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Ovarian cancer

Cancer of the ovaries accounts for about 4% of cancers in women, with approximately 235,000 cases worldwide in 2012ANCHOR. The five-year survival rates for ovarian cancer have doubled in the past 30 years and are now roughly 40%, although this depends on the age of the patient and stage of the cancerANCHOR ANCHOR ANCHOR. This is due to the greater use of platinum-based compounds and greater effectiveness in treating recurrent cancers.

Diagnosis
Treatments
Potential treatments
References

Diagnosis

A blood test for elevated levels of the protein CA125 is used to inform doctors if ovarian cancer is present and how it is responding to treatment. CA125 is a protein made by some ovarian cancer cells and it is the most common biomarker used for detecting ovarian cancer. As the test has a high false positive rate, it is generally not recommended for women with an average risk of ovarian cancer. It is often used for those with higher risk or are presenting symptoms consistent with the disease. CA125 was first discovered using a mouse monoclonal antibody in 1981. The protein was named cancer antigen 125 because it was the 125th antibody produced against the ovarian cancer cell line that was being studiedANCHOR.

For women with a family history of breast or ovarian cancer, doctors can offer tests for forms of genes that are linked to these cancers. The main genes associated with these are BRCA1 and BRCA2, which help to suppress tumours from developing and growing. The way this happens has been extensively studied and understood through experiments on miceANCHOR ANCHOR ANCHOR.

Treatments

The main treatments for ovarian cancer are carboplatin (Paraplatin) and Taxol (paclitaxel).

Taxol (paclitaxel) was one of the first drugs to treat ovarian cancer and is found in the bark of the Pacific yew tree. It was discovered through a large project of cataloguing chemicals found in plants and animals for their anti-cancer properties. The chemicals isolated from these plants were screened against cancer cells for signs of activity and the yew tree extract was noted in 1965. Taxol was one of the most promising candidates found in the program, but its scarcity and unusual chemical structure meant that it received little attention. This was until 1979, when it was shown to have completely new mechanism for killing cancer cells and was capable of shrinking breast cancer tumours in nude miceANCHOR ANCHOR. Five years later, taxol was given approval for clinical trials, where it shrank tumours in 30% of women with ovarian cancer – an unprecedented success in treating this difficult diseaseANCHOR.

Carboplatin is a platinum-based drug and has fewer side-effects than the classic drug cisplatin, which was the first of this family of drugs. Cisplatin was originally created by accident while using platinum electrodes in electrolysis. It was the noted that cisplatin prevents cell division in bacteria and later its anti-tumour properties were discovered through experiments on miceANCHOR.

There are a range of other treatments that are available for more advanced or recurrent cancers. Among these is Avastin (bevacizumab), a humanised mouse antibody that slows the growth of new blood vessels. This helps to starve the tumour of oxygen and nutrients. Hormone treatments, such as tamoxifen, are being studied to see how effective they are in treating resistant ovarian cancers. These treatments are commonly already used in breast cancer treatment.

Potential treatments

In 2005, researchers discovered that cells missing either the BRCA1 or BRCA2 genes were very sensitive to a compound that blocked the action of PARP-1, a DNA repair proteinANCHOR ANCHOR. These cells were then transplanted into nude mice to check that the same effect was seen in vivo. Indeed, the PARP inhibitor blocked the growth of BRCA2-deficient tumours and had little effect on tumours without the mutation. Research also showed that genetically modified mice which did not have any PARP-1 were still healthyANCHOR. This indicated that there would not be any serious side effects when using a drug to block PARP in humans. This increased interest in the potential for PARP inhibitors as cancer drugs. There are now estimated to be 60 PARP inhibitors in development worldwide, with at least six phase III trials ongoing at the end of 2013ANCHOR.

Another approach is to target the CD44 protein, which helps cancer cells to grow out of control and develop resistance to standard treatments. Researchers have successfully used small, inhibiting RNA molecules to block the CD44 gene from functioning in mice, which shrinks their tumoursANCHOR.


Referencias

  1. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray, F. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet].Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr, accessed on 03/03/2014.
  2. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray, F. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet].Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr, accessed on 03/03/2014.
  3. Kitchener HC (2008) Survival from cancer of the ovary in England and Wales up to 2001. Br J Cancer 99 Suppl 1:S73-4.
  4. SEER 9 Incidence & U.S. Mortality 1975-2010
  5. Schmidt C (2011) CA-125: a biomarker put to the test Journal of the National Cancer Institute 103(17): 1290–1 doi:10.1093/jnci/djr344
  6. Deng CX (2002) Tumor formation in Brca1 conditional mutant mice Environ Mol Mutagen 39:171-7
  7. Brodie SG, Deng CX (2001) BRCA1-associated tumorigenesis: what have we learned from knockout mice? Trends Genet 17:S18-22
  8. Deng CX (2001) Tumorigenesis as a consequence of genetic instability in Brca1 mutant mice Mutat Res 477:183-9
  9. Schiff PB (1979) Promotion of microtubule assembly in vitro by taxol Nature 22;277(5698):665-7
  10. http://www.rinr.fsu.edu/fall2002/taxol.html
  11. Rowinsky EK et al (1988) Phase II study of taxol in advanced epithelial malignancies Proceedings of the Association of Clinical Oncology 7:136
  12. Rosenberg B, Vancamp L, Trosko JE, Mansour VH (1969) Platinum Compounds: a New Class of Potent Antitumour Agents Nature 222, 385-386 doi:10.1038/222385a0
  13. Bryant HE, Schultz N, Thomas HD et al (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase Nature 434:913-7
  14. Farmer H, McCabe N, Lord CJ et al (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy Nature 434:917-21
  15. Wang ZQ, Stingl L, Morrison C et al (1997) PARP is important for genomic stability but dispensable in apoptosis Genes Dev 11:2347-58
  16. Garber K (2013) PARP inhibitors bounce back Nature Reviews Drug Discovery 12, 725–727 doi:10.1038/nrd4147
  17. Shah V et al (2013) Targeted Nanomedicine for Suppression of CD44 and Simultaneous Cell Death Induction in Ovarian Cancer: An Optimal Delivery of siRNA and Anticancer Drug Clin Cancer Res 19;6193 doi:10.1158/1078-0432

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