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PF-2341066, Sunitinib, Temsirolimus, Vorinostat, Abiraterone & more. We have headquarters in both United States and Europe, and also has 38 distributors worldwide. We provide overnight delivery in North America and Europe.">BRCA1 and BRCA2 were so named because they were discovered due to their association with breast cancer (BReast CAncer 1 and2). Both proteins are involved in double strand repair of DNA. DNA is frequently damaged during replication in several different ways. Fortunately, there are several mechanisms in place to repair the damage that occurs. The BRCA proteins are one such mechanism; they repair double-stranded breaks in DNA. Mutations in the genes that interrupt this repair pathway can be disastrous, as is manifested in HBOC. When there is a BRCA mutation, there is still one good copy that allows enough DNA repair for the cells to live, but also allows enough DNA damage to give rise to cancer. Women with harmful mutations in BRCA 1 or 2 have a 5 fold higher risk of breast cancer and a 10-30 fold higher risk of ovarian cancer. For these reasons, the BRCA genes and proteins have been examined as potential therapeutic targets. In 2005, while screening for compounds to treat cells with BRCA mutations, researchers identified PARP inhibitors. The double stranded DNA breaks that must be repaired by BRCA proteins are preceded by single-stranded “nicks” in the DNA. There are several mechanisms for repairing these single-strand nicks but at the front of these pathways lies a gatekeeper known as poly (ADP-ribose) polymerase (PARP). PARP binds to sites with single-strand DNA nicks and recruits the machinery necessary for repair. When PARP is inhibited, the single-strand breaks cannot be repaired and more and more double strand breaks are formed. In cancer cells, which are also deficient in BRCA, not enough of these double strand breaks can be repaired between divisions and the cell dies. Non-cancerous cells can survive the inhibition of PARP because they replicate much slower than cancer cells. So, PARP inhibitors have emerged as potential therapeutics for BRCA-associated breast and ovarian cancer. The first PAPR inhibitor to be developed was BS-201, which later became known as iniparib. Preliminary results in 2009 showed iniparib to be clinically effective in treating triple-negative breast cancer (the most difficult form to treat). These results led the FDA to “fast-track” the clinical trials of iniparib for this indication. However, Phase III results released in January 2011 proved to be very disappointing prompting abandonment of the development of the drug for now. However, there are some who argue that the drug still has great potential and that Phase III trials only missed the objectives due to overaggressive endpoints, insufficient statistical power, and imbalances in factors known to affect outcome. So, while iniparib may be sidelined for the time-being, other PARP inhibitors are still being investigated. Olaparib (AZD-2281) is currently entering Phase II clinical trials and appears to be very promising resulting in a 65% decrease in the hazard ratio for progression. Two newer drugs, Recuparib and Veliparib, are currently entering Phase II trails . The PARP inhibitors have been the most exciting and most talked about compounds in oncology in the last five years. The discovery and early development of these drugs was touted as the first great leap in personalized medicine as they are primarily designed to treat HBOC. Early clinical trial results were promising, but two of the drugs have since been side-lined after disappointing phase III results. Nonetheless, new PARP inhibitor drugs are still in the pipeline and it is likely that one or more of these compounds will prove to be effective and successful in treating HBOC. REFERENCES 1. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly (ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361:123-34. 2. Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 2010;376:235-44. 3. Gelmon KA, Hirte HW, Robidoux A, et al. Can we define tumors that will respond to PARP inhibitors? A phase II correlative study of olaparib in advanced serous ovarian cancer and triple-negative breast cancer. J Clin Oncol. 2002;28:15s 4. Drew Y, Ledermann JA, Jones A, et al. Phase II trial of the poly(ADP-ribose) polymerase (PARP) inhibitor AG-014699 in BRCA 1 and 2–mutated, advanced ovarian and/or locally advanced or metastatic breast cancer. J Clin Oncol. 2011;29 5. Schelman WR, Sandhu SK, Moreno Garcia V, et al. First-in-human trial of a poly(ADP)-ribose polymerase (PARP) inhibitor MK-4827 in advanced cancer patients with antitumor activity in BRCA-deficient tumors and sporadic ovarian cancers (soc). J Clin Oncol. 2011;29 6. O’Shaughnessy J, Osborne C, Pippen JE, et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. 2011;364:205-14. 7. O’Shaughnessy J, Schwartzberg LS, Danso MA, et al. A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin in metastatic triple-negative breast cancer J Clin Oncol. 2011;29: 8. Guha M. PARP inhibitors stumble in breast cancer. 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