HomeENGLISH MAGAZINEFighting ovary cancer: DNA synthesis may be a more fruitful target than...

Fighting ovary cancer: DNA synthesis may be a more fruitful target than deemed before

Uterine cancer is the most common gynecological cancer in the United States, with over 60,000 cases diagnosed each year. The endometrioid subtype is the most common and generally responds well to targeted immunotherapies. In contrast, the serous uterine subtype has few genetic mutations that would make it a candidate for targeted therapies, and patients face rapid disease progression and poor prognosis. While uterine serous carcinoma accounts for only 10% of uterine cancers, it accounts for the majority of deaths. There is currently only one first-line chemotherapy for serous uterine cancer: the drug called carboplatin. This is why a team of scientists led by the University of Michigan Health Rogel Cancer Center investigated advanced options, and found that a class of FDA-approved drugs can effectively stop the highly aggressive type of serous uterine cancer . This will likely open a rapid path to new treatment strategies for deadly cancer with limited treatment options.

Collaborating with researchers at Case Western Reserve University and Memorial Sloan Kettering Cancer Center, the team showed that inhibitors of the enzyme ribonucleotide reductase, or RNR, affect two mutations in the gene that codes for the tumor suppressor PP2A, present up to 40% of serous carcinomas of the uterus. This new research has shown that the PP2A mutation is common in serous uterine cancer and a potential new treatment option has been found for these patients. PP2A is a so-called tumor suppressor (similar to the famous p53 gene), it blocks the growth of cancer by deactivating the process of protein phosphorylation, which is why it is called a phospho-protein phosphatase. Phosphorylation of proteins or enzymes is often associated with their activation. This is the case of the components of the transduction pathway known as MAP-kinase (ERK), necessary for cell replication, on which PP2A has a deactivating effect. And it is precisely in cases of oncogenic mutations that PP2A can no longer act as a “brake” on cell growth.

To begin, the researchers performed a high-throughput screening of 3,200 drug compounds against uterine serous cell samples from patients with recurrent cancer. The results showed that a family of anticancer drugs called ribonucleic reductase inhibitors killed the cancer cells that harbored the mutations. RNR is an enzyme necessary for DNA synthesis: without it the nucleotides cannot be converted into the form that enters the very constitution of DNA. RNR inhibitors have been known for many decades and interfere with the growth of cancer cells by blocking the formation of DNA. The first and still used is hydroxyurea, which is used in chronic myeloid leukemia, multiple myeloma and bone marrow disorder syndromes (myelodysplasia). The researchers then narrowed their attention to one of the pharmacological RNR inhibitors, clofarabine, and tested it in a mouse model of serous uterine cancer. Consistent with cell-based drug screening data of the American National Cancer Institute (NCI), clofarabine shrunk tumors in mice.

To further explore RNR inhibition as a potential therapeutic strategy for serous uterine cancer, the team performed a retrospective analysis of patients treated with another previously discovered RNR inhibitor, gemcitabine, as the next-line therapy for it. THis drug was also effective for serous ovary carcinoma subtype, compared to patients with the endometrioid subtype. The research team is now planning to begin a clinical trial of gemcitabine in patients with uterine serous carcinoma. They also plan to extend this work to other cancers that harbor PP2A mutations, including lung, colon and ovarian cancer. Although RNR inhibitors are not routinely used for uterine cancers, a retrospective analysis of patients treated with gemcitabine as second-line or later therapy revealed a trend for better outcomes in patients with the serous form treated with gemcitabine compared to patients with endometrioid histology. So it was also a past clinical experience that was not considered and rediscovered almost out of need for further study.

This is also demonstrated by the fact that already in 2011 a first study was published on how to inhibit the growth of uterine carcinoma with another RNR inhibitor, called triapine (code name NSC 663249 in the NCI chemical database). In that study, triapine sensitized uterine cancer tumor cells to radiation exposure and showed synergistic effect with cisplatin and carboplatin, which damage DNA with a radiation-like (radiomimetic) effect. Clinical trials have also later been conducted with this drug, alone and in association with platinum derivatives and radiotherapy. So far the results are promising and interested research groups are further investigating.

  • edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

O’Connor CM et al. Cancer Res 2021 Dec; 19872021.

Kim L et al. Internat J Mol Sci. 2021; 22(16):8693.

Kunos CA, Chu E et al. Front Oncol. 2017 Apr; 7:62.

Kunos CA et al. Gynecol Oncol. 2013; 130(1):75-80.

Kunos CA et al. Clin Cancer Res. 2010; 16(4):1298.

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento enzimaticamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (Leader of the R&D for the partnership CoFood s.r.l.) - Autore di articoli su informazione medica e salute sul sito www.medicomunicare.it (Medical/health information on website) - Autore di corsi ECM FAD pubblicizzati sul sito www.salutesicilia.it
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