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Old 06-26-2013, 09:31 PM
gdpawel gdpawel is offline
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Default Article reveals new resistance mechanism to chemotherapy in ovarian cancer

It is estimated that between 5% and 10% of breast and ovarian cancers are familial in origin, which is to say that these tumours are attributable to inherited mutations from the parents in genes such as BRCA1 or BRCA2. In patients with these mutations, PARP inhibitors, which are currently in clinical trials, have shown encouraging results that make them a new option for personalised cancer treatment, an alternative to standard chemotherapy. Nevertheless, the latest studies indicate that a fraction of these patients generate resistance to the drug and, therefore, stop responding to the new treatment.

The team led by Spanish National Cancer Research Centre researcher ”scar FernŠndez-Capetillo, head of the Genomic Instability Group, together with researchers from the National Cancer Institute in the US, have participated in a study that describes the causes that explain why tumours with BRCA1 and BRCA2 mutations stop responding to PARP inhibitor drugs.

"PARP inhibitors are only toxic in tumours that have an impaired DNA repair mechanism, such as those that contain BRCA1/2 mutations" says MarŪa Nieto-Soler, a researcher from FernŠndez-Capetillo's team.

According to the researchers, the problem arises when these tumours, in addition to having BRCA1 and/or BRCA2 mutations, also contain secondary mutations in other proteins such as 53BP1 or PTIP, whose function is to restrain DNA repair. In these cases, the mutations mutually compensate for each other, the tumour cells recover the ability to repair their DNA and the drug stops working.

FernŠndez-Capetillo says: "This is one of the first studies to demonstrate that secondary mutations can make tumours resistant when faced with specific treatments like, in this case, PARP inhibitors."

When the researchers compared different treatments, they observed that for those tumours with BRCA1 and/or BRCA2 mutations that also presented mutations in 53BP1 or PTIP, standard treatment with cisplatin was more efficient than personalised therapy.

"These data indicate that only patients containing mutations in BRCA1 and/or BRCA2, but not in the secondary genes we have described, would be candidates for an effective personalised therapy with PARP inhibitors", explains FernŠndez-Capetillo, concluding that: "Our results suggest that 53BP1 and PTIP genes would need to be evaluated in patients with familial breast and ovarian cancer when deficiencies in the BRCA genes were present before deciding on their treatment."

In this context, researchers intend to warn healthcare providers in personalised medicine that the challenge, in addition to the search for markers of drug sensitivity for new pharmacological compounds, also encompasses the search for secondary resistance markers. The aim would be to bring about significant improvements in treatment outcomes.

Source: Centro Nacional de Investigaciones Oncologicas (CNIO)

Poly(ADP-ribose) polymerase (PARP) catalyzes the polyADP-ribosylation of proteins involved in DNA repair. Inhibitors of PARP were originally developed for cancers with homologous recombination deficiencies, such as those harboring mutations in BRCA1 or BRCA2 genes. However, pre-clinical research and clinical trials have suggested that the activity of PARP inhibitors is not limited to those with BRCA mutations. PARP inhibitors may have activity in cancers deficient in other DNA repair genes, signaling pathways that mitigate DNA repair, or in combination with DNA-damaging agents independent of DNA repair dysfunction. Currently there are seven different PARP inhibitors in clinical development for cancer. While there has been promising clinical activity for some of these agents, there are still significant unanswered questions regarding their use. Going forward, specific questions that must be answered include timing of therapy, use in combination with cytotoxic agents or as single-agent maintenance therapy, and whether there is a predictive biomarker that can be used with PARP inhibition. Even with large strides in the treatment of many gynecologic malignancies in recent years, it is imperative that we develop newer agents and methods to identify patients that may benefit from these compounds. The focus of this review will be on pre-clinical data, current clinical trials, and the future of PARP inhibitors in the treatment of ovarian, endometrial, and cervical cancer.

Gregory D. Pawelski

Last edited by gdpawel : 10-08-2013 at 12:32 PM. Reason: additional info
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Old 09-07-2017, 12:16 AM
gdpawel gdpawel is offline
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Default Recurrent BRCA Positive Ovarian Cancer: An Unexpected Opportunity

Robert A. Nagourney, M.D.
Medical and Laboratory Oncologist

For the over 22,000 women in the United States diagnosed each year with OVARIAN CANCER outcomes have improved slowly, yet the majority of these women still do not survive five years.

Despite these statistics, ovarian cancer remains one of the most chemo-responsive diseases treated by medical oncologists and there is renewed reason for hope.

We now recognize that the responsiveness of ovarian cancer cells to platinum-based (Cisplatin and Carboplatin) chemotherapy is actually a ďhard-wiredĒ feature of this disease. The term applied is Homologous-DNA-Repair (HDR) deficiency and the most common inheritable form of this abnormality is known as BRCA mutation.

Patients with BRCA-related cancers share features with a rare childhood illness known as Fanconiís anemia (see picture of FA cells above), named after first being described by Guido Fanconi (1892-1979). This syndrome is also caused by DNA repair deficiency.

Indeed, an older diagnostic test for Fanconiís anemia exposed bone marrow cells of affected children to the chemotherapy drug Mitomycin-C to identify the characteristic DNA damage under the microscope. Cisplatin and carboplatin affect the DNA in much the same way, thus a connection between this childhood illness and these adult cancers.

Case in Point: BRCA Positive Stage 4 Ovarian Cancer

This bit of history recently came into focus when I was asked to see a 66-year-old woman with rapidly progressive BRCA-positive stage 4 ovarian cancer who had failed all therapy.

After progressing on Carboplatin plus Taxol she went on to Doxil plus Avastin and then in June of 2017 began treatment with Niraparib, a member of the newest class of drugs for BRCA (+) tumors known as the PARP inhibitors.

Things went from bad to worse as the CA 125 tumor marker rose from 1122 to 5968 in just under 6 weeks and all areas of measureable disease worsened. A biopsy of a chest wall mass was conducted by our surgeon and provided ample cells for EVA/PCD STUDY

Her Functional Profiling Results

The results were extremely interesting, as the patientís tumor revealed utter resistance to the currently fashionable PARP inhibitors yet a striking degree of sensitivity to Mitomycin-C (the drug used to diagnose Fanconiís anemia in children) and very good activity for the related combination of Cisplatin plus Gemcitabine.

It seemed that the patientís tumor still remembered its heritage as a DNA repair deficient cancer (like Fanconiís anemia) but didnít much care for the current crop of ďtargetedĒ PARP inhibitors.

While the new drugs appeared useless, a simple and readily available drug doublet appears highly likely to work.

Functional analyses, like the EVA-PCD assay, enable us to explore drugs, both new and old.

I tested Mitomycin-C, in part, to probe this patientís tumor.

In essence, I used this potent DNA damaging agent to confirm the presence of Fanconi's anemia-like biology. Just like that pediatric test of old, this patientís result informed us that DNA-damaging combinations still held promise.

While it is too early to be sure that this ovarian cancer patient will respond I am optimistic.

Impressed by the results with Mitomycin-C and itís similarity to Cisplatin plus Gemcitabine our functional analysis not only confirmed resistance to the PARP inhibitor but also identified sensitivity to drugs that might otherwise not have been tried.

While the new classes of signal inhibitors revealed no activity, a readily available chemotherapy doublet can now be administered:

A simple solution to a complex problem.
Gregory D. Pawelski
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