Pathway Profiling and Rational Trial Design for Studies in Advanced Stage Cervical Carcinoma: A Review and a Perspective

Table 2

Potential biomarkers according to pathway.

Pathway activation	Reagents	Diagnostic or predictive biomarkers under scrutiny
PI3K/PTEN*	PI3K inhibitors: PI103, BGT226 mTor inhibitors: temsirolimus, everolimus, ridaforolimas; AKT inhibitors: perifosine, GSK690693 and MEK inhibitors	? pERK
Ras/raf pathway**	Ras inhibitors: tipifanib, lonafnaib; Raf inhibitor: sorafenib,PLX4032; MAPK inhibitor: AZD6244,XL518	tbd
HIF-1𝛼 (angiogenesis)	Bevacizumab, VEG105281, Brivanib, Sunitinib, AZD2171; HIF1𝛼 inhibitor: Adaphostin	Tbd
G1 checkpoint	Checkpoint inhibitor: MK1775***; ****? Retinoic acid and Topotecan	? p53, p63, p73; ? Wee-1, Myt1, ChK1, CDC2
Apoptosis*****	? Anti HPV vaccine indicated here	? p53, p63, p73; ? Inactivation of p15; ± RB,bcl-xl
DNArepair: homologous recombination deficient	PARP inhibitors	? DNA damage control deficiency/Homologous recombination; BRCA2 mutation (rare)
Jak/stat	? PV-701 (oncolytic virus) targets interferon; pathway defects which are induced by HPV E6 and E7	? IL8 (−); ? B cell signature (+); ? T regulatory cells (−)
TGF 𝛽	?	?IL10, TGF 𝛽
Adhesion	?	Tbd
Hedgehog	BMS-83392, IPI 926, LDE225, LEQ 506, GDC-0449, PF 04449913, TAK 441,	Tbd
Wnt/𝛽 Catenin******	Wnt1, Wnt2: neutralizing antibodies AINS, Vit D; PKF115-584, PKF222-815, CPG049090; NSC668036; Oncolytic adenoviruses modified to target Tcf-𝛽 Catenin; Antisense Avi-4126 targets end product c-myc
Notch	Neutralizing Antibodies against ligand	Tbd, ? AKT
—	Farletuzumab	Folate receptor
—	Folate receptor coupled to vinca drug	Folate receptor
Neighboring cells	Active on tumour micro-environment	Tbd
Multi pathway inhibitors	Pazopanib******	Tbd

*PIK3 amplification or mutational activation or PTEN loss. Activation of the PIK3/AKT/mTOR pathway was associated with a worse prognosis and chemoresistance in cervical cancers [78].
“?” means not validated.
**Ras/raf pathway alterations in colon cancer render these tumours resistant to an EGFR inhibitor. Ras inhibitors such as Tipifanib or lonafanib did not show relevant clinical activity in phase II and III studies in various tumour types [79] and may be worth assessing again in single and dual targeting in selected preclinical models. ***E6 mediated inactivation of p53 upregulates VEGF and angiogenesis. ****Retinoic acid and topotecan may be useful in tumours with checkpoint activation [80]. *****There is evidence that human papillomavirus infection enhances phosphorylation of retinoblastoma protein and decreases apoptosis in a particularly aggressive type of squamous cell carcinoma of the uterine cervix [20–23]. ******Wnt/𝛽 Catenin inhibition: by antibodies [81–83], AINS, [84–86], VitD3 [87], or small molecules [88–90] or oncolytic viruses [91]. Also antisense, molecule to end product c-myce [92].