The Treatment of Clear Cell Ovarian Cancer with the Poly(ADP- Ribose) Polymerase (PARP1) Inhibitors (AG14361,Veliparib,Olaparib) as Chemosensitizers. The Treatment of Clear Cell Ovarian Cancer with PARP inhibitors
Abstract
Introduction: Most of those who get ovarian cancer will die from this cancer. Of the major types of ovarian cancer clear cell carcinoma is the most aggressive and chemoresistant type of epithelial ovarian cancer. Here the sensitivity of clear cell ovarian carcinoma to poly adenosine diphosphate [ADP-ribose] polymerase (PARP) inhibitors is tested. Methodology: Ovarian cancer cell lines were treated with the PARP inhibitors AG14361, Veliparib, or Olaparib alone or in combination with cisplatin, carboplatinum, doxorubicin, 5-fluorouracil (5-FU), gemcitabine and paclitaxel for 72 hours. The IC50 concentrations were calculated. Each experiment was replicated 10 times. Results: As single agents the PARP inhibition of ovarian cancer among serous, endometroid and clear cell ovarian cancer cell lines was similar. Clear cell ovarian cancer seemed particularly susceptible to chemo-sensitization by PARP inhibitors with paclitaxel, 5-FU, carboplatin, doxorubicin and/or cisplatin. Antagonism was seen with gemcitabine. Conclusion: PARP inhibitors are exceptional chemosensitizers of clear cell ovarian cancer to treatment with most standard chemotherapy agents.
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1) De Vita V, Lawrence T, Rosenberg S (2019). Cancer Principles & Practice of Oncology, Wolters Kluwer Publishers.
2) Reid BM, Permuth JB, Sellers TA. Epidemiology of ovarian cancer: a review, Cancer Biol Med, 2017;14(1):9-32.
3) Yamashita Y. Ovarian cancer: new developments in clear cell carcinoma and hopes for targeted therapy. Japanese Journal of Clinical Oncology 2015;45(5):405-407.
4) Mateo J, Lord CJ, Serra V, Tutt A, Balmana J, et al. A decade of clinical development of PARP inhibitors in perspective. Annals of Oncology DOI: 10.1093/anon/mdz192.
5) Farmer H, McCabe N, Lord CJ, Tutt A, Johnson DA. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005 Apr 14;434(7035):917-21.
6) Fong PC, Yap TA, Boss DS, Tutt A., Wu P, et al. Poly(ADP-ribose) polymerase inhibition: Frequent durable responses in BRCA carrier correlating with platinum –free survival. JCO 2010;28:2512-2519.
7) De Soto JA, Wang X, Tominaga Y et al. (2006). The inhibition of treatment of breast cancer with poly(ADP-ribose) polymerase (PARP-1) inhibitors. Int. J. Biol. Sci. 2006;2(4):179-185.
8) Calabrese CR, Almassy R, Barton S, et al. Anticancer chemosensitization and radiosensitization by the novel poly(ADP-ribose) polymerase-1 inhibitor AG14361. J Natl Cancer Inst. 2004;96:56-67.
9) McCabe N, Lord CJ, Tutt AN, Martin NM, Smith G, et al. BRCA2-deficient CAPAN-1 cells are extremely sensitive to the inhibition of Poly (ADP-Ribose) polymerase: an issue of potency. Cancer Biol Ther 2005 Sep;4(9):934-6. doi: 10.4161/cbt.4.9.2141
10) Spriggs DR, Longo DL. PARP Inhibitors in Ovarian Cancer Treatment. NEJM 2016 DOI 10.10.1056/NEJMe1612843.
11) Underhill C, Toulmonde M, Bonnefoi H. A review of PARP inhibitors: from bench to bedside. Ann Oncol. 2010 Jul 19.
12) Moore KN, Pothuri B, Monk B, Coleman RL. PARP inhibition in recurrent ovarian cancer. Clinical advances in hematology & Oncology. 2020;18:10
13) Campos SM, Ghosh S. A current review of targeted therapeutics for ovarian cancer. J. Oncology 2010:2010;149362.
14) Kummar S, Kinders R, Gutierrez ME, et al. Phase 0 clinical trial of the poly(ADP-Ribose) polymerase inhibitor ABT-888 in patients with advanced malignancies. JCO 2009;27:2705-2711.
15) Lau DH, Lewis AD, Ehsan MN, et al. Multifactorial mechanisms associated with broad cross-resistance of ovarian carcinoma cells selected by cyanomorpholino doxorubicin. Cancer Res. 1991; 51:5181-7.
16) Provencher DM, Lounis H, Champoux L, et al. Characterization of four novel epithelial cancer cell lines. In Vitro Cell. Dev. Biol. Anim. 36: 357-361, 2000.
17) Lounis H, Mes-Masson AM, Dion F et al. Mapping of chromosome 3p deletions in human epithelial ovarian tumors. Oncogene 17: 2359-2365, 1998.
18) Mukhopathy A, Elattar A, Cerbinskaite A. Development of a functional assay for homologous recombination status in primary cultures of epithelial ovarian tumor and correlation with sensitivity to poly(ADP-ribose) polymerase inhibitors. Clin Canc Res 2010;16:2344-2351.
19) Lee HY, Hong JH, Byun JH, Kim HJ, Baek SK. Clinical characteristics of clear cell ovarian cancer: A retrospective multicenter experience of 308 patients in South Korea. Cancer Res Treat. 2020 Jan;52(1):277-283.
20) Nagasawa S, Ikeda K, Horie-Inoue K, et al. Systematic Identification of characteristic genes of ovarian clear cell Carcinoma compared with high grade serous carcinoma based on RNA sequencing. International Journal of Molecular Sciences. 2019 Sep; 20(18): 4330.
21) Gentles L, Goranov B, Matheson, et al. Exploring the frequency of homologous recombination DNA repair dysfunction in multiple cancer types. Cancers 2019 Mar; 11(3): 354.
22) Press JZ, De Luca A, Boyd N. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities. BMC Cancer 2008:8:17-28.
23) Papa A, Caruso D, Strudel M et al., Update on Poly-ADP-ribose polymerase inhibition for ovarian cancer treatment. Journal of Translational Medicine. 2016;14:267.
24) Hennessy BT, Timms KM, Carey MS et al., Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly(ADP-ribose) polymerase inhibitors in ovarian cancer. JCO 2010;28:3570-3576.
25) Chang P, Jacobson MK, Mitchison TJ. Poly(ADP-ribose) is required for spindle assembly and structure. Nature 2004;432:645-649.
26) Gien LT, Mackay HJ. The emerging role of PARP inhibitors in the treatment of epithelial ovarian cancer. J Oncol. 2010;2010:151750.
27) Swisher EM, Sakai W, Karlan BY, et al. Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance. Cancer Res 2008;68:2581-2886.
28) Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, et al. Olaparib maintenance in platinum – sensitive relapsed ovarian cancer. 2012;366:1382-92.
Authors
de Soto, J. (2020). The Treatment of Clear Cell Ovarian Cancer with the Poly(ADP- Ribose) Polymerase (PARP1) Inhibitors (AG14361,Veliparib,Olaparib) as Chemosensitizers. : The Treatment of Clear Cell Ovarian Cancer with PARP inhibitors. Journal of Current Medical Research and Opinion, 3(11), 732–738. https://doi.org/10.15520/jcmro.v3i11.362
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