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DNA repair: still promising in cancer?

Despite some setbacks in clinical trials, compounds such as the new PARP inhibitor class, which obstruct the repair of DNA by cells, could represent a promising new weapon
DNA_damage

The concept of fighting cancer by interrupting the process of DNA repair in cells has been discussed by scientists for decades, but it was only in the early years of the last decade that the first drug candidates started to enter clinical trials.

Foremost among these are inhibitors of PARP (poly [ADP-ribose] polymerase), an enzyme which is critical to maintaining genetic stability in cells by locating and repairing breaks in DNA.

DNA damage is a fact of life for a cell and is a consequence of a large number of normal endogenous activities such as metabolism. It is estimated that between 10,000 and 40,000 separate breakage events can occur in a cell each day, so robust repair mechanisms are needed to try to keep the integrity of DNA intact.

PARP was first discovered in the 1960s by researchers investigating why cells treated with cytotoxic drugs underwent a profound suppression of glycolysis, the metabolic pathway in the cell in which energy is produced from glucose. It was found that the reduction in glycolysis was linked to reduced levels of NAD+, a co-enzyme involved in the production of the energy-rich compound NADH (nicotinamide adenine dinucleotide). 

Further research revealed that the NAD+ was being consumed by the enzyme PARP and, in turn, that the enzyme was activated by single-strand breaks in DNA caused by the cytotoxic drug treatment.

Cancer cell susceptibility
The rationale behind the development of PARP inhibitors was that inhibiting this repair mechanism – known as homologous recombination (HR) – could render a cancer cell more susceptible to cytotoxic drugs, potentially compromising the viability of a cancer cell even without chemotherapy.

Initial efforts focused on breast cancer and, specifically, on the 5-10 per cent of tumours associated with mutations in the BRCA gene (BRCA1 and BRCA2). Both PARP and BRCA proteins are involved in DNA repair, so it was postulated that, by inhibiting PARP in a tumour that already lacks a BRCA gene, cancer cells would be prevented from repairing their DNA, either spontaneously or by enhancing the effectiveness of DNA-damaging chemotherapy, and cause them to die via a process known as synthetic lethality.

It is now eight years since the first PARP inhibitor (Agouron/Pfizer's PF-01367338; formerly AG014699) entered clinical testing and the initial enthusiasm has hit the almost inevitable roadblocks, although eight compounds in the class remain in clinical development for cancer applications.

PARP inhibitors in development for cancer

Compound
Sponsors
Phase
iniparib (BSI-201)
Sanofi (BiPar Sciences)
phase III
olaparib (AZD2281)
AstraZeneca (KuDOS Pharmaceuticals)
phase II
PF-01367338 (AG014699)
Pfizer
phase II
veliparib (ABT-888)
Abbott Laboratories
phase II
MK4827
Merck & Co
phase I
E7016/GPI 21016
Eisai/MGI Pharma
phase I
CEP-9722
Cephalon
phase I
BMN 673 (LT 673) BioMarin phase I

Early knockbacks
In January 2011, Sanofi reported that its iniparib candidate, currently the furthest along in development, failed to prolong survival in a phase III trial involving patients with metastatic, triple-negative breast cancer (TNBC), although it should be acknowledged that this is a hard-to-treat disease with few treatment options.

That was followed swiftly by an announcement by AstraZeneca that it would not pursue phase III development of olaparib, its own lead PARP inhibitor, in patients with hereditary BRCA1- and BRCA2-associated breast cancer after the drug failed to improve progression-free survival.

Subsequent to these announcements, there was a short period of despondency about the class, quickly superseded by an acknowledgement that the failures adhered to the usual risk profile of new drug development, and that PARP inhibitors may still play a key role in cancer therapy in future, once the optimal way to use them is established. One suggestion has been that they may best be used after initial chemotherapy as a maintenance treatment, for example.

Iniparib – acquired by Sanofi from BiPar Sciences when it bought the firm for $500m in 2009 – remains in development for TNBC, with data presented at this year's American Society of Clinical Oncology (ASCO) meeting showing a trend towards increased survival in a predefined subgroup analysis.

"Patients with metastatic triple-negative breast cancer have very few treatment options available to them," said Joyce O'Shaughnessy, of Baylor-Charles A. Sammons Cancer Center in Texas, US, the lead investigator in the trial. "I am encouraged by the second- and third-line data from this trial and believe further investigation is warranted in an effort to alleviate this unmet medical need."

The company also presented preliminary phase II data on iniparib in combination with other drugs in patients with recurrent ovarian cancer, with response rates ranging from 25 per cent to 65 per cent depending on whether the patients had been treated previously with platinum-based chemotherapy. It is also in a phase III trial in squamous non-small cell lung cancer and phase II testing for ovarian cancer and gynaecological indications including uterine carcinosarcoma.

Many family members
Nevertheless, the trial results have led to speculation about whether iniparib is a true PARP inhibitor. It appears to exert weaker activity against PARP1 than some of its peers in the group and may be acting via different, as-yet uncharacterised, mechanisms. PARP – like just about any other molecule – is a complex target that has a number of functions in the cell. In addition to DNA repair, for example, it also plays a role in gene transcription, while there are some 18 members of the PARP enzyme family.

Preliminary phase II data on iniparib in combination with other drugs in … recurrent ovarian cancer had response rates of 25 to 65 per cent

Writing in the October 2011 edition of the journal Oncology, Debu Tripathy of the University of Southern California in Los Angeles notes that in breast cancer 'it will be important to assess each [PARP inhibitor] separately, both in terms of the clinical endpoints as well as with regard to any information that can be gleaned from the small number of tumour tissue and germ-line correlative studies,' and that this will provide insight into the genetic profiles of patient subtypes among responders and non-responders.

Meanwhile, it remains unclear whether AstraZeneca's decision to drop the development of olaparib in hereditary BRCA1- and BRCA2-associated breast cancer is related to any misgivings about the efficacy of the drug in this indication.

The company has said in the past that one of the problems experienced with olaparib in its studies is that the current formulation requires patients to take multiple tablets in order to receive the correct dose of the drug, and it is developing a higher-dose formulation to take into a phase III programme. The new formulation may also help overcome some other issues with the drug, namely managing toxicities when used in combination with chemotherapy.

AstraZeneca said at the time that it dropped the phase III programme in breast cancer that it might revisit the indication at a later date. In the meantime, it is focusing on phase II trials in ovarian cancer – another disease related to BRCA deficiency – and gastric cancer, while developing olaparib in earlier-stage trials for pancreatic cancer, glioblastoma and colorectal cancer.

Critical to the future prospects of the PARP inhibitor class is that sensitivity to their action has been observed in cells with defects in DNA repair other than BRCA deficiency.

'The therapeutic potential of single-agent PARP inhibitors extends beyond BRCA1/2 mutation carriers,' according to Nicola Curtin of Newcastle University in the UK in a recent review of the field published in the British Journal of Cancer, co-authored with Milind Javle of the MD Anderson Cancer Center in the US.

Because defects in homologous recombination are common in many cancers, 'it is evident that single-agent PARP inhibitors have broader application than initially supposed,' they write.

Confidence in the future
That view has already been borne out in a phase II trial of olaparib in TNBC patients whose tumours were either BRCA-negative or unknown, as well as in BRCA-negative ovarian cancer patients. Abbott Laboratories is carrying out early-stage trials of its veliparib candidate in non-BRCA TNBC, although the drug's most advanced indications is neo-adjuvant breast cancer (phase II).

Despite the disappointments in early 2011, observers seem confident that PARP inhibitors will eventually come into their own as a class.

Market research firm Decision Resources said recently it believed the leading seven drug candidates would garner a collective $5bn in seven major world markets by 2019, led by iniparib, which it predicted would achieve sales in excess of $1bn a year.


Phil Taylor
The Author

Phil Taylor is a freelance journalist specialising in the pharmaceutical industry

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24th November 2011

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