Possible drug targets found for HPV-linked cervical cancer
Researchers have identified some specific molecules and pathways as potential drug targets to treat women who have cervical cancer linked to Human Papillomavirus (HPV) infection.
Based on patient data and computational predictions, they suggest several transcription factors and other signalling proteins, which regulate processes like cell growth and division, could be targeted simultaneously by therapies.
Nearly 90% of cervical cancer cases occur in less developed countries, where the burden of disease is disproportionately high. It is the deadliest cancer for women, killing more than 300 000 women globally per year.
Before this study, the Cancer Genome Atlas Project, among others, mapped many of the genes and proteins involved in cervical cancer. On a molecular level, they revealed in detail how the landscape of a cancerous cervix differs from a healthy cervix.
This study sought to identify exactly how those differences arise; in other words, how the proteins and genes involved in cervical tumours are turned on, off, up or down. By identifying key molecules involved in the network that regulates these genes and proteins, researchers can develop drugs that block their specific pathways.
To identify these regulatory molecules and pathways, researchers from Zambia and South Africa compared genetic data from cervical cancer patients who were positive for HPV, cancer patients negative for HPV, as well as data from patients without cervical cancer. Once they identified significant differences in the HPV positive group, they used powerful software to predict the regulatory pathways and molecules involved.
Their main finding was that HPV affects pathways involved in cell growth and division, so the authors suggest that cervical cancer might respond to drugs that target these pathways. This supports existing clinical findings that cervical cancers exhibit a high therapeutic response to drugs that arrest cell cycle processes.
The researchers say more work is needed to find differences between the molecular pathways involved in different cancer subtypes.
Since almost 95% of cervical cancer cases are associated with persistent infection with high-risk HPV, uncovering how the disease interacts with molecules in the body is key to finding better therapies for women in Africa and the world.
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Cervical cancer has remained the most prevalent and lethal malignancy among women worldwide and accounted for over 250,000 deaths in 2019. Nearly ninety-five per cent of cervical cancer cases are associated with persistent infection with high-risk Human Papillomavirus (HPV), and seventy per cent of these are associated with viral integration in the host genome. HPV-infection imparts specific changes in the regulatory network of infected cancer cells that are of diagnostic, prognostic and importance. Here, we conducted a systems-level analysis of the regulatory network changes, and the associated regulatory proteins thereof, in HPV-positive cervical cancer. We applied functional pathway analysis to show that HPV-positive cancers are characterised by perturbations of numerous cellular processes, predominantly in those linked to the cell cycle, mitosis, cytokine and immune cell signalling. Using computational predictions, we revealed that HPV-positive cervical cancers are regulated by transcription factors including, SOX2, E2F, NANOG, OCT4, and MYC, which control various processes such as the renewal of cancer stem cells, and the proliferation and differentiation of tumour cells. Through the analysis of upstream regulatory kinases, we identified the mitogen-activated protein kinases; among others, MAPK1, MAPK3 and MAPK8, and the cyclin-dependent kinases; among others, CDK1, CDK2 and CDK4, as the key kinases that control the biological processes in HPV-positive cervical cancers. Taken together, we uncover a landscape of the key regulatory pathways and proteins in HPV-positive cervical cancers, all of which may provide attractive drug targets for future therapeutics.
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