A Breakthrough in Cancer Treatment: How Successful is Antisense Oligonucleotides (ASOs)

 

Oligonucleotides

Small sequences of nucleic acids, either DNA or RNA that have many important applications in genetic research are called oligonucleotides.

 

Antisense oligonucleotides (ASOs)

These are designed in the laboratory having a specific sequence complementary to our sequence of interest. They bind to mRNA that has that specific sequence and can stop the translation of mRNA into proteins. Thus, they down-regulate the expression of mRNA in the cell. They can also inhibit the transport of mRNA from the nucleus into the cytoplasm for the translation of proteins. Moreover, these antisense oligonucleotides can also degrade the mRNA to which they bind, by activating the enzyme RNase H which is an endonuclease and cleaves mRNA thus degrading it.

The cancers that are caused by an abnormality in the Ras oncogene pathway can be treated with ISIS-2503 which is an ASO. It has a sequence that is complementary to 5-UTR of H-Ras gene mRNA. It binds them and silences the mRNA thus inhibiting the translation process. This drug has passed the Phase-1 clinical trials and is being administered to patients intravenously. it has proved to be a safe and effective drug for cancer patients and can be used in combination with chemotherapy for more effectiveness (Bartolucci et al., 2022).

 

Antisense Oligonucleotide Therapy (AOT)

The use of oligonucleotides started about 20 years ago. It has been proved that these can be used for the diagnosis and treatment of different diseases like neurodegenerative disorders and cancer by following different mechanisms of action. Their mechanism of action usually depends on the structure and composition. They can regulate the expression of any specific gene in the cell by binding upstream of that gene (Takakura et al., 2019).

 

The Success rate of Antisense Oligonucleotides in Cancer Therapeutics

Oligonucleotides are used as a therapeutic modality for many disorders. They have also proved to be effective against cancer in many preclinical and clinical trials. Some of the ASOs that are being tested clinically again different cancer types are mentioned below.

 

ISIS-2503

This is an antisense oligonucleotide that binds the complementary sequence in the 5-end untranslated region of the H-Ras gene. Most cancers result from mutations in the Ras oncogene. These can be treated by using this ASO. It will bind the UTR in the mRNA of H-Ras and block the synthesis of protein. Thus, inhibiting signaling in tumor cells and ultimately cells will not be able to survive. This has passed the phase-1 clinical trials and entered phase-2 trials on human patients. It is also proven safe and effective in cancer patients (Alberts et al., 2004).

 

OT-101

This is another antisense oligonucleotide that silences the secretion of TGF-β in tumor cells. TGF- β plays a very important role in the progression of different cancer types, particularly pancreatic cancer. OT-101 ASO binds the mRNA of TGF as it has a complementary sequence and silences the translation of TGF protein in the tumor cell. So that the tumor cannot increase its size (D’Cruz et al., 2018).

This ASO was given to 37 pancreatic cancer patients with an aggressive form of the disease and was seen that the overall survival of all these patients increased. Moreover, this was also tried on Glioblastoma patients and similar positive outcomes were observed in these patients as well. Thus, this ASO can be used in the treatment of aggressive cancers. It has passed clinical trials of phases 1 and 2 (Takakura et al., 2019).

 

AZD9150

STAT is a signal transduction and activator of transcription protein on which many cancer cells depend for the progression of tumors. AZD9150 is an oligonucleotide that has sequence similarity with STAT protein. Cancer cells have high expression and activity of STAT as compared to normal cells. So, targeting STAT for the treatment can be a good option. Clinical trials were performed on patients with leukemia and lung cancers, and a reduction in tumor size was observed. This ASO has tumor-suppressive activity when given to cancer patients. For neuroblastoma patients, it is observed that when this ASO is given in combination with chemotherapy, it has effective outcomes.

 

AEG-35156

XIAP X-linked inhibitor of apoptosis is upregulated in the cancer cells and helps them to escape apoptotic cell death. Thus, making the survival of cancer cells possible. AEG-35156 is an antisense oligonucleotide that targets XIAP in tumor cells and decreases the threshold of apoptosis making cells more prone to the apoptotic process. It is observed in clinical trials that this ASO increases the expression of tumor necrosis factor TNF and ligand-mediated apoptosis in patients with pancreatic cancer. 14 patients were given a dose of AEG-35156 and tolerance to the tumor was observed in them during the clinical trial.

 

OGX-427

Heat shock protein 27 plays a crucial role in almost all types of cancers. It is highly upregulated in tumors and is involved in the folding of proteins. Proper folding of proteins is important to play their normal function in the cell. When HSP-27 is upregulated, the expression of many proteins is also increased in the cell which will help the cancer cells to proliferate indefinitely and survive for a longer period of time. So, targeting this HSP-27 can be an important therapeutic modality for different cancer types.

During phase 1 clinical trials, patients with pancreatic cancer were given this ASO and it was observed that the progression of the tumor was inhibited in these patients. Moreover, it was also given to patients who show resistance to gemcitabine which is a chemotherapeutic drug. In such patients, OGX-427 increases the sensitivity of gemcitabine and no resistance was observed later (Meslar, 2020).

 

Aptamers

Aptamers are single-stranded oligonucleotides having sequence specificity to bind the target protein. They inhibit the function of the target protein by binding its 3D structure in the cell. Aptamers have been found to be very crucial for the suppression of many oncogenes in the cell.

PAUF is a protein that is involved in the progression of cancer in pancreatic cancer patients. P12FR2 is an aptamer that is designed in the laboratory and binds PAUF in pancreatic tumor cells. It inhibits the physiological action of this protein and suppresses the progression of tumors in patients. It has passed clinical trials. They will hopefully prove to be one of best therapies against cancer.

 

Conclusion

Oligonucleotides are DNA or RNA sequences that can bind mRNA or proteins in the cell and can suppress their activities. These are being used in many disorders for the cure. In cancer, they are also making the way for treatment. Many oligonucleotides have been proven safe and effective against different cancer types in preclinical and clinical trials. They have oncogenic suppressive activities in cancer cells. And inhibit the progression of cancer. They also make the survival of tumor cells difficult. Many examples of oligonucleotides have been discussed in the article that can be used against cancer.

 

References

Alberts, S. R., Schroeder, M., Erlichman, C., Steen, P. D., Foster, N. R., Moore, D. F., Rowland, K. M., Nair, S., Tschetter, L. K., & Fitch, T. R. (2004). Gemcitabine and ISIS-2503 for patients with locally advanced or metastatic pancreatic adenocarcinoma: A North Central Cancer Treatment Group phase II trial. Journal of Clinical Oncology, 22(24), 4944–4950. https://doi.org/10.1200/JCO.2004.05.034 https://sci-hub.hkvisa.net/10.1056/NEJMra1404198

 

Bartolucci, D., Pession, A., Hrelia, P., & Tonelli, R. (2022). Precision Anti-Cancer Medicines by Oligonucleotide Therapeutics in Clinical Research Targeting Undruggable Proteins and Non-Coding RNAs. Pharmaceutics, 14(7). https://doi.org/10.3390/pharmaceutics14071453

D’Cruz, O. J., Qazi, S., Hwang, L., Ng, K., & Trieu, V. (2018). Impact of targeting transforming growth factor β-2 with antisense OT-101 on the cytokine and chemokine profile in patients with advanced pancreatic cancer. OncoTargets and Therapy, 11, 2779–2796. https://doi.org/10.2147/OTT.S161905 https://sci-hub.hkvisa.net/10.2147/OTT.S161905

 

Meslar, E. (2020). Pancreatic adenocarcinoma. JAAPA : Official Journal of the American Academy of Physician Assistants, 33(11), 50–51. https://doi.org/10.1097/01.JAA.0000718300.59420.6c

Takakura, K., Kawamura, A., Torisu, Y., Koido, S., Yahagi, N., & Saruta, M. (2019). The clinical potential of oligonucleotide therapeutics against pancreatic cancer. International Journal of Molecular Sciences, 20(13). https://doi.org/10.3390/ijms20133331