Molecular targets in urothelial cancer: detection, treatment, and animal models of bladder cancer

Figures & data

Table 1 Clinical staging of bladder cancer

Stage	Tumor (T)	Lymph node involvement (N)	Metastasis (M)
Stage 0a	Ta: noninvasive papillary carcinoma	N0	M0
Stage 0is	Tis: carcinoma in situ	N0	M0
Stage I	T1: has grown into connective tissue	N0	M0
Stage II	T2a: has grown into inner half of muscle layer	N0	M0
	T2b: has grown into outer half of muscle layer	N0	M0
Stage III	T3a: microscopic invasion of surrounding fatty tissue	N0	M0
	T3b: macroscopically detectable invasion of surrounding fatty tissue	N0	M0
Stage IV	T4a: spread into prostate (men) and uterus (women)	N0	M0
	T4b: has grown into pelvic or abdominal wall	N0	M0
	Any T	N1–3: lymph node involvement in proximal or distal lymph nodes	M0
	Any T	Any N: any lymph node involvement	M1: metastasis present

Notes: According to American Joint Committee on Cancer (AJCC). N0, no lymph node involvement; M0, No signs of metastasis.

Table 2 Overview of clinical trials for bladder cancer

Target pathway	Drug	Mechanism/target	Trial phase	Reference
Tyrosine kinase	Bevacizumab	VEGF-A binding/inhibition	III	^Citation95
	Ziv-aflibercept^Citation196	VEGF binding/inhibiting agent	I	^Citation196
	Cabozantinib	VEGFR-2 inhibitor	II	^Citation197
	Pazopanib	Inhibitor of several tyrosine kinases	II	^Citation198
	Tamoxifen	Antagonist of estrogen receptors	II	^Citation199
	Buparlisib	PI3K inhibitor	II	^Citation200
	Dovitinib	FGFR and VEGFR inhibitor	II	^Citation201
	MEK162	MEK inhibitor	II	^Citation202
	MGAH22	HER2-targeting antibody	I	^Citation203
	Afatinib	EGFR and HER2 inhibitor	II	^Citation94
	AZD5312	Androgen receptor antisense inhibitor	I	^Citation204
PI3K/AKT/mTOR	Everolimus	mTOR inhibitor (mTORC1 and mTORC2)	I, II	^Citation205
	Rapamycin	mTOR inhibitor	I, II	^Citation206
	ABI-009 (albumin-bound rapamycin)	mTOR inhibitor	I, II	^Citation207
Immunotherapy	ALT-801	p53/HLA-A2-expressing tumor cells	I, II	^Citation84
	HS-410	Immune activator along with BCG	I, II	^Citation208
	ALT-803	Immune activator through IL-15	I, II	^Citation209
	Ipilimumab	CTLA-4 antibody	II	^Citation117
	MEDI4736	PDL1 antibody antagonist	I	^Citation111
	Tremelimumab	CTLA-4 antibody Down regulation of T-reg cells	I	^Citation210
	AGS15E	Slitrk6 targeting immunotherapy	I	^Citation211
	MK-3745 (pembrolizumab)	PDL1	I, II	^Citation110
	Ad/HER2/Neu vaccine	Vaccination/immune activation	I	^Citation212
	SAR566658	Anti-CA6-DM4 immunotherapy	I	^Citation213
	Lenalidomide	Immunomodulation	I	^Citation214
	MPDL3280A	Anti-PDL1 immunotherapy	II	^Citation112
Cell cycle	Eribulin mesylate	Microtubule formation/mitosis	I, II	^Citation215
	Abraxane	Protein-bound paclitaxel – mitosis	I, II	^Citation216
	Tesetaxel	Tubulin stabilization – antimitotic	II	^Citation217
	ASG-22CE	Inhibition of tubulin formation in cancer cells by targeting cells expressing adhesion molecule nectin-4 with monomethyl auristatin E	I	^Citation218
	Amrubicin	Anthracycline targeting topoisomerase II	II	^Citation219
	Gemcitabine	Nucleoside analog targeting S phase	III	^Citation220
Epigenetic changes	5-Fluoro-2-deoxycytidine with tetrahydrouridine	Inhibition of DNA methylation/cytosine deamination	II	^Citation129
	Romidepsin	HDAC inhibitor	I	^Citation128
Other targets	BBI608	Cancer cell stemness	I, II	^Citation221
	Ganetespib	Inhibition of HSP90	I	^Citation125
	OGX-427	HSP27 inhibitor	II	^Citation126
	Veliparib	PARP inhibitor	I	^Citation222

Notes: Several studies used drugs in combination with other drugs as part of the traditional protocols for treatment of bladder cancer. This table does not represent all clinical trials sponsored by NCI, but a selected subset of trials with relevance to this review article.

Abbreviations: VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; mTOR, mechanistic target of rapamycin; mTORC, mTOR complex; PDL1, programmed death ligand 1; EGFR, epidermal growth factor receptor; BCG, bacillus Calmette–Guérin; NCI, National Cancer Institute; HDAC, histone deacetylase; PARP, poly ADP ribose polymerase. FGFR, fibroblast growth factor receptor; MEK, mitogen-activated protein kinase kinase; PI3K, phosphatidylinositol-3-kinases; HER2, human epidermal growth factor receptor 2; HLA-A2, human leukocyte antigen A2; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; HSP, heat shock protein.

Table 3 Advantages and disadvantages of animal models of bladder cancer

Type	Mechanism	Advantages	Disadvantages	Remarks
Chemically induced mice model	Induced by carcinogens: BBN, FANFT, and MNU	Provides information about the risk of chemical exposure	Low-grade tumors and low rates of metastasis Tumor induction depends on carcinogen and dosage	Studies to validate the effects of the environmental agents and for evaluation of molecular mechanisms during carcinogenesis
Genetically engineered mice model	Induced by cloning oncogenes and/or deleting tumor-suppressing genes	Provides information on the role of specific genes such as oncogenes and tumor suppressors	Homogeneous population of cancer cells	Studies to evaluate the effects of specific genes for bladder tumorigenesis Studies to test novel therapeutic, imaging, or preventive agents
Xenogeneic mice model	Induced by implanting bladder cancer cells, eg, human into immune-deficient mouse	Tumors are of nonrodent origin eg, human	Immune response cannot be assessed Homogeneous population of cancer cells	Studies to test novel therapeutic, imaging, or preventive agents
Syngeneic mice model	Induced by implanting rodent bladder cancer cells into immune-deficient mouse	Tumor microenvironment is same as the tumor is of rodent origin Tumors induced are of rodent origin	Homogeneous population of cancer cells	To test novel therapeutic, imaging, or preventive agents
Orthotopic mice model	Induced by implanting the bladder cancer cells into bladder	Mimic human bladder cancer behavior as microenvironment is closer to natural conditions	High morbidity of mice connected with the surgery of the bladder cancer cells implantation Homogeneous population of cancer cells	To test novel therapeutic, imaging, or preventive agents
Heterotopic mice model	Induced by implanting the bladder cancer cells at the different sites/organs such as bladder, usually subcutaneous	Technically simple model Tumor can be noninvasively detected	Inoculation site/organ is different, thereby the tumor microenvironment is altered Homogeneous population of cancer cells	To test novel therapeutic, imaging, or preventive agents
Companion animals with bladder cancer	Spontaneously occurring bladder cancer in dogs and cats	Naturally occurring heterogeneous population of cancer cells More similar biological and histological appearance to human cancer response to cytotoxic agents Shorter overall life span and more rapid disease progression	More costly than rodent model	To test novel therapeutic, imaging, or preventive agents for papillary and muscle-invasive bladder cancer Epidemiological studies

Abbreviations: BBN, N-butyl-N-(4-hydroxybutyl) nitrosamine; FANFT, N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide; MNU, N-methyl-N-nitrosourea.

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