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Chemo Resistance, BRCA & Parp Inhibitors

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123Donna View Drop Down
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    Posted: Jun 18 2013 at 7:11pm
New Resistance Mechanism to Chemotherapy in Breast and 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 Óscar Fernández-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 María Nieto-Soler, a researcher from Fernández-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.

Fernández-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 Fernández-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.

http://www.sciencedaily.com/releases/2013/06/130618113856.htm#.UcDDP9v0ipI


DX IDC TNBC 6/09 age 49, Stage 1,Grade 3, 1.5cm,0/5Nodes,KI-67 48%,BRCA-,6/09bi-mx, recon, T/C X4(9/09)
11/10 Recur IM node, Gem,Carb,Iniparib 12/10,MRI NED 2/11,IMRT Radsx40,CT NED11/13,MRI NED3/15

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SagePatientAdvocates View Drop Down
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Post Options Post Options   Thanks (0) Thanks(0)   Quote SagePatientAdvocates Quote  Post ReplyReply Direct Link To This Post Posted: Jun 18 2013 at 8:28pm
Thanks for posting Donna..

Maybe they are getting a bit closer to figuring it out. So very, very complex, huh?

hugs,

Steve
I am a BRCA1+ grandson, son and father of women affected by breast/oc-my daughter inherited mutation from me, and at 36, was dx 2004 TNBC I am a volunteer patient advocate with SAGE Patient Advocates
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123Donna View Drop Down
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Jun 19 2013 at 9:41pm
Steve,

I agree, very complex.  Maybe the key to this mystery is personalized medicine where they look at each unique genetic tumor makeup and target treatment that will give the optimum response, instead of the one size fits all approach?  We're getting closer . . . .

Donna
DX IDC TNBC 6/09 age 49, Stage 1,Grade 3, 1.5cm,0/5Nodes,KI-67 48%,BRCA-,6/09bi-mx, recon, T/C X4(9/09)
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Mar 18 2019 at 10:13pm
Drug target identified for chemotherapy-resistant ovarian, breast cancer

Study finds mimic for BRCA genes that could be targeted to improve treatment

Researchers at Washington University School of Medicine in St. Louis may have found a path toward improving the effectiveness of chemotherapy in people with breast or ovarian cancer caused by defects in one of the BRCA genes. The researchers identified a pair of genes that operate in parallel to BRCA and may increase susceptibility to chemotherapy drugs.

. . . A class of drugs known as PARP inhibitors was designed to target tumors with defective BRCA genes. Sold under brand names such as Lynparza, Rubraca and Talzenna, the drugs offered new hope to people with ovarian or breast cancer. But in the five years since the first one was approved, PARP inhibitors haven’t lived up to their promise. Tumors typically shrink when first hit with a PARP inhibitor, but they soon become resistant, and the cancer returns.

Now, researchers may have found a path toward improving the effectiveness of chemotherapy in people with breast or ovarian cancer that is caused by BRCA defects. Researchers at Washington University School of Medicine in St. Louis identified a pair of genes that operate in parallel to BRCA. Knocking down the genes increases tumor cells’ susceptibility to a toxic chemical – and potentially to chemotherapy drugs as well.

“Women treated with PARP inhibitors typically go into remission relatively quickly, but a lot of these cancers then become resistant partly because there are other proteins in the cell that can compensate for the lack of BRCA,” said Andrea Byrum, a graduate student and the study’s co-first author. “If we target these other factors, we might be able to make the tumor sensitive to these drugs again.”

The findings are available online in the Journal of Cell Biology.

BRCA helps repair damaged DNA, fending off the errors that threaten to transform normal cells into cancer cells. When a person has a BRCA gene that isn’t working properly, his or her cells struggle to heal injuries to their DNA. PARP inhibitors knock out another arm of the cell’s DNA repair system. Together, a flawed BRCA gene and a PARP inhibitor leave tumor cells with a fatal inability to fix DNA damage, and the cells die.

But the DNA repair system is complex and redundant, and some tumor cells with nonfunctioning BRCA genes are able to effectively restore BRCA function by boosting another aspect of the system. That’s where this latest study comes in. The researchers found a way to make tumor cells that have BRCA act like they don’t so they can be more easily killed. Their findings point the way toward making resistant tumor cells susceptible to PARP inhibitors once again.

Nima Mosammaparast, MD, PhD, an assistant professor of pathology and immunology, Byrum, and colleagues found that a complex of the proteins TPX2 and Aurora A could mimic the effects of the BRCA proteins.

“If you lose this complex, it’s like you lose BRCA,” said Mosammaparast, the study’s senior author. “The nice thing is that there are inhibitors to Aurora A already in clinical trials for other types of cancer such as lymphoma and melanoma. We could combine an Aurora inhibitor and a PARP inhibitor to more effectively target these cancers. . .”

https://medicine.wustl.edu/news/drug-target-identified-for-chemotherapy-resistant-ovarian-breast-cancer

DX IDC TNBC 6/09 age 49, Stage 1,Grade 3, 1.5cm,0/5Nodes,KI-67 48%,BRCA-,6/09bi-mx, recon, T/C X4(9/09)
11/10 Recur IM node, Gem,Carb,Iniparib 12/10,MRI NED 2/11,IMRT Radsx40,CT NED11/13,MRI NED3/15

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