{"id":27295,"date":"2021-07-27T12:00:00","date_gmt":"2021-07-27T12:00:00","guid":{"rendered":"https:\/\/www.cancer.gov\/news-events\/cancer-currents-blog\/2021\/novobiocin-cancer-parp-inhibitor-resistance-1"},"modified":"2024-11-03T15:14:34","modified_gmt":"2024-11-03T15:14:34","slug":"can-an-antibiotic-treat-cancers-that-become-resistant-to-parp-inhibitors","status":"publish","type":"post","link":"https:\/\/ogkologos.com\/en\/can-an-antibiotic-treat-cancers-that-become-resistant-to-parp-inhibitors\/","title":{"rendered":"Can an Antibiotic Treat Cancers that Become Resistant to PARP Inhibitors?"},"content":{"rendered":"

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Image showing human DNA polymerase \u03b8 (POLQ) in human cells. This enzyme (stained green) helps repair damaged DNA. <\/p>\n

Credit: The Protein Atlas. CC BY-SA 3.0.<\/p>\n<\/div>\n<\/figcaption><\/figure>\n<\/div>\n

For a second time, researchers will test an antibiotic discovered in the 1950s as a potential treatment for cancer. <\/p>\n

The first attempt to study the drug, novobiocin<\/a>, in patients with cancer was a small clinical trial conducted 30 years ago<\/a>. A young woman with advanced breast cancer responded to the drug and survived for 2 years, but most of the other participants in the trial did not benefit. <\/p>\n

Three decades later, researchers at the Dana-Farber Cancer Institute have \u201crediscovered\u201d novobiocin. They found it while testing thousands of compounds<\/a> against cancer cells that had become resistant to drugs known as PARP<\/a> inhibitors. These drugs are used to treat patients with various cancers, including ovarian, breast, and prostate cancers.<\/p>\n

\u201cLo and behold, novobiocin was one of the very top hits in our drug screen,\u201d said Alan D\u2019Andrea, M.D., who directs the Center for DNA Damage and Repair at Dana-Farber. Although novobiocin is no longer used to treat bacterial infections in people, the drug is still produced for veterinary medicine and remains in drug libraries for research. <\/p>\n

Novobiocin blocks the activity of a protein<\/a> called DNA polymerase theta (Pol\u03b8 or POLQ), which helps repair DNA that has become damaged as cells grow and divide. Cancer cells that cannot repair their damaged DNA die. <\/p>\n

Pol\u03b8 and the protein targeted by PARP inhibitors are both involved in a \u201cbackup\u201d form of DNA repair. These backup pathways become particularly important when a repair process known as homologous recombination stops working, as happens in some cells with mutations<\/a> in the BRCA1<\/a><\/em> or BRCA2<\/a><\/em> genes.<\/p>\n

In a new study, Dr. D\u2019Andrea and his colleagues found that novobiocin killed cancer cells with deficiencies in homologous recombination repair<\/a>. The drug also shrank tumors in mouse models of triple-negative breast cancer<\/a> that had mutations in DNA-repair genes. The researchers reported their findings in Nature Cancer<\/em> on June 17.  
 
\u201cMost important, we found that novobiocin killed tumors that had become resistant to a PARP inhibitor,\u201d said Dr. D\u2019Andrea. \u201cNovobiocin was even more effective in combination with a PARP inhibitor.\u201d <\/p>\n

Based on these results, his team is developing NCI-supported clinical trials to test the drug\u2019s ability to treat cancers that have become resistant to PARP inhibitors.<\/p>\n

The Dana-Farber team is not alone in finding that a Pol\u03b8 inhibitor may have anticancer activity. Scientists from the Institute for Cancer Research in London and their colleagues have reported that a Pol\u03b8 inhibitor called ART558 also can kill cancer cells and tumors that have become resistant to PARP inhibitors<\/a>. <\/p>\n

Using a Pol\u03b8 inhibitor in combination with a PARP inhibitor in patients with cancers that have mutations in BRCA<\/em> genes might prevent resistance from emerging in the first place, the latter group of researchers reported in Nature Communications<\/em> on June 17.<\/p>\n

The company that developed the drug, Artios, said that it plans to test the drug in clinical trials.<\/p>\n

Trying to Solve a Pressing Clinical Problem<\/h2>\n

PARP inhibitors, including olaparib (Lynparza)<\/a> and talazoparib (Talzenna)<\/a>, block an enzyme called poly (ADP-ribose) polymerase, or PARP, that helps repair damaged DNA. The drugs are used to treat cancers that have alterations in DNA-repair genes, namely BRCA1<\/em> or BRCA2<\/em>. <\/p>\n

Cells that have BRCA<\/em> mutations are forced to rely on an alternative DNA repair process that involves PARP. As a result, these cells are particularly sensitive to PARP inhibitors and die. This is known as synthetic lethality<\/a>.<\/p>\n

BRCA<\/em> gene alterations occur most often in ovarian, breast, pancreatic, and prostate cancers. PARP inhibitors have been mainstays for treating breast cancers that have BRCA<\/em> mutations<\/a>, and the drugs have recently been approved for treatment of prostate cancers with the mutations<\/a>. <\/p>\n

However, cancers eventually find ways to bypass the loss of PARP. \u201cNearly all women with ovarian cancer who are treated with PARP inhibitors will experience a relapse,\u201d said Dr. D\u2019Andrea. \u201cWhen the tumor grows back, it is resistant to PARP inhibitors, and at this point there are no treatments\u2014it\u2019s a terrible clinical problem.\u201d <\/p>\n

In 2015, Dr. D\u2019Andrea\u2019s team reported that tumors that are deficient in homologous recombination repair become overly dependent for their growth and survival on POL\u03b8. <\/p>\n

The new study of novobiocin suggests that synthetic lethality may arise from the inhibition of Pol\u03b8 in cancer cells that have defects in homologous recombination repair. The researchers cautioned that novobiocin \u201ccan overcome some but not all mechanisms of PARP resistance.\u201d<\/p>\n

In an editorial in Nature Cancer<\/em><\/a>, Thomas Helleday, Ph.D., of the Karolinska Institute, wrote that novobiocin showed \u201cimpressive anticancer activity\u201d in the laboratory and was \u201ceven better when used in combination with a PARP inhibitor.\u201d
 
Dr. Helleday noted that although ART558 and novobiocin inhibit Pol\u03b8 through different mechanisms, the results were similar. In the laboratory, ART558 killed cancer cells and shrank tumors in rats, the researchers found. <\/p>\n

Both novobiocin and ART558 \u201cconstitute powerful tools that demonstrate the relevance of targeting Pol\u03b8 in cancer,\u201d Dr. Helleday wrote. It remains to be seen whether these drugs benefit people with cancer, he added, but the strategy of inhibiting Pol\u03b8 in tumors with defects in homologous recombination appears \u201cpromising.\u201d <\/p>\n

A Clinical Trial through NCI\u2019s NExT Program <\/h2>\n

In recent months, Dr. D\u2019Andrea has worked with Geoffrey Shapiro, M.D., Ph.D., of Dana-Farber and Percy Ivy, M.D., of NCI\u2019s Division of Cancer Treatment and Diagnosis, to develop clinical trials of novobiocin through the NCI Experimental Therapeutics (NExT) Program<\/a>. <\/p>\n

NExT provides resources to develop promising treatments that address unmet needs in cancer care and that might not be adequately supported by the private sector. As part of this general support, NCI\u2019s Developmental Therapeutics Program<\/a> will ensure that capsules containing the appropriate doses of novobiocin (the drug is given by mouth) are available for participants in the trial. <\/p>\n

The study will test novobiocin, both alone and in combination with a PARP inhibitor, in patients whose tumors have developed resistance to PARP inhibition, according to Dr. D\u2019Andrea. The study will primarily include patients with ovarian or breast cancers and could start enrolling patients later this year. <\/p>\n

\u201cWe all want to better understand how to effectively treat patients whose cancers develop resistance to PARP inhibitors,\u201d said Dr. Ivy. \u201cI\u2019m cautiously optimistic about novobiocin based on the outstanding preclinical data, but we have to do the study.\u201d <\/p>\n

The clinical trial could help researchers understand the impact of inhibiting Pol\u03b8 on multiple DNA repair pathways. \u201cWe want to know whether novobiocin pushes a cancer cell beyond its ability to compensate for losing DNA repair pathways, leading to its death,\u201d Dr. Ivy said. <\/p>\n

How Science Happens: A Patient\u2019s Legacy <\/h2>\n

One of the challenges in the research, Dr. D\u2019Andrea said, has been to identify patients with cancer who are likely to respond to novobiocin. \u201cIdentifying potential responders to any cancer therapy is a challenge, and until now, we haven\u2019t known whom to give novobiocin to,\u201d he added. <\/p>\n

Their efforts got a big boost from the first attempt to repurpose the drug for patients with cancer. \u201cAs we read about that research, we thought that we might be on to something and moved forward with our own study of novobiocin,\u201d said Dr. D\u2019Andrea. <\/p>\n

The researchers were most intrigued by the woman with advanced breast cancer in the trial who responded to the drug after running out of other treatment options. At the time, surviving with metastatic disease for 2 years was exceptional. <\/p>\n

\u201cAlthough there was no way of knowing with any certainty, we suspected that this patient may have had a BRCA<\/em> mutation,\u201d said Joseph Paul Eder, M.D., who led the 1991 clinical trial of novobiocin. \u201cShe had the right family history<\/a> and family background for a BRCA<\/em> mutation.\u201d <\/p>\n

At the time, the BRCA<\/em> genes had not yet been discovered, but the woman\u2019s exceptional response suggested that the drug might help treat certain cancers. <\/p>\n

Now at the Yale Cancer Center, Dr. Eder credits Dr. D\u2019Andrea and others for identifying the target of novobiocin and demonstrating the drug\u2019s potential as a cancer therapy. But the \u201cchance finding\u201d of his patient\u2019s exceptional response 30 years ago may have played a small role in the current research, he noted. <\/p>\n

\u201cWe always hope that no patient\u2019s willingness to participate in a clinical trial will be in vain,\u201d said Dr. Eder. \u201cHere we have an example of how people who have volunteered for a clinical trial and have died from cancer can, decades later, bring us a step closer to helping others with this dreaded disease.\u201d <\/p>\n

Another author of the 1991 study, Lowell E. Schnipper, M.D., of Harvard Medical School agreed.<\/p>\n

\u201cIt\u2019s striking that when you plant a seed, it may germinate three decades later and take a form you had no idea about,\u201d Dr. Schnipper said. \u201cThat is how science works.\u201d<\/p>\n