The abnormal growth of cells in the colon or rectum, which are components of the large intestine, is referred to as colorectal cancer. When cancer cells from the primary site spread to other organs or tissues, it is known as metastatic colorectal cancer. This advanced stage of the disease poses substantial challenges and requires aggressive treatment approaches. The survival rates for these patients are, nevertheless, depressing due to the lack of effective treatments.
Medical research breakthroughs have produced ground-breaking treatments for several diseases. In recent years, researchers have started looking into the possibility of repurposing existing drugs to treat different conditions. Lamivudine, which is largely used to treat HIV/AIDS, is one such drug that is currently being examined to treat metastatic colorectal cancer [1,2].
Understanding lamivudine
Lamivudine, often commonly referred to as 3TC, is a member of the class of drugs known as nucleoside reverse transcriptase inhibitors (NRTIs), which inhibit the reverse transcriptase of retroviruses like HIV. The use of lamivudine in combination with other antiretroviral medications is now recommended for the treatment of HIV-1 infection as well as chronic hepatitis B (HBV) virus infection that is accompanied by active liver inflammation and signs of viral replication. Patients with HBV infections who receive anticancer chemotherapy may experience life-threatening complications both during and after the treatment. During and after chemotherapy, lamivudine and other antiretrovirals are used to stop the reactivation of HBV [1,3].
Additionally, research indicates that lamivudine sensitizes cancer cells to chemotherapy. Independent of chemotherapy or radiotherapy, lamivudine and other analogs with a similar mechanism of action directly benefit people with hepatitis B or HIV by preventing the development of cancer. Cancer treatment researchers are interested in this potential involvement [1].
Lamivudine and its mechanism of action
The combination of preclinical and clinical outcomes provides a path for the evaluation of NRTIs like lamivudine as a new class of anticancer therapeutics. It has been observed that lamivudine can decrease the migration of TP53-mutant colorectal cancer cell lines partially through a:
STING (stimulator of interferon genes)-dependent nucleic acid mechanism. STING pathway controls anti-viral responses, along with anti-tumor adaptive immunity.
reduction in S100A4 protein levels, which is a member of the S100 superfamily of calcium-binding proteins. S100A4 protein is linked to lymph node metastasis and poor prognosis in colorectal cancer.
Reduction of cytoplasmic dsDNA species and increased RNA: DNA hybrids from lamivudine induce DNA damage. These combined effects of lamivudine had antitumorigenic effects in mouse models and potential benefits to patients in a clinical trial. However, these mechanisms require further elucidation.
Furthermore, the lack of substantial dose-limiting toxicity of lamivudine in patients with metastatic colorectal cancer allows for the use of lamivudine or related compounds in combination with both conventional and cutting-edge cancer therapies in upcoming clinical trials to increase the effectiveness of these medications in colorectal cancer [1,3].
Emerging research and clinical trials
Colorectal cancer commonly exhibits retro transposition and altered RNA expression of repetitive sequences. This suggests that repeat activity has a functional role to play in the development of cancer. With the help of NRTIs, which are frequently used to treat viral infections, colorectal cancers that exhibit abundant repeat elements within a life cycle like a virus, can be therapeutically addressed.
In colorectal cancer preclinical models, it has been demonstrated that lamivudine targets the activity of these repetitive elements with a preference for p53-mutant cell lines. Additionally, NRTIs cause DNA damage and an interferon response that offer a novel anticancer therapeutic approach. Clinical trials have produced some encouraging results, even if the idea of employing lamivudine as an anti-cancer medication is still in its early phases [1,3].
A phase II clinical trial evaluated the safety and effectiveness of lamivudine in patients with p53 mutant metastatic colorectal cancer. The primary endpoint was not met by the trial. However, remarkably, stable disease was observed in 25% (8 of 32) patients on single-agent lamivudine with a median progression-free survival of 149 days (ClinicalTrials.gov Identifier: NCT03144804) [4].
Currently, further research is underway to investigate the potential benefits of lamivudine in metastatic colorectal cancer treatment.
Buoyant outlook
The potential repurposing of lamivudine, an HIV drug, as a treatment for metastatic colorectal cancer, is a fascinating area of research. Early studies have shown the anticancer activity of lamivudine, but it is important to consider that the research is still in its early stages. Thus, more detailed clinical trials are required to validate these findings. As research progresses, the possible role of lamivudine in slowing disease progression in metastatic colorectal cancer may become more clear.
References
1. Yang, J. et al. 'Safety and efficacy of pharmacotherapy containing INSTIs and chemotherapy drugs in people living with HIV and concomitant colorectal cancer'. AIDS Research and Therapy. (2022) 19(1), 45. DOI: 10.1186/s12981-022-00470-3.
2. García-Trejo, J.J. et al. 'Putative Repurposing of Lamivudine, a Nucleoside/Nucleotide Analogue and Antiretroviral to Improve the Outcome of Cancer and COVID-19 Patients'. Front Oncol. (2021) 11, 664794. DOI: 10.3389/fonc.2021.664794.
3. Rajurkar, M. et al. 'Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer'. Cancer Discovery. (2022) 12(6), 1462–1481. DOI: 10.1158/2159-8290.CD-21-1117.
4. 'A Phase 2 Study of Lamivudine in Patients With p53 Mutant Metastatic Colorectal Cancer - Full Text View - ClinicalTrials.gov' [https://classic.clinicaltrials.gov/ct2/show/NCT03144804].
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