Cervical cancer therapies: Current challenges and future perspectives

Abstract

Cervical cancer is the fourth most common female cancer worldwide and results in over 300 000 deaths globally. The causative agent of cervical cancer is persistent infection with high-risk subtypes of the human papillomavirus and the E5, E6 and E7 viral oncoproteins cooperate with host factors to induce and maintain the malignant phenotype. Cervical cancer is a largely preventable disease and early-stage detection is associated with significantly improved survival rates. Indeed, in high-income countries with established vaccination and screening programs it is a rare disease. However, the disease is a killer for women in low- and middle-income countries who, due to limited resources, often present with advanced and untreatable disease. Treatment options include surgical interventions, chemotherapy and/or radiotherapy either alone or in combination. This review describes the initiation and progression of cervical cancer and discusses in depth the advantages and challenges faced by current cervical cancer therapies, followed by a discussion of promising and efficacious new therapies to treat cervical cancer including immunotherapies, targeted therapies, combination therapies, and genetic treatment approaches.

Keywords: Cervical cancer; Combination therapy; HPV E6/E7 oncoproteins; HPV therapeutic Vaccines; Immune checkpoint inhibitors; Targeted therapy.

Fig. 1

Anatomical location of cervical cancer origin and progression from a normal cervix to invasive squamous cell carcinoma mediated by HPV. A) Anatomical diagram representing the female reproductive organs. B) Schematic representation of HPV infection and cervical cancer development. Post infection, HPV oncoproteins are overexpressed and play key roles in altering host cellular function. This results in precursor lesions, cervical intraepithelial neoplasia, which progresses over time to invasive cancer. Adapted from the World Cancer Report, 2014, The International Agency for Research on Cancer [152].

Fig. 2

Overview of the management and treatment of cervical cancer based on stage of disease. Interventions written in orange refer to surgical, green refer to radiotherapy and blue refer to chemotherapy based treatment options. PLND, pelvic lymph node dissection; SLN, sentinel lymph node biopsy; CRT, chemoradiotherapy; RT, radiotherapy. Adapted from Marth et al. (2017). [46]. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

Simplified Diagram of the role of Wee1 and the Wee1 inhibitor, MK-1775, in the cell cycle. WEE1 is overexpressed in various tumour cells with replication stress DNA damage, including cervical cancer tumours. Wee1 inhibitors, for example MK-1775, abrogate G2 arrest by increasing the activity of Cyclin B/Cdk1/Cdk 2, leading to cells with unrepaired DNA damage to enter into mitosis and undergo mitotic catastrophe. Processes shown in red are as a result of/affected by MK-1775 [98,99]. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 4

Therapeutic agents targeting biological pathways and their main molecular targets in various stages of cervical cancer.

Fig. 5

Schematic diagram showing mechanisms by which HPV E6 and E7 can be targeted in cervical cancer by A) CRISPR/Cas9 and B) RNA interference (RNAi). PAM, protospacer-adjacent motif; AAV, adeno-associated virus.