Cervical cancer is the most prevalent gynecologic malignancy, accounting for over 600,000 cases worldwide each year. Currently, the majority of cervical cancer cases have a fatal prognosis and account for over 340,000 fatalities per year globally. The burden is most significant in underdeveloped nations with limited access to resources for appropriate screening and treatment. While there has been minimal progress in systemic therapy for patients with locally advanced cervical cancer, the addition of bevacizumab, pembrolizumab, cemiplimab, and the antibody-drug combination tisotumab vedotin has shown promising results in increasing overall survival.
The vast majority of patients around the world continue to lack access to expensive targeted agents. Therefore, it is crucial to expand research into cervical cancer and look into new opportunities. However, recent research has shed light on a promising candidate like nelfinavir in the fight against cervical cancer [1,2].
The drug nelfinavir, which was designed primarily as a protease inhibitor for the treatment of HIV/AIDS, is known to have radio-sensitizing properties. However, in recent years, interest in its potential for repurposing in cancer treatment has grown. Numerous preclinical research suggests that nelfinavir may also be utilized to treat cervical cancer. According to preclinical research, nelfinavir exhibits anti-cancer properties by targeting crucial cellular pathways involved in tumor growth and progression. Nelfinavir is expected to have anticancer effects through several pathways, including disruption of autophagy, apoptosis, induction of endoplasmic reticulum stress, and suppression of Akt signaling, angiogenesis, and cell invasion [2,3].
Radio sensitization effects of Nelfinavir
Radiation therapy is the most common treatment modality for cervical cancer. However, some tumors that exhibit radiation resistance limit the use of radiation therapy. Nelfinavir has demonstrated the ability to enhance the sensitivity of cancer cells to radiation, which may help patients with cervical cancer receive radiotherapy more effectively. Pre-clinical evidence suggests that nelfinavir achieves this radio sensitization by inhibiting Akt phosphorylation and subsequently downregulating the PI3K/Akt signaling pathway. This pathway is critical for cellular proliferation, migration, angiogenesis, overall growth, and survival. The combination of nelfinavir and radiation therapy presents new possibilities for more effective and specialized treatment techniques [2,3].
Nelfinavir alters autophagy
Autophagy, a process of cytoplasm recycling in which a cell degrades and eliminates old, damaged, or aberrant proteins and other substances in its cytoplasm, has been identified as a possible biological target for the treatment of cervical cancer. It has been found that nelfinavir alters autophagy. It works by burdening the autophagy process to reduce tumor cell survival and somewhat increase apoptosis. This targeted strategy might be significantly more advantageous than conventional cancer treatments in terms of minimizing harm to healthy tissues and reducing the side effects of conventional cancer treatments [3,4].
Ongoing and completed clinical trials
Although preclinical research has shown encouraging findings, clinical trials are necessary to confirm the efficacy and safety of nelfinavir in cervical cancer patients. Nelfinavir is being tested in several ongoing studies to determine how it affects the effectiveness of existing therapy, survival rates, and potential adverse effects. The outcomes of these trials will offer significant new information on the potential of nelfinavir as a cervical cancer treatment.
To find out whether nelfinavir works well as a cancer treatment agent, several clinical trials have been started or have already been completed. In most of the clinical trials, patients with cancers such as rectal cancer, non-small cell lung cancer, and glioblastoma, where chemoradiotherapy is a key treatment strategy, are being treated. To date, two phase I trials (NCT01485731 and NCT02363829) are completed and one recruiting phase III trial (NCT03256916) is ongoing with the use of nelfinavir to treat cervical cancer. Patients with locally advanced squamous cell cervical carcinoma were treated with a combination of twice-daily 1250 mg nelfinavir and cisplatin-based chemoradiotherapy in the phase I study, and both treatments were shown to be safe and tolerable .
Nelfinavir holds tremendous potential as a revolutionizing treatment for cervical cancer. It provides new hope in combating this devastating disease because of its capacity to stimulate apoptosis, alter autophagy, and enhance radiosensitivity. However, additional investigation is required to confirm its effectiveness and safety in clinical settings.
1. Polten, R. et al. 'Towards Novel Gene and Cell Therapy Approaches for Cervical Cancer'. Cancers. (2023) 15(1), 263. DOI: 10.3390/cancers15010263.
2. Chopra, S. et al. 'Concurrent chemoradiation and brachytherapy alone or in combination with nelfinavir in locally advanced cervical cancer (NELCER): study protocol for a phase III trial'. BMJ Open. (2022) 12(4), e055765. DOI: 10.1136/bmjopen-2021-055765.
3. I, R.C. et al. 'Drug repurposing as a potential source of innovative therapies in cervical cancer'. International Journal of Gynecologic Cancer. (2022), ijgc. DOI: 10.1136/ijgc-2022-003585.
4. Davis, M.-A. et al. 'Nelfinavir is effective against human cervical cancer cells in vivo: a potential treatment modality in resource-limited settings'. Drug Des Devel Ther. (2016) 10, 1837–1846. DOI: 10.2147/DDDT.S102241.