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From Bench to Bedside for Cancer Signatures

Every research scientist dreams of publishing a Nature or Science paper, making a ground breaking discovery in their field and impacting on future research around the world. One of the main questions in Oncology is “what happens next”? How is high impact research turned in to improved therapeutic options?

Within cancer research, major breakthroughs are being made in genetic imprints and signatures left by DNA-damaging processes that lead to cancer. In August 2013, Nature published a paper originating from the Wellcome Trust Sanger institute, in which the researchers uncovered more than 20 signatures of processes that mutate DNA. For many of the signatures, they also identified the underlying biological process responsible. While the scientific merit of these discoveries cannot be disputed, the true test of the data will be seen by how it translates into new or improved therapies for patients.

And it seems that this is could be occurring in the near future for cancers originating from a BRCA1/2 mutation. BRCA1 and 2 are tumor suppressor genes involved in the homologous recombination (HR) pathway of DNA repair. Mutation of the BRCA1 or 2 gene leads to a predisposition to breast and ovarian cancers, which can be as high as a 90% lifetime risk of developing breast cancer in some families with BRCA1 mutations. These statistics are resulting in an increasing number of gene carriers undergoing prophylactic mastectomies and/or removal of their ovaries to reduce their chances of developing the disease, the most high profile of which in recent times has been the actress Angelina Jolie.

Increased Role for PARP Inhibitors?

Potential therapeutic options are available for cancer patients with the mutated BRCA1/2 gene - success has been seen in clinical trials using PARP inhibitors, which generate DNA strand breaks which cannot be repaired by the HR-deficient cell leading to cell death. There are currently multiple Phase 3 clinical trials ongoing for PARP inhibitors in patients with germline BRCA mutations. Tumors exhibiting wild‑type BRCA1/2 have historically been thought of as not sensitive to PARP inhibition, with the exception of sporadic cancers which have “BRCA-ness” or are “BRCA-like” which may also respond to DNA damaging agents. It was identified in the Nature publication that almost all cancer cases with BRCA1/2 mutations showed a large contribution from one specific signature (Signature 3). However, the research also revealed that some cancers with a substantial contribution from Signature 3 did not have BRCA1/2 mutations.

Crown Bioscience had the chance to see a presentation of the results from the Sanger Institute a short while ago, and got a sneak peek in to the therapeutic applications for BRCA1/2 that are being generated from this work. The research paper around this application is still in submission to a high impact journal, and for now the therapy in question was named only as “Therapy X”. The new unpublished research will show that treatment of wild-type BRCA1/2 cells with “Therapy X” did result in some responses, dependent on whether a lot or a little of Signature 3 was present in the cancer. Presuming that “Therapy X” is a PARP inhibitor, it looks possible that the presence of Signature 3 within tumors is more predictive to therapy response than simply looking at the mutation status of BRCA. This could be a step forward in predicting which patients would benefit from treatment with PARP inhibitors, revealing a subset of patients with wild-type BRCA who may have previously been overlooked. Crown Bioscience looks forward to fully exploring these results upon their publication, and the impact for future BRCA and PARP inhibitor research and therapies.

Progress Your Research With Crown Bioscience

Crown Bioscience supports breast cancer research through the use of our XenoSelect™ cell lines, and clinically relevant Xenograft and Patient-Derived Xenograft models with BRAC1/2 mutations, all available for drug discovery and translational science programs. Contact us today at busdev@crownbio.com to discover how Crown Bioscience can help move your BRCA-related drug discovery from the bench to the bedside.

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