplimab	Human	PD-1	NCT04157985. Ongoing	Phase III study: evaluating length of treatment with cemiplimab and other inhibitors in solid tumor patients	Ongoing
Atezolizumab	Humanized	PD-L1	NCT02788279. Completed	Phase III study: atezolizumab with or without cobimetinib vs regorafenib in previously treated mCRC	Did not meet its primary endpoint of improved OS with atezolizumab plus cobimetinib or atezolizumab vs regorafenib
			NCT05118724. Ongoing	Phase II study: atezolizumab with/without IMM-101 in patients with MSI-H/dMMR stage III CRC ineligible for oxaliplatin	Ongoing
			NCT05456165. Ongoing	Phase II study: atzolizumab in combination with neoantigen targeting vaccine	Ongoing
Avelumab	Human	PD-L1	NCT03854799. Ongoing	Phase II study: avelumab + capecitabine combined with radiation	Ongoing
			NCT03475953. Ongoing	Phase I/II Study: regorafenib plus avelumab in solid tumors	Ongoing
Dostarlimab	Humanized	PD-1	NCT04165772. Ongoing	PD-1 blockade in dMMR, locally advanced rectal cancer	Ongoing: dMMR, locally advanced rectal cancer was highly sensitive to single-agent PD-1 blockade. Longer follow-up is needed to assess the duration of response
Pembrolizumab	Humanized	PD-1	June 29, 2020	Pembrolizumab for first-Line treatment of patients with unresectable or metastatic MSI-H or dMMR CRC	Approved based on Phase III Keynote-117 Trial in which pembrolizumab significantly reduced the risk of disease progression or death by 40%[158]
Relatimab	Human	LAG-3	NCT05328908. Ongoing	Phase III study of nivolumab-relatlimab fixed-dose combination vs regorafenib or TAS-102 in participants with mCRC	Ongoing
			NCT03642067. Ongoing	Study of nivolumab and relatlimab in patients with MSS advanced CRC	Ongoing
Peptide based vaccines[80]
SART3	-	Metastatic	2001	Used with adjuvant incomplete Freund’s adjuvant	Increased cellular immune responses to both CRC cells and the vaccinated peptide
Recombinant Ep-CAM (with liposome carrier)	-	I-III	2001	Used with adjuvant alum	The overall immune response was safe and effective for patients with CRC and advanced cancer against Ep-CAM
		II-IV	2004	Used with adjuvant GM-CSF
		Metastatic	2004	Used with adjuvant GM-CSF
CTP37-DT	-	III-IV	2002	Used with adjuvant Nor-MDP (Muramyl dipeptide)	Longer OS with an excellent safety profile in patients with CRC
Recombinant CEA expressed in baculovirus system	Expressed in baculovirus-insect cell system	Stage I-III	2004	Used with adjuvant alum and GM-CSF	Potent and long lasting antigen specific IgG and T cell response
Survivin-2B Human	-	Metastatic	2004	Used with adjuvant UFT (uracil-tegafur)	Excellent safety profile with potent immune response against HLA-A24-expression in patients with CRC
G17DT (N-terminus of gastrin 17)	-	Metastatic	2014	Used with adjuvant diphtheria toxoid	In combination with irinotecan this vaccine has an acceptable immune response with significantly longer survival
OCV-C02	-	Metastatic	2017	Two peptide epitopes derived from RNF43 and TOMM34 and used with adjuvant montanide ISA 51	Safe immune response in recurrent or advanced stage CRC patients resistant to standard chemotherapy
RNF43 and TOMM34-derived peptides	-	III	2018	Used with uracil-tegafur/leucovorin, montanide ISA 51	Strong immune response with increased OS in patients with stage III CRC
PolyPEPI1018	-	Metastatic	2020	Used with adjuvant montanide ISA 51 Human	Safe and well-tolerated and induced robust CRC-specific T cell responses, similar to personalized neoantigen vaccines
mRNA-based vaccines[80]
NCI 4650 (mRNA 4650)	-	Metastatic	2019	-	Partly safe and neoantigen specific CD8 and CD4 T cells responses against CRC neoepitopes
mRNA 4157	-	Metastatic	2019	In combination with pembrolizumab	Partly safe and strong neoantigen specific T cell responses against CRC neoepitopes
V 941 (mRNA 5671)	-	Metastatic	2019, NCT03948763	In combination with pembrolizumab	KRAS vaccine clinical trial is underway, and the results are eagerly awaited
RO 7198457 (RG 6180)	-	Metastatic	2020	In combination with atezolizumab	Partly safe and strong neoantigen specific immune responses
Cell based vaccines[80]
Tumor cell	Tumor cell	II and III	2000	In combination with BCG	Less potency with 5-yr OS of 84.6%
Cancer Vax	Tumor cell	IV	2001	In combination with BCG	Significant increase in anti-TA90 IgG and IgM titers, and the OS was 21.9 mo
HSPPC-gp96	Tumor cell	IV	2003	-	Two-year overall survival and disease-free survival improved
CEA mRNA	DCs	IV	2003	In combination with IL-2	Well tolerated and safe immunization observed in patients with advanced malignancies
OPA-DC	DCs	Metastatic	2011	CEA peptide-loaded DCs matured with a combination of OK432, prostanoid, and interferon-α	Increased CEA-specific cytotoxic T cell response and NK cell levels in 8 patients with stable disease
Autologous tumor lysate DC (ADC)	DCs	Metastatic	2016	-	Not recommended: the use of ADC alone, in a phase III trial
Autologous tumor antigens-loaded DC	DCs	Metastatic	2018	In combination with 5-fluorouracil	Treatment was safe and had shown particularly prominent IL-12 production for immunization against neoantigens
Vector based vaccines
ALVAC-CEA/B7	Canary pox virus vector	Metastatic	2008; 2013	In combination with chemotherapy	Acceptable safety profile and induced CEA-specific T cell responses in patients with mCRC
AVX701	Alphavirus vector	III	2010	VRP expressing CEA	Well tolerated and elicit robust CEA-specific T cell and antibody responses in patients with CRC
GI-6207	Saccharomyces cerevisiae	Metastatic	2014	-	Strong antigen-specific CD8+ T cells and CD4+ T responses and extended stable disease
GI-6301	Saccharomyces cerevisiae	Metastatic	2015	-	Decreased tumor density and serum CEA levels in CRC treated patients
pLADD	Listeria monocytogenes	Metastatic	2017, NCT03189030	Listeria bacterial vector in combination with neoantigens	Induced neoantigen-specific CD8+ T cells and gamma delta T cells
Cholera	Bacteria	I-IV	2018	-	Cholera vaccination largely decreased the mortality rate of CRC
GI-4000	Saccharomyces cerevisiae	Metastatic	2018	-	Excellent safety profile and favorable immunogenicity in the majority of subjects
ADXS-NEO	-	Metastatic	2019	Bacteria expressing personalized tumor antigens	Increased CD4+/CD8+ T cell-mediated immune response

ADC: Antibody drug conjugate; BCG: Bacillus Calmette–Guérin; CEA: Carcinoembryonic antigen; CRC: Colorectal cancer; CTLA-4: Cytotoxic T-Lymphocyte-associated antigen-4; DCs: Dendritic cells; dMMR/MSI-H: Microsatellite instability high and deficient mismatch repair; EGFR: Epidermal growth factor receptor; Ep-CAM: Epithelial cell adhesion molecule; FOLFIRI: 5-flurouracil, leucovorin, and irinotecan; FOLFOX4/6: 5-flurouracil, leucovorin, and oxaliplatin; GM-CSF: Granulocyte macrophage colony-stimulating factor; HLA: Human leukocyte antigen; HSPPC-gp96: Heat shock protein peptide glycoprotein Complex-96; Ig: Immunoglobin; IL: Interleukin; LAG-3: Lymphocyte activation gene 3; mCRC: Metastatic colorectal cancer; MSS: Microsatellite stable; NK: Natural killer cell; Nor-MDP: Nor-muramyl dipeptide; OS Overall survival; PFS: Progression-free survival; PD-1: Programmed cell death receptor 1; PD-L1: Programmed cell death ligand 1; RNF43: Ring finger protein 43; SART3: Squamous cell carcinoma antigen identified by T cells 3; TOMM34: Translocase of outer mitochondrial membrane 34; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor; WT: Wild-type.

Table 3 microRNAs and small interfering RNAs as therapeutics for colorectal cancer in clinical trials

Therapeutic name	Target gene/protein	Route of administration	Phase/status	Clinical trial identifier	Outcome
siRNA targeted therapeutics
ALN-VSP02	VEGF, KSP	Systemic	Phase I (2011)/terminated	NCT00882180	It was well-tolerated and had antitumor activity
		IV infusion	Phase I (2012)/completed	NCT01158079
Atu027	PKN3	Systemic	Phase I (2012)	NCT00938574	It was safe in patients with advanced solid tumors
		IV infusion	Phase I/II (2016)/completed	NCT01808638
CALAA-01	RRM 2	Systemic; IV infusion	Phase I (2013)/terminated	NCT00689065	It was well tolerated during the initial dose escalation portion of the phase Ia study
siRNA-EphA2-DOPC	EphA2	Systemic; IV infusion	Phase I 2015/active	NCT01591356	It was well tolerated at all doses tested in preclinical studies
TKM-PLK1 (TKM-080301)	PLK-1	Systemic; IV infusion	Phase I/II (2016)/completed	NCT02191878	It was tolerated and showed preliminary antitumor efficacy
DCR-MYC (DCRM1711)	MYC	Systemic	Phase I (2017)	NCT02110563	It was well tolerated and showed promising initial clinical and metabolic responses across various dose levels
		IV infusion	Phase Ib/2 (2016)/terminated	NCT02314052
NBF-006	GSTP	Systemic; IV infusion	Phase1 (2019)/active	NCT03819387	Significant tumor growth inhibition and overall survival benefit was observed
miRNA targeted therapeutics
MRX34	miR-34a mimic	IV infusion	Phase I/terminated-2016. Phase I-II/withdrawn-2016	NCT01829971	Unexpected severe immune-mediated toxicities observed
				NCT02862145

DCR-MYC: Lipid nanoparticle-formulated small inhibitory RNA; EphA2: Ephrin type-A receptor 2; GSTP: Glutathione S-transferase pi gene; IV: Intravenous; KSP: Kinesin spindle protein; miRNA: MicroRNA; PKN3: Protein kinase N3; PLK-1: Polo-like kinase 1; RRM2: Ribonucleotide reductase regulatory subunit M2; siRNA: Small interfering RNA; VEGF: Vascular endothelial growth factor.