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Published on: April 20, 2018
Molecular approaches to cervical cancer therapy
Luis M Alvarez-Salas1, Joseph A DiPaolo
1Departamento de Genética y Biologia Molecular, CINVESTAV, México.
Abstract:
Cervical cancer is the second most common malignancy in women worldwide. Two HPV strains, HPV-16 and 18, occur in the 70% of untreated cancers. Expression of viral oncogenes E6 and E7 disrupt the cell cycle by interfering with p53 and p107(Rb). It is known that HPV infection is necessary but insufficient to cause malignancy. Furthermore, persistence of HPV-16 or 18 in women does not necessarily result in cancer. Persistence indicates the importance of other factors for malignant conversion of high-grade HPV infection. The multi-step cervical carcinogenesis process is amendable to molecular therapeutics such as therapeutic nucleic acids (TNAs). TNA-based therapies for cervical carcinoma include ribozymes, antisense oligonucleotides (AS-ODNs) and small interfering RNAs (siRNAs). In vitro experiments with TNAs successfully inhibited E6/E7 expression and caused induction of apoptosis and/or senescence in cervical carcinoma cells. Early ribozyme and AS-ODN approaches showed promise as therapeutic moieties for cervical cancer. Despite the very high in vitro efficiency of siRNA-based therapies they present the same issues that burdened clinical development of ribozymes and AS-ODNs. These issues include intracellular target accessibility, specificity and delivery. Ribozymes are useful for functional genomic studies including diagnosis. Moreover, AS-ODNs appear better suited for clinical protocols because recent advances in nucleic acid chemistry allow higher cell uptake with very low off-target effects leading to actual AS-ODNs clinical applications. By using combined treatments with multiple targets it will be possible to apply TNAs directly to the cancerous cervix to destroy viral RNA and obliterate the tumor.
Insights
Therapeutic nucleic acids (TNAs) show promise for treating cervical cancer by inhibiting human papillomavirus (HPV) oncogenes. Antisense oligonucleotides (AS-ODNs) are particularly suited for clinical application due to improved delivery and specificity.
Area of Science:
- Oncology
- Molecular Biology
- Virology
Background:
- Cervical cancer is a major global malignancy, with HPV-16 and 18 strains implicated in 70% of cases.
- HPV infection alone is insufficient for malignancy; persistent infections and other factors drive carcinogenesis.
- Therapeutic nucleic acids (TNAs) offer a molecular approach to target the multi-step cervical carcinogenesis process.
Purpose of the Study:
- To evaluate the potential of TNAs, including ribozymes, antisense oligonucleotides (AS-ODNs), and small interfering RNAs (siRNAs), as therapeutics for cervical cancer.
- To assess the efficacy of TNAs in inhibiting viral oncogene expression and inducing apoptosis or senescence in cervical cancer cells.
- To compare the clinical suitability of different TNA modalities, focusing on delivery, specificity, and off-target effects.
Main Methods:
- In vitro experiments utilizing TNAs to target HPV E6/E7 oncogene expression.
- Assessment of TNA-induced apoptosis and/or senescence in cervical carcinoma cell lines.
- Evaluation of TNA characteristics such as intracellular target accessibility, specificity, and delivery mechanisms.
Main Results:
- TNAs demonstrated successful inhibition of HPV E6/E7 expression in vitro.
- TNA treatment led to the induction of apoptosis and/or senescence in cervical carcinoma cells.
- While siRNAs showed high in vitro efficiency, they share delivery and specificity challenges with earlier ribozyme and AS-ODN approaches. AS-ODNs show promise due to advances in nucleic acid chemistry.
Conclusions:
- TNAs, particularly AS-ODNs, represent a promising therapeutic strategy for cervical cancer.
- Advances in AS-ODN chemistry enhance cell uptake and reduce off-target effects, making them suitable for clinical development.
- Combined TNA treatments targeting multiple viral RNAs could offer a direct method for eradicating HPV and tumors in the cervix.
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