First pictures of BRCA2 protein show how it works to repair DNA

In continuation of my update on BRCA2 

Scientists have taken pictures of the BRCA2 protein for the first time, showing how it works to repair damaged DNA. The findings showed that each pair of BRCA2 proteins binds two sets of RAD51 that run in opposite directions. This allows it to work on strands of broken DNA that point in either direction. They also show that BRCA2's job is to help RAD51 form short filaments at multiple sites along the DNA, presumably to increase the efficiency of establishing longer filaments required to search for matching strands.

Researchers at Imperial College London and the Cancer Research UK London Research Institute purified the protein and used electron microscopy to reveal its structure and how it interacts with other proteins and DNA. The results are published today in Nature Structural and Molecular Biology.

Around one in 1000 people in the UK have a mutation in the BRCA2 gene. The lifetime risk of breast cancer for women with BRCA2 mutations is 40 to 85 per cent, depending on the mutation, compared with around 12 per cent for the general population. Many women who test positive for BRCA1 and BRCA2 mutations choose to undergo surgery to reduce their risk of breast cancer. Mutations can also raise the risk of other cancers, such as ovarian, prostate and pancreatic cancer.

The BRCA1 and BRCA2 genes encode proteins involved in DNA repair. The DNA in our cells undergoes damage thousands of times a day, caused by toxic chemicals, metabolic by-products and ultraviolet radiation. Repair mechanisms correct most of this damage, but unrepaired damage can lead to cancer.

The study was led by Professor Xiaodong Zhang from the Department of Medicine at Imperial College London and Dr Stephen West at the London Research Institute.

"This study improves our understanding of a fundamental cause of cancer," said Professor Zhang, a Wellcome Trust Senior Investigator. "It's our first view of how the protein looks and how it works, and it gives us a platform to design new experiments to probe its mechanism in greater detail.

"Once we have added more detail to the picture, we can design ways to correct defects in BRCA2 and help cells repair DNA more effectively to prevent cancer. We can also think about how to make the repair process less effective in cancer cells, so that they die."

The study found that BRCA2 proteins work in pairs -- which the researchers found surprising since BRCA2 is one of the largest proteins in the cell.

BRCA2 works in partnership with another protein called RAD51. BRCA2 helps RAD51 molecules to assemble on strands of broken DNA and form filaments. The RAD51 filaments then search for matching strands of DNA in order to repair the break.

The findings showed that each pair of BRCA2 proteins binds two sets of RAD51 that run in opposite directions. This allows it to work on strands of broken DNA that point in either direction. They also show that BRCA2's job is to help RAD51 form short filaments at multiple sites along the DNA, presumably to increase the efficiency of establishing longer filaments required to search for matching strands.

Ref : http://dx.doi.org/10.1038/nsmb.2899

First pictures of BRCA2 protein show how it works to repair DNA  

Targeted therapy rucaparib shows promise in treating pancreatic cancer patients with BRCA mutation

The targeted therapy rucaparib, which has demonstrated robust clinical activity in ovarian cancer patients with a BRCA mutation, also showed promise in previously treated pancreatic cancer patients with the mutation, according to results from a phase II clinical study presented by Susan M. Domchek, MD, executive director of the Basser Center for BRCA at the Abramson Cancer Center of the University of Pennsylvania, at the American Society of Clinical Oncology (ASCO) Annual Meeting. (Abstract # 4110).

rucaparib

Overall, a clinical benefit was observed in 32 percent of patients (6 of 19) treated with rucaparib. Of the 19 pancreatic patients, one had a complete response and two had partial responses, while four patients had stable disease. The objective response rate, the primary endpoint for the study, was 16 percent (3 of 19).

"These results are encouraging and further demonstrate the clinical significance of the BRCA cancer genes outside of breast and ovarian, and not just in women," Domchek said. "Importantly, it points us to a potential new treatment avenue for pancreatic cancer, an aggressive disease that's often caught in the later stages. Though smaller in number, some patients with advanced disease and carrying a BRCA mutation may benefit from the same targeted therapy being used today in the clinic to successfully treat some ovarian cancer patients."

Given the poor prognosis and limited treatment options in pancreatic cancer, new therapies to combat the disease are desperately needed: Earlier this year, the American Cancer Society reported that it is estimated that in 2016, nearly 42,000 people will die from the disease, surpassing the number of deaths from breast cancer by more than 1,000.

Recent studies have shown that rucaparib, a PARP inhibitor, effectively treats patients with platinum-sensitive, relapsed, high-grade ovarian cancer harboring a BRCA mutation. In a study presented at ASCO in 2015, researchers showed that treatment resulted in a 69 percent RECIST response rate in these patients. In April 2015, it received a U.S. Food and Drug Administration (FDA) Breakthrough Therapy designation. The FDA's designation, created in 2012, is intended to expedite the development and review of new medicines - both drugs and biologic agents - that treat serious or life-threatening conditions, if the therapy has demonstrated substantial improvement over available therapies.

The success in ovarian patients prompted a clinical study in pancreatic patients with the same mutation--about nine percent of pancreatic patients are BRCA1/BRCA2 positive.

The team enrolled participants with measurable, relapsed disease who received one to three prior rounds of chemotherapy for locally advanced or metastatic cancer. The trial included 11 male and eight female patients, with a median age of 57. Twenty-one percent of the patients tested positive for the BRCA1 mutation, while 79 percent tested positive for BRCA2.

The disease control rate (defined as partial response or stable disease for more than 12 weeks) for all patients was 32 percent (6 of the 19 patients) and 50 percent (three of six patients) in patients who received one prior line of chemotherapy. Four patients had stable disease, nine patients had progressive disease, and three were not evaluable for response. One patient was on the drug for 72 weeks and is continuing to receive the drug. The drug had an acceptable safety profile. Common treatment-emergent side effects included nausea (63 percent) and anemia (47 percent).

All patients who responded received only one prior line of chemotherapy therapy, suggesting that the drug may be an option earlier in the treatment course.

Targeted therapy rucaparib shows promise in treating pancreatic cancer patients with BRCA mutation

Breast Cancer Drug Promising in Phase 3 Trial

 For women with advanced breast cancer who carry the BRCA1 and BRCA2 gene mutations, an experimental drug could improve survival, a new study suggests.

The BRCA mutations are linked with a greater risk for aggressive breast and ovarian cancer. The drug, talazoparib, works by blocking an enzyme called poly ADP ribose polymerase (PARP), thus preventing cancer cells from killing healthy ones.

In a phase 3 trial of 431 women, funded by the drug's maker, those who received talazoparib lived longer without their cancer progressing than women treated with standard chemotherapy by an average of three months, researchers found.

"For women with metastatic breast cancer and a BRCA mutation, PARP inhibitors may be considered for their treatment," said lead researcher Dr. Jennifer Litton, an associate professor of breast medical oncology at the University of Texas M.D. Anderson Cancer Center in Houston.

When it's functioning properly, BRCA actually helps repair damaged DNA and prevents tumors, but when BRCA1 and BRCA2 go awry, they encourage breast cancers.

PARP inhibitors such as talazoparib appear to interfere with the function of mutated BRCA in breast cells, causing them to die rather replicate.

In addition, several ongoing studies are looking at combinations with PARP inhibitors "to try to expand who may benefit or lengthen how long they may work," Litton said.The trial results are preliminary, as talazoparib has not yet been approved by the U.S. Food and Drug Administration.

In January, the FDA approved the first PARP inhibitor, Lynparza, to treat BRCA-mutated breast cancer.

Similar drugs have already been used to treat advanced, BRCA-mutated ovarian cancer, according to the agency.

In the current trial, the women who were randomly selected to receive talazoparib had a higher response rate to treatment than women who received standard chemotherapy: 63 percent versus 27 percent, the researchers found.

The drug does have side effects. Among women receiving talazoparib, 55 percent had blood disorders, mostly anemia, compared with 38 percent of those receiving standard chemotherapy.

In addition, 32 percent of the women receiving talazoparib had other side effects, compared with 38 percent of those on standard chemotherapy.

Oncologist Dr. Marisa Weiss is the founder and chief medical officer of Breastcancer.org. "Smart medicines like this PARP inhibitor work better than traditional chemo in women with HER2-negative metastatic disease and a BRCA1/2 genetic mutation," she said.

This targeted form of treatment takes advantage of a weakness in the BRCA gene to further cripple the cancer cell's ability to repair itself, grow and spread, said Weiss, who was not involved with the study.

Normal cells are mostly spared. As a result, more cancer cells are killed with fewer side effects, Weiss said.

"Most importantly, patients themselves have reported a better experience with less hair loss and improved quality of life," she said.

Weiss advises women with advanced breast cancer to have genetic testing.

"In both my clinical practice and within the online support community, we advise women with metastatic breast cancer to get genetic testing upon diagnosis, in order to get the best care first," she said.

The trial was funded by drug maker Pfizer, and the results were published Aug. 15 in the New England Journal of Medicine.

https://www.nejm.org/doi/full/10.1056/NEJMoa1802905

Ref : https://en.wikipedia.org/wiki/Talazoparib

Ovarian cancer drug shows promise in pancreatic cancer patients with BRCA mutation

In continuation of my update on Rucaparib

A targeted therapy that has shown its power in fighting ovarian cancer in women including those with BRCA1 and BRCA2 mutations may also help patients with aggressive pancreatic cancer who harbor these mutations and have few or no other treatment options. An international team of researchers led by the Perelman School of Medicine and the Basser Center for BRCA at the University of Pennsylvania reported their findings this week in JCO Precision Oncology.

The drug, PARP inhibitor rucaparib, which was approved by the U.S. Food and Drug Administration (FDA) last month for the treatment of women with ovarian cancer who have recurrent disease or received prior therapies, showed its clinical benefit in previously treated pancreatic patients with BRCA mutations in a phase II clinical trial. Of the 19 patients treated, four had responses and two additional patients had stable disease.

"These results not only point us in a new treatment direction to further investigate for patients with pancreatic cancers, but it also reinforces the clinical significance of the BRCA genes beyond ovarian and breast cancer and the utility of PARP inhibitors in other cancers," said Susan M. Domchek, MD, executive director of the Basser Center for BRCA at the Abramson Cancer Center of the University of Pennsylvania.

PARP—poly (ADP-ribose) polymerase—is an enzyme used by healthy cells to repair themselves. However, cancer cells also use PARP to repair DNA damage, thus extending their growth and possible lethality. Preliminary results from the study, which included patients from seven centers around the globe, were presented at the annual meeting of the American Society of Clinical Oncology in 2016. These latest findings represent the full study.

Pancreatic cancer, which is often caught in later, more aggressive stages, is projected to become the second leading cause of cancer death by 2020, emphasizing the need for a larger and more effective arsenal of treatments to combat the disease. Only about 32 percent of patients respond to a first line of chemotherapy, and less than 20 percent who don't respond to a first line of chemotherapy end up responding to a second.

This underscores the importance of looking outside of chemotherapy options, the authors said, particularly in patients with targetable mutations, like BRCA.

Importantly, Domchek said, none of the patients who benefited from rucaparib had tumors that had progressed on a prior platinum-based chemotherapy, suggesting a potential role for rucaparib as an earlier treatment for patients whose tumors are not resistant to such treatments.

Rucaparib is a PARP inhibitor shown to be an effective therapy in ovarian cancers with BRCA 1/2 mutations. In 2016, the drug was approved by the FDA for women with BRCA-associated ovarian cancer who received two or more prior chemotherapies. And in April 2018, the approval was extended to women with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are having a complete or partial response to platinum-based chemotherapies.

The success of rucaparib in ovarian cancers is what prompted the clinical study in pancreatic patients with the same mutation. About nine percent of pancreatic patients have BRCA/2 mutation associated pancreatic cancer.

Overall, a clinical benefit was observed in 32 percent of patients (6/19) treated with rucaparib, and 45 percent in patients (4/9) who had received only one prior chemotherapy for locally advanced or metastatic disease. Nine patients had progressive disease, and three were not evaluable for response. The objective confirmed response rate, the primary endpoint for the study, was 16 percent (3/19).

The trial included 11 men and eight women, with a median age of 57. Twenty-one percent of the patients had BRCA1mutation-associated pancreatic cancer, while 79 percent were associated with BRCA2 mutations.

"Consideration should be given to use of this therapy for treatment of patients whose tumors have not progressed on prior platinum therapy," the authors wrote. "Future studies should focus on better understand the sequencing of PARP inhibitor treatment and potential maintenance therapy, as well as potential predictors of resistance to therapy."

Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer — NEJM

We know that Olaparib, is a experimental chemotherapeutic agent, developed by KuDOS Pharmaceuticals and later by Astra Zeneca, that failed to progress through clinical trials to approval. It is an inhibitor of poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair. It acts against cancers in people with hereditary BRCA1 or BRCA2 mutations, which includes many ovarian, breast and prostate  

Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer — NEJM

Niraparib Plus AAP Improves Survival in mCSPC With HRR Gene Alterations

In continuation of my update on Niraparib

For patients with metastatic castration-sensitive prostate cancer (mCSPC) with homologous recombination repair (HRR) gene alterations, the addition of niraparib to abiraterone acetate and prednisone (AAP) is beneficial, according to a study published online Oct. 7 in Nature Medicine.

Gerhardt Attard, M.D., Ph.D., from University College London, and colleagues conducted a double-blind trial that evaluated combining niraparib with AAP versus placebo and AAP in mCSPC with HRR gene alterations. A total of 696 patients were randomly assigned to niraparib or placebo (348 each).

Of the patients, 56 percent had BRCA1 or BRCA2 alterations and 78 percent had high-volume metastases. The researchers first observed significant improvement in radiographic progression-free survival in the BRCA subgroup (median not reached at the time of analysis for the niraparib and AAP group versus 26 months for the AAP group; hazard ratio, 0.52). Significant improvement was also seen in the intention-to-treat population (hazard ratio, 0.63). For overall survival, the data were immature but favored niraparib. The incidence of grade 3 or 4 adverse events was 75 and 59 percent in the niraparib and placebo groups, respectively; in the niraparib and AAP group, the most frequent adverse event was anemia (29 percent), with 25 percent of patients needing a blood transfusion.

"For cancers with a mutation in one of the eligible HRR genes, where niraparib has been approved, a doctor should consider a discussion that balances the risks of side effects against the clear benefit to delaying disease growth and worsening symptoms," Attard said in a statement.

Several authors disclosed ties to the biopharmaceutical industry, including Johnson & Johnson, which funded the study.

Abstract/Full Text

https://en.wikipedia.org/wiki/Niraparib

Niraparib Plus AAP Improves Survival in mCSPC With HRR Gene Alterations - Drugs.com MedNews

PARP inhibitor, MK-4827, shows anti-tumour activity in first trial in humans....

MK-4827 , (S)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide hydrochloride.

A recent study claim that the new drug MK-4827 (see structure), that targets proteins responsible for helping cancer cells to repair damage to their DNA has shown promising anti-tumor activity in its first trial in humans. Some patients with a range of solid tumors, many of whom had been treated unsuccessfully for their cancer with other therapies, have seen their tumors shrink or stabilize for periods of between 46 days to more than a year.

Laboratory studies of the drug, MK-4827, have shown that it inhibits proteins called PARP1 and PARP2  (poly(ADP)-ribose polymerase). PARP is involved in a number of cellular processes and one of its important functions is to assist in the repair of single-strand breaks in DNA. As per the claim by the researchers, drug act by inhibiting the action of PARP, double-strand breaks occur, leading to cell death. Researchers add that tumors that are caused by a mutation in the BRCA1 or BRCA2 genes are susceptible to cell death through PARP inhibition because correctly functioning BRCA genes assist in repairing double-strand DNA breaks via a process called homologous-recombination-dependent DNA repair, whereas mutated versions are unable to perform this role. Normal cells don't replicate as often as cancer cells and they still have homologous repair operating; this enables them to survive the inhibition of PARP and makes PARP a good target for anti-cancer therapy.

In a Phase I trial conducted at the H Lee Moffitt Cancer Center (Tampa Florida, USA), University of Wisconsin-Madison (Madison, USA) and the Royal Marsden Hospital (London, UK), MK-4827 was given to 59 patients (46 women, 13 men) with a range of solid tumors such as non-small cell lung cancer (NSCLC), prostate cancer, sarcoma, melanoma and breast and ovarian cancers. Some patients had cancers caused by mutations in the BRCA1/2 genes, such as breast and ovarian cancer, but others had cancers that had arisen sporadically.

The researchers saw anti-tumor responses in both sporadic and BRCA1/2 mutation-associated cancers. Ten patients with breast and ovarian cancers had partial responses, with progression-free survival between 51-445 days, and seven of these patients are still responding to treatment. Four patients (two with ovarian cancer and two with NSCLC) had stable disease for between 130-353 days.

More...