Novel anticancer strategy targets DNA repair
Could poly(ADP–ribose) polymerase inhibitors provide a major advance in the therapy of difficult-to-treat tumours, such as triple-negative breast cancer?
News & ANAlysis NATURe RevIewS | Drug Discovery vOlUMe 8 | JUNe 2009 | 437
By Alisa Opar
In April, Sanofi–Aventis announced that it will acquire BiPar Sciences, a California-based company that is developing novel cancer therapies, for up to US$500 million in milestone payments, including an undisclosed upfront payment. Among the agents that Sanofi–Aventis will gain is BiPar’s promising anticancer compound, BSI-201 — a potential first-in-class poly(ADP–ribose) polymerase (PARP) inhibitor that is currently in Phase II clinical trials.
PARP1, the major PARP isoform, is an enzyme involved in the repair of DNA damage, particularly under stressful conditions, such as exposure to radiation, carcinogens or anti-tumour drugs. Preclinical studies indicate that PARP inhibitors could enhance the efficacy of radiation therapy and chemotherapies such as alkylating agents and platinum-based drugs by preventing cancer cells from repairing DNA damage, thereby promoting apoptosis.
It is hoped that this therapeutic strategy could soon show clinical success for cancers that are currently difficult to treat. “It’s exciting because not only is this a new class of agents, but they may target some cancers that have been pretty resistant to treatment, like high-grade ovarian cancers and triple-negative breast cancers (TNBCs),” says Karen Gelmon, Professor of Medicine at the British Columbia Cancer Agency, Canada, who is the lead investigator of a Phase II trial of another PARP inhibitor, olaparib (AstraZeneca).
The eagerly awaited results of Phase II trials of both olaparib and BSI-201 will be presented at the American Society for Clinical Oncology (ASCO) meeting in Orlando, Florida, USA, from 29 May to 2 June 2009. BSI-201 has been studied in combination with chemotherapy (gemcitabine and the platinum-based drug carboplatin) in patients with metastatic TNBC — so called because the cancer cells lack receptors for oestrogen and progesterone and do not overexpress the human epidermal growth factor receptor 2 (HeR2). This cancer subtype, which accounts for about 15% of all breast cancers, does not respond to current hormone-based and HeR2-targeted therapies and does not have an approved standard of care.
BiPar reported interim safety data from this trial at the annual San Antonio Breast Cancer Symposium in December 2008, showing that the drug was well tolerated with no added toxicities compared with chemotherapy alone. The company also presented an interim analysis of gene expression data showing that, in tumours of the first 50 patients enrolled (there were 89 patients altogether), there was significant upregulation of PARP expression. “I think there is a possibility that this kind of agent will allow for a reduction in some of the doses of standard chemotherapy,” says Barry Sherman, BiPar’s executive vice President of Development. “As we go forward, we’ll use these drugs to get greater efficacy with fewer side effects.”
Next, as a wholly owned subsidiary of Sanofi–Aventis, BiPar plans to move its PARP inhibitor into Phase III trials for TNBC. BiPar will keep its name and maintain operations in California, says Hoyoung Huh, BiPar’s President and Chief executive Officer. “Obviously, Sanofi will provide a lot of the commercial input and late-stage development support, as well as the resources needed to accelerate the development and launch of this promising compound,” he says, adding that the deal ensures “...the momentum and the culture...” of BiPar will continue. looking ahead, Huh expects to continue ongoing trials of BSI-201 and chemotherapy in gliobastoma multiforme, uterine cancers and ovarian cancers.
Ovarian cancers and TNBC are both often characterized by mutations in the genes encoding breast cancer type 1 susceptibility protein (BRCA1) and BRCA2, which are normally involved in the repair of double-stranded DNA breaks through homologous recombination. Indeed, among the current clinical trials of PARP inhibitors (Table 1), the most advanced trials involve patients with mutations in BRCA genes, as early investigations showed BRCA-deficient cells to be particularly sensitive to PARP inhibition.
In addition to enhancing the effects of DNA-damaging chemotherapies, it is hoped that PARP inhibitors will also show activity as monotherapies in patients with BRCA mutations. This might provide a pioneering demonstration of the clinical exploitation of a general concept known as ‘synthetic lethality’ — that a loss of the function of either of two proteins alone is compatible with cell viability, but loss of both functions causes cell death (Nature Rev. Cancer 5, 689–698; 2005). In this case, the BRCA mutation gives rise to a defective homologous recombination pathway, and so the loss of further DNA repair pathways owing to PARP inhibition could result in synthetic lethality in the BRCA-mutant cancer cells, whereas normal cells with functional BRCA alleles survive.
“If you put together inhibition of PARP and lack of function of BRCA1 or BRCA2, you suddenly get a perfect storm of DNA repair deficiency and genome instability in the tumour, and tumour-selective killing,” says Andrew Tutt, Director of the Breakthrough Breast Cancer Research Unit at King’s Health Partners’ Academic Health Sciences Centre in london, UK. At ASCO, Tutt will present Phase II trial data of olaparib as a monotherapy for the treatment of patients with advanced breast cancer that have inherited mutations of BRCA1 or BRCA2. “The use here is based not on synergy with chemotherapy, but synergy with a tumour-restricted genetic defect in DNA repair.”
Breakthrough Breast Cancer and Cancer Research UK contributed to the development of the synthetic lethality hypothesis and preclinical proof of concept. In Phase I trials, olaparib showed significant efficacy and modest toxicity in patients with mutated BRCA1 or BRCA2. And the synthetic lethality approach may not be limited to carriers of BRCA1 or BRCA2 mutations, says Tutt. “It may occur in a wider range of cancers as yet to be defined.”
Currently, there are ~20 trials for olaparib in clinical development for the treatment of BRCA1- and BRCA2-defective breast cancers and ovarian cancers, as well as TNBC; serous ovarian, pancreatic and colorectal tumours; and melanoma. The compound is being investigated both as a monotherapy and in combination with platinum-based DNA-damaging agents, cytotoxic drugs and radiotherapy. Olaparib was originally developed by the UK biotechnology company KuDOS, which has been a wholly owned subsidiary of AstraZeneca since 2006. “we have been maintained as a specialized discovery unit in Cambridge, where we focus on finding new inhibitors of DNA damage-response that will then be developed by AstraZeneca,” says KuDOS’s Chief Scientist, Mark O’Connor.
Gabriel Hortobagyi, Chairman of the Department of Breast Medical Oncology at MD Anderson Cancer Center in Houston, Texas, USA, emphasizes that there is still much to be discovered about PARP inhibitors and the various cancers linked to BRCA mutations. “we haven’t even started to scratch the surface of whether PARP inhibitors would be similarly effective in BRCA-related prostate and pancreatic cancers.”
KuDOS is investigating which other types of tumours might have lost the homologous recombination repair pathway, says O’Connor. “It seems the more we look into this, the greater the potential is for targeting HRD [homologous recombination deficiency] tumours. So, I think the loss of this pathway might be a relatively common event in both solid tumours and haematological tumours.”
“I think it remains to be seen how common synthetic lethal interactions with cancer-relevant mutations will be in cancer cells,” says william Kaelin, of the Dana–Farber Cancer Institute in Boston, Massachusetts, USA. “But I think there’s still hope that the general concept is correct, and that we should be looking for vulnerabilities that are created upon the mutation of specific cancer genes, either alone or in combination, in cancer cells.”
Ultimately, Hortobagyi and Gelmon expect the drugs to be used in combination with other therapies and, at the very least, to provide the first somewhat specific agents for patients with BRCA1- and BRCA2-related cancers.
“I think that PARP inhibitors are not going to be without their toxicities,” says Gelmon. “But there’s so much potential in understanding more about how genes might cause cancers to occur. Once you start targeting a gene, then you can start saying, ‘can we prevent this gene from misbehaving and causing cancer?’
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