J Gynecol Oncol.  2014 Jul;25(3):249-259. 10.3802/jgo.2014.25.3.249.

Beyond angiogenesis blockade: targeted therapy for advanced cervical cancer

• Eskander R
• Tewari KS

• KMID: 2130106
• DOI: http://doi.org/10.3802/jgo.2014.25.3.249

Abstract

The global burden of advanced stage cervical cancer remains significant, particular in resource poor countries where effective screening programs are absent. Unfortunately, a proportion of patients will be diagnosed with advanced stage disease, and may suffer from persistent or recurrent disease despite treatment with combination chemotherapy and radiation. Patients with recurrent disease have a poor salvage rate, with an expected 5-year survival of less than 10%. Recently, significant gains have been made in the antiangiogenic arena; nonetheless the need to develop effective alternate targeted strategies is implicit. As such, a review of molecular targeted therapy in the treatment of this disease is warranted. In an era of biologics, combined therapy with cytotoxic drugs and molecular targeted agents, represents an exciting arena yet to be fully explored.

Keyword

Angiogenesis; Recurrent cervical cancer; Targeted therapy

MeSH Terms

Angiogenesis Inhibitors/therapeutic use
Antineoplastic Agents/*therapeutic use
Female
Histone Deacetylase Inhibitors/therapeutic use
Humans
Molecular Targeted Therapy/*methods
Receptor, Epidermal Growth Factor/antagonists & inhibitors
Salvage Therapy/methods
Uterine Cervical Neoplasms/*drug therapy
Angiogenesis Inhibitors
Antineoplastic Agents
Histone Deacetylase Inhibitors
Receptor, Epidermal Growth Factor

Figure

• 

  Fig. 1 Cytoplasmic/traditional and nuclear modes of the epidermal growth factor receptor (EGFR) signalling pathway. The EGFR signalling pathway exerts its biological effects via two major modes of actions, namely, cytoplasmic/traditional (A) and nuclear (B) modes. (A) The cytoplasmic EGFR pathway is consisted of four major modules: PLC-γ-CaMK/PKC, Ras-Raf-MAPK, PI-3K-Akt-GSK and signal transducer and activator of transcriptions (STATs). Activation of these signalling modules often leads to tumorigenesis, tumour proliferation, metastasis, chemoresistance and radioresistance. (B) The nuclear EGFR pathway can be initiated by ligand binding and exposure to vitamin D, radiation, cisplatin, heat and H2O2. Following nuclear translocalization, nuclear EGFR interacts with DNA-binding transcription factors, E2F1 and STAT3, and activates expression of B-Myb and inducible nitric oxide synthase (iNOS), respectively. Nuclear EGFR also upregulates cyclin D1 gene expression. Increased expression of cyclin D1 and B-Myb contributes to accelerated G1/S cell cycle progression and, on the other hand, elevated iNOS is associated with tumour proliferation and metastasis. Upon DNA damage and oxidative/heat stress, EGFR enters the cell nucleus and interacts with DNA-PK, leading to DNA repair and radioresistance. Reprinted from Lo and Hung [23].

• 

  Fig. 2 The Notch signaling pathway and its roles in cancer metastasis. The Notch receptors are activated by the Delta-like and Jagged families of ligands expressed on adjacent cells. Upon γ-secretase-mediated proteolysis, NICD proteins translocate to the nucleus and bind to the DNA binding protein CSL, taking the place of the corepressors (CoRs). NICD forms a complex with the DNA binding protein CSL and coactivators (CoAs), leading to the transcriptional activation of Notch target genes. The activation of Notch signaling in tumor microenvironment could promote epithelial-mesenchymal transition (EMT), the anoikis-resistance of tumor cells and maintain the homeostasis of angiogenesis, the morphology of vasculatures and the self-renewal of cancer stem cells (CSCs). Reprinted from Hu et al. [54] with permission from Springer.

• 

  Fig. 3 The cancer chaperone Hsp90. Hsp90 plays a central role in supporting all of the six hallmark traits of cancer, suggested by Hanahan and Weinberg, by chaperoning a subset of client proteins as shown. CDK4, 6, cyclin-dependent kinase 4, 6; HIF-1α, hypoxia-inducible factor-1α; IGF-1R, insulin-like growth factor-1 receptor; IKK, inhibitor of kappa B kinase; MMP2, matrix metalloproteinase 2; RTK, receptor tyrosine kinase; VEGF, vascular endothelial growth factor. Reprinted from Koga et al. [63] with permission from International Institute of Anticancer Research.

• 

  Fig. 4 Mechanism for synthetic lethality in breast cancer susceptibility gene (BRCA) 1/2 deficient cancer. Poly ADR-ribose polymerase (PARP) inhibition produces tumor-selective synthetic lethaity. When PARP action is inhibited, SS are converted to double strand break (DSB) at replication. In cells with functional HR pathway, the DSB will be repaired. In cells with a dysfunctional HR pathway, as is the case with BRCA 1 and 2, the lesions go unrepaired and cell death ensues. HR, homologous recombination; SSB, single-strand break. Reprinted from Saijo [70].

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