Combatting platinum resistance in ovarian cancer

Ovarian cancer is the deadliest gynaecologic cancer and the fifth-leading cause of cancer-related deaths among women (1, 2). Commonly known as “The Whispering Disease” (3, 4), the symptoms of ovarian cancer are often difficult to detect in its early stages; symptoms can be very subtle, completely absent or misinterpreted as other benign conditions (5). This, in part, results in many patients being diagnosed at advanced stages of the disease, by which time the tumour has metastasised and is unfortunately far more challenging to treat (6). 

Although there have been significant developments in the treatment of ovarian cancer in recent years, survival rates have only modestly improved — just 48% of ovarian cancer patients will survive 5 years after diagnosis (7, 8). As such, there is an urgent need for more efficacious treatment options for patients. 

In addition to difficult detection of ovarian cancer, another major challenge for the clinical management of the disease is platinum resistance, whereby the cancerous cells become resistant to platinum-based chemotherapy, rendering the therapy ineffective (9). Platinum-based chemotherapy is a standard first-line chemotherapy, and while 70% of patients initially respond well to this treatment, a striking 80% will experience a recurrence of the disease at some stage (10, 11). Platinum resistance can result in the disease returning as little as six months after treatment and devastatingly limits a patient’s response to further treatment, ultimately, impeding their survival (12). A such, combatting — or preventing — platinum resistance remains a key unmet medical need in the management of ovarian cancer (13). Fortunately, there are emerging treatment options making noise in the landscape of the whispering disease, which may be able to address this. 

The exact mechanisms underlying platinum resistance in ovarian cancer are yet to be fully unravelled, however, a role of a complex interaction of various DNA repair pathways has been posited (11). Ongoing research is striving to delineate these mechanisms and elucidate potential therapeutic targets, and a number of novel drug candidates and drug combinations —which are thought to counteract these mechanisms — are currently under clinical investigation. 

One such novel candidate has generated promising results in a recent study, and is comprised of two key components: i) a modified platinum-based chemotherapy; and, ii) a molecule called texaphyrin which directly delivers the chemotherapy to the cancerous cells. This targeted drug delivery system avoids damage to healthy cells, thereby minimising the likelihood of the toxic and debilitating side effects of platinum-based chemotherapy which may otherwise compromise optimal dosing of the drug, and hence the efficacy of the treatment (14). Importantly, experimental studies support that the candidate can counteract a key mechanism of platinum resistance (15).

There are also ongoing and emerging clinical trials investigating the administration of approved platinum-based drugs in combination with new candidates as a method to overcome platinum resistance (16, 17). For example, niraparib (a platinum-based chemotherapy) in combination with dostarlimab (an investigational monoclonal antibody designed to treat cancer) has demonstrated promising anti-platinum-resistant effects in pre-clinical studies, and a phase 2 study of the efficacy and safety of this combination is currently underway (17, 18). 

If approved, these anti-platinum-resistant therapeutic options are set to revolutionise the treatment landscape for ovarian cancer. Outcomes of ongoing clinical trials must be heard and understood by healthcare professionals involved in the clinical management of this whispering disease to improve health outcomes for their patients: it could be within the next 5–10 years that we see platinum-resistant tumours finally silenced by a treatment. 

Here at The Corpus, we are looking to develop a new ovarian cancer programme that will focus on unmet educational needs in this therapy area, such as understanding emerging therapies to overcome platinum resistance. If you would like to find out more about how you can support programmes in this therapy area, or any other therapy area, please contact us at communications@the-corpus.com.

References: 

1. Coburn, S.B. et al. (2017) International patterns and trends in ovarian cancer incidence, overall and by histologic subtype. International Journal of Cancer, 140(11), pp. 2451-2460.  
2. https://www.cancer.org/cancer/ovarian-cancer/about/key-statistics.html#:~:text=Ovarian%20cancer%20ranks%20fifth%20in,is%20about%201%20in%20108. Accessed March 2021 
3. Blewitt, K. (2010). Ovarian Cancer: Listen to the disease that whispers. Nursing, 40(11), p. 24-31  
4. Jasen, P. (2009). From the “silent killer” to the “whispering disease”: ovarian cancer and the uses of metaphor. Medical History, 53(4), pp. 489-512  
5. Committee on the State of the Science in Ovarian Cancer Research; Board on Health Care Services; Institute of Medicine; National Academies of Sciences, Engineering, and Medicine. (2016). ‘Diagnosis and Treatment’, in Ovarian Cancers: Evolving Paradigms in Research and Care. Washington, DC: The National Academies Press, pp. 147-213  
6. Doubeni, C.A., Doubeni, A.R.B. and Myers, A.E. (2016). Diagnosis and management of ovarian cancer. American Family Physician, 93(11), pp. 937-944  
7. Timmermans, M. et al. No improvement in long-term survival for epithelial ovarian cancer patients: A population-based study between 1989 and 2014 in the Netherlands. European Journal of Cancer, 88, pp. 31-33  
8. American Cancer Society. Cancer Facts and Figures 2020.  https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf. Accessed March 2021 
9. Davis, A., Tinker, A.V. and Friedlander, M. (2014). “Platinum-resistant” ovarian cancer: what is it, who to treat and how to measure benefit? Gynecologic oncology, 133(3), pp. 624-631 
10. Muñoz-Galván, S. et al. (2019). New markers for human ovarian cancer that link platinum resistance to the cancer stem cell phenotype and define new therapeutic combinations and diagnostic tools. Journal of Experimental and Clinical Cancer Research, 38(234),  
11. Damia, G. and Brogini, M. (2019). Platinum resistance in Ovarian Cancer: Role of DNA Repair. Cancers (Basel), 11(1), pp. 19 
12. https://www.cancerresearchuk.org/about-cancer/ovarian-cancer/treatment/if-your-cancer-comes-back. Accessed March 2021 
13. Blagden, S.P. and Nicum, S. (2021). A source of hope for platinum-resistance cancer? The Lancet, 397(10271), pp. 254-256  
14. Thibaud, G. et al. (2020). Oxaliplatin Pt(IV) prodrugs conjugated to gadolinium-texaphyrin as potential antitumor agents. PNAS, 117(13), pp. 7021-7029  
15. Arambula, J.F., Sessler, J.L. and Siddik, Z.H. (2012). A texaphryin-oxaliplatin conjugate that overcomes both pharmacologic and molecular mechanisms of cisplatin resistance in cancer cells. Medchemcomm, 3(10), pp. 1275-1281  
16. Tomao, F. et al. (2017). Overcoming platinum resistance in ovarian cancer treatment Expert Opinion Pharmacotherapy, 18(14), pp. 1443-1455  
17. Randall, L.M. et al. (2020). 883TiP MOONSTONE/GOG-3032: A phase II, open-label, single-arm study to evaluate the efficacy and safety of niraparib + dostarlimab in patients with platinum-resistant ovarian cancer, 31(4), pp. S646-S647  
18. https://clinicaltrials.gov/ct2/show/NCT03955471. Accessed March 2021