Journal of the National Cancer Institute Advance Access originally published online on October 9, 2007
JNCI Journal of the National Cancer Institute 2007 99(20):1505-1509; doi:10.1093/jnci/djm194
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© Oxford University Press 2007.
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Combining Carefully Selected Drug, Patient Genetics May Lead to Total Tumor Death
Drug combinations carefully designed to maximize the agents' effects are nothing new in cancer care. But researchers developing a new targeted therapy are taking the approach one step farther. Instead of combining it with another drug, they are following geneticists and relying on existing mutations in the cancer cells to give the drug its extra power.
They are using a small-molecule inhibitor that blocks one type of DNA repair to fight tumors that already have mutations in another DNA repair pathway. Although neither the drug nor the mutation alone is enough to kill tumor cells, inhibiting two DNA repair systems appears to be lethal. With early clinical data hinting that the approach will work, a select group of international researchers are testing the idea in ovarian and breast cancer patients who carry mutations in the BRCA1 or BRCA2 gene. Many companies have taken note and aim to capitalize on the drug–mutation combination—called a synthetic lethal approach—in one manner or another.
The drugs generating the buzz inhibit poly(ADP-ribose) polymerase (PARP). PARP detects single-strand breaks in DNA and is required for their repair in a pathway called base excision repair. Because many chemotherapy drugs are DNA-damaging agents, the inhibitors could help commonly used anticancer drugs work better when used in combination therapy. The synthetic lethal approach is likely to be even more powerful, however.
"What excites us is the whole synthetic lethal approach," said Vincent Giranda, M.D., Ph.D., a project leader in cancer research at Abbott in Abbott Park, Ill. "That hasn't been very successful over the years, where zero plus zero equals something. But (for) cancer—where DNA repair is often compromised—the base excision repair pathway, of which PARP is an essential part, is conserved."
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That conservation suggests that tumor cells rely heavily on the base excision repair pathway—and that blocking it could be a serious problem for tumors, especially if another DNA repair pathway is already compromised by a mutation. Abbott is one of the companies developing a PARP inhibitor.
Preclinical data support the synthetic lethal approach. Alan Ashworth, Ph.D., and colleagues at the Breakthrough Breast Cancer Research Centre at the Institute of Cancer Research in London, have reported that tumor cells that lack either the BRCA1 or BRCA2 gene, which is required for repair of double-strand DNA breaks, are especially sensitive to PARP inhibition. Wild-type cells and those with one functional copy of a BRCA gene and one mutant copy could grow in the presence of a PARP inhibitor. By contrast, cells that were deficient in either BRCA1 or -2 rapidly stopped growing, showed chromosome instability, and underwent apoptosis, or programmed cell death. The team saw similar results when they tested cells in vitro and in animal models. Because the drug is not toxic to wild-type and BRCA heterozygous cells, it could be useful in selectively killing tumor cells, with few toxic effects.
Following up on those laboratory data, AstraZeneca sponsored a phase I trial with its PARP inhibitor, AZD2281 (previously KU-59436). Early results, presented at the annual meeting of the American Society for Clinical Oncology in June, showed that the agent was relatively well tolerated, with some rare, reversible side effects (low mood and grade 4 reduction in platelet cells) and more common, but less severe, nausea and fatigue. The data also hint that the drug alone has some activity in patients with hereditary ovarian cancer, whose tumors are deficient in BRCA1 or -2 (six of 11 patients showed some response). Few breast cancer patients are enrolled in the phase I study, so the drug's potential activity for those patients is still unknown.
"As a concept, there are a number of hypothetical areas where you could combine loss of one pathway and block off another and get an enhanced effect. But I think this is certainly one of the first, if not the first, experiments aimed at trying to show that effect and succeeding in a clinical trial," said James Carmichael, M.D., chief medical officer at KuDOS Pharmaceuticals in Cambridge, UK, which originally developed AZD2281.
Trials for BRCA-Deficient Tumors
Two international phase II trials are now under way to test the synthetic lethal approach by using the PARP inhibitor AZD2281 in BRCA mutation carriers. The ICEBERG 1 (International Collaborative Expertise for BRCA Education and Research through Genetics) trial aims to enroll 40 women with confirmed BRCA1- or BRCA2-deficient breast cancer, and ICEBERG 2 aims to enroll 40 with BRCA1- or BRCA2-deficient ovarian cancer. Twenty-four centers are participating in the trials, all with a strong tie between their cancer genetics and clinical oncology groups, says Andrew Tutt, M.D., consultant oncologist and clinician scientist at the Breakthrough Breast Cancer Research Centre Institute, which is leading both trials.
AstraZeneca may be the first company to get its PARP inhibitor into phase II trials, but other companies are not far behind. And the competition have taken note of the phase I data in BRCA mutation carriers, though no companies were willing to say explicitly whether they would be running similar trials in that patient group.
"We are not pursuing the BRCA population as it is conventionally defined, but we are taking advantage of that information in our strategy more broadly," said Barry Sherman, M.D., executive vice president of development at BiPar Sciences in Brisbane, Calif., which has a PARP inhibitor in phase I trials. Sherman and chief executive officer Tom White said that the company researchers had used genomics to look for markers that could guide development of the drug. Those data, which they plan to present at meetings this fall, have pointed to several target populations, including some breast and ovarian cancer patients. "None of these indications are being pursued by the competitors," White said. The company is testing its PARP inhibitor, BSI-201, in phase I trials, both as a single agent and in four different combinations, including with DNA-damaging agents such as platinum-based drugs. (The team declined to specify exactly which chemotherapeutics they are testing.)
Researchers from the National Cancer Institute's cancer therapy evaluation program presented phase 0 trial data on Abbott's PARP inhibitor, ABT-888, at ASCO's meeting in June. The scientists found that the drug efficiently inhibited the PARP pathway in peripheral blood mononuclear cells and in tumor biopsy samples.
The company is now sponsoring a phase I trial at the Mayo Clinic, testing ABT-888 in combination with temozolomide. Temozolomide is a DNA-alkylating agent that induces a type of DNA damage that would normally be repaired by PARP-dependent base excision repair. The researchers chose the combination because overexpression of a DNA methylation repair enzyme is often associated with temozolomide resistance. Preclinical data indicate that adding a PARP inhibitor may overcome that obstacle. The researchers hope to eventually use the combination as a melanoma treatment, where temozolomide is often used, though the drug is not approved to treat that cancer.
Interestingly, Abbott's Giranda said that their preclinical tests with ABT-888 indicate that there doesn't seem to be a direct one-to-one link between the loss of BRCA gene function and PARP inhibitor activity. Thus, not all patients with BRCA-deficient tumors may benefit from the drug equally. Also, there may be other patient populations who could benefit from PARP inhibition. The BRCA-deficient background tends to increase sensitivity to PARP inhibition, especially when the drug is combined with DNA-damaging agents, but the situation may not be as simple as the ICEBERG researchers might hope.
Given the relatively untested synthetic lethal approach and the remaining questions about exactly which patients will most benefit from PARP inhibitions, KuDOS and AstraZeneca are not putting all their efforts into single-agent activity. They are currently testing the drug in combination with various DNA-damaging agents, including several platinum-based drugs as well as gemcitabine, dacarbazine, and topotecan. Yet Carmichael remains enthusiastic about the synthetic lethal approach with AstraZeneca's PARP inhibitor, AZD2281. He said that the companies are exploring the possibility that mutations in other genes in the BRCA pathway, which occur in a variety of solid tumors, suffer a similar demise when treated with the drug.
What isn't yet clear is whether the PARP agents are going to be the first in a wave of synthetic lethal drugs that turn a tumor's own traits against itself or are just a rare hit. "It's hard to know whether other drugs will work in a similar way in terms of generating a synthetic lethal approach. In many areas of oncology, people are looking at combinations that have that sort of effect," Carmichael said. "But whether other approaches will follow that remains to be seen."
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  A. Ashworth A Synthetic Lethal Therapeutic Approach: Poly(ADP) Ribose Polymerase Inhibitors for the Treatment of Cancers Deficient in DNA Double-Strand Break Repair J. Clin. Oncol., August 1, 2008; 26(22): 3785 - 3790. [Abstract] [Full Text] [PDF]
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