• Triple Helix

Inhibition at its Finest

Writer: Bobby Zhu '26

Editor: Jason Johnston '23


Imagine a disease that not only spreads to other areas of the body but can also mutate to adapt to the available treatments. Now, imagine you only have 5 years left to live because of such a disease [1]. Adding on the fact that ovarian cancer causes more deaths than other other cancer of the female reproductive systems, victims of this illness are stuck between 5 years and a hard place [2]. As such, the need to fight against this disease is dire and different methods have been developed to target it.


First Line of Defense

Cisplatin chemotherapy was used by physicians beginning in the 1980s as a front-line defense against ovarian cancer [3]. Cisplatin was used because of its ability to bind to DNA, inhibiting DNA replication and transcription [4]. As a result, these cancerous cells would not be able to divide, as they could not double their DNA to form a second cell. Also, with DNA transcription being compromised, these cells lacked the capability to produce proteins, which are important to carry out the living functions of the cell. Therefore, this treatment was a great way to prevent the cell from propagating further through the body.


Unfortunately, due to cancer’s ability to continue mutating through corrupted DNA replication, ovarian cancer cells were able to develop resistance against chemotherapy. They did so by limiting their uptake of cisplatin or by pumping cisplatin out [5]. It’s as if someone realized candy was bad for them so they chose to eat less candy or spit the candy out before it could have an effect on them. Correspondingly, these cancer cells persisted in the host body and now new drugs have been investigated to target and destroy them.


PARPi

One of the new techniques that have been developed to destroy ovarian cancer is Poly ADP-Ribose Polymerase Inhibition (PARPi). The “Poly ADP-Ribose” stands for the multiple molecules called ADP-Ribose that are attached to DNA by the polymerase. By attaching these Poly-ADP Ribose groups, DNA repair proteins are recruited to the site of damage and help repair the DNA accordingly. However, by inhibiting these Poly ADP-Ribose polymerases, the recruitment of DNA repair proteins to the sites of DNA damage can be halted [6]. As these DNA damages accumulate, many vital functions of the cell become impaired and the cell dies as a result.


While early trials of this treatment had promising results, problems arose regarding PARPi. For one, there are limitations to who can use this treatment. Only people who have ovarian cancer because of BRCA1/BRCA2 mutations are eligible as these mutations cause them to lack homologous repair. Homologous repair is a DNA repair process that can cover for the lack of DNA repair proteins when Poly ADP-Ribose Polymerases are inhibited; it is essentially a backup mechanism when the main DNA repair process is compromised. Researchers were able to utilize the lack of homologous recombination repair in ovarian caner cells by preventing these cells from healing themselves when crucial parts of DNA are damaged. Unfortunately, when patients relapse, their cancer cells regain the homologous repair mechanism, making PARPi ineffective as a treatment.


PARGi

Due to cancer cells constantly finding ways to evade treatment, researchers developed a new method of inducing cell death. This treatment was Poly ADP-Ribose Glycohydrolase Inhibition, which is similar to PARPi in that it prevents DNA repair. However, the difference lies in the inclusion of glycohydrolase, a protein with the capability to remove other proteins from certain molecules. In the case of PARGi, inhibition of glycohydrolase prevents the DNA repair proteins that have already been recruited from leaving the DNA that they just repaired. Now, with these repair proteins stuck to the DNA, the cell cannot affect more DNA repair since most of the repair proteins are already bound to the DNA. In addition, DNA replication is inhibited because the repair proteins act as roadblocks to the proteins that cause replication [7]. As such, the cell is stuck in a purgatory-like state where it cannot do anything but exist as that one cell. With the ability to metastasize gone, ovarian cancer becomes a cluster of cells fated to die at the end of their lifespan.


Future Directions

While PARGi is currently a strong technique in fighting ovarian cancer, it is likely that cancer cells will find a way around it. Consequently, research is currently being conducted in other areas, like glutamine metabolism, in hopes of finding additional treatments to cancer before it builds resistance. In fact, cancer cells are surprisingly glutamine dependent, and destroying the connection between glutamine and energy metabolism could have potential benefits in preventing cancer cells from metastasizing [8]. In combination with PARGi, such a treatment may lead to positive results for ovarian cancer patients. So while ovarian cancer is evasive, human ingenuity and scientific developments allow us to be at the forefront of medicine.

 

References

  1. Stewart C, Ralyea C, Lockwood S. Ovarian cancer: An integrated review [Internet]. Seminars in Oncology Nursing. W.B. Saunders; 2019 [cited 2022 Nov 6]. Available from: https://www.sciencedirect.com/science/article/pii/S0749208119300129

  2. Davis A, Tinker AV, Friedlander M. "platinum resistant" ovarian cancer: What is it, who to treat and how to measure benefit? [Internet]. Gynecologic Oncology. Academic Press; 2014 [cited 2022 Nov 6]. Available from: https://www.sciencedirect.com/science/article/pii/S0090825814002029

  3. First-line treatment of advanced ovarian cancer: Current research and perspectives [Internet]. Taylor & Francis. [cited 2022 Nov 6]. Available from: https://www.tandfonline.com/doi/full/10.1586/era.09.167

  4. Salerno D, Beretta GL, Zanchetta G, Brioschi S, Cristofalo M, Missana N, et al. Platinum-based drugs and DNA interactions studied by single-molecule and bulk measurements [Internet]. Biophysical journal. The Biophysical Society; 2016 [cited 2022 Nov 6]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880801/#:~:text=Platinum%2Dcontaining%20molecules%20are%20widely,and%20transcription%20are%20severely%20hampered

  5. Davis A, Tinker AV, Friedlander M. "platinum resistant" ovarian cancer: What is it, who to treat and how to measure benefit? [Internet]. Gynecologic Oncology. Academic Press; 2014 [cited 2022 Nov 6]. Available from: https://www.sciencedirect.com/science/article/pii/S0090825814002029

  6. Davis A, Tinker AV, Friedlander M. "platinum resistant" ovarian cancer: What is it, who to treat and how to measure benefit? [Internet]. Gynecologic Oncology. Academic Press; 2014 [cited 2022 Nov 6]. Available from: https://www.sciencedirect.com/science/article/pii/S0090825814002029

  7. Harrision D, Gravells P, Thompson R, Bryant HE. Poly(ADP-ribose) glycohydrolase (PARG) vs. poly(adp-ribose) polymerase (PARP) – function in genome maintenance and relevance of inhibitors for anti-cancer therapy [Internet]. Frontiers. Frontiers; 1AD [cited 2022 Nov 6]. Available from: https://www.frontiersin.org/articles/10.3389/fmolb.2020.00191/full

  8. Altman BJ, Stine ZE, Dang CV. From Krebs to clinic: Glutamine metabolism to cancer therapy [Internet]. Nature News. Nature Publishing Group; 2016 [cited 2022Nov12]. Available from: https://www.nature.com/articles/nrc.2016.71


2 views0 comments

Recent Posts

See All

Written by Yaffa Segal '26 Edited by Lisa Liong '25 Have you ever wanted to visit the Amazon Rainforest? Or go on safari? Imagine visiting the rich landscapes our natural world has to offer. Feel the