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Unlocking the cell

Inhibiting Aurora kinases is key to developing efficacious and effective cancer therapies

missing image fileOne in four deaths in the developed world is attributed to cancer - a group of diseases characterised by uncontrolled growth and spread of cells. Cells re-
produce by means of the cell cycle, a series of events which lead to the division of a cell into two daughter cells. Cell division depends on the replication of chromosomes followed by the segregation of the duplicates to opposite poles of the cell.

The cell cycle

The cell cycle is divided into four events referred to as:

  • G1 (Gap1) - chromosomes are prepared for replication
  • S (synthesis) - replication occurs
  • G2 (Gap2) - cells are prepared for the initiation of mitosis
  • M (mitosis) - chromosomes separate and cell division occurs. Mitosis is further divided into phases outlined below.

Centrosomes are the organisation centres for the microtubules which form the 'scaffolding' of the cell. In the first phase of mitosis - prophase - they separate. Some fibres cross the cell to form a central mitotic spindle. In the nucleus of the cell, the chromatin (DNA, RNA and protein) condenses into chromosomes - macro-molecules made up of two identical strands of DNA called chromatids. The nucleus then breaks down.

In the next phase, metaphase, the chromosomes align along the central spindle, this process ensures that when they split each daughter cell will have one of the two chromatids. In anaphase, the chromosomes separate. Next comes telophase, where each chromatid decondenses back into chromatin and moves to opposing poles of the original cell. Here new membranes start to form around the chromatin as they start to become the nuclei of each daughter cell. Telophase is followed by cytoplasmic division (cytokinesis) producing two identical daughter cells.

To ensure the integrity of the cell cycle, cells activate a number of checkpoints throughout the events from G1 into S-phase, during S-phase, from G2 into mitosis and during mitosis. These enable the cell to check for and repair any DNA damage, ensure DNA replication is complete, make sure all the chromosomes are correctly aligned on the spindle and that the cytoskeleton of each daughter cell is normal.

External factors, including tobacco, radiation or chemicals and internal factors, such as inherited mutations can lead to inactivation of those checkpoints. Without functioning checkpoints cells can develop gross proliferative imbalances such as incomplete genomes or aneuploidy - where the daughter cells are not identical and have different chromosome numbers. The resulting genomic instability is characteristic of most cancer cells.

Cancer therapy

Treatments for cancer, including surgery, radiation and chemotherapy, stop the cancer cells from dividing and reproducing themselves. The Thomson Pharma database contains entries for more than 900 cancer drugs in clinical development.

Worldwide sales of the anticancer monoclonal antibodies Herceptin (trastazumab) and Avastin (bevacizumab) are both predicted to quadruple by 2010 from sales of about $1.5bn in 2005
to $6bn.

Other top anticancer agents like the protein kinase inhibitors Tarveva (erlotinib), Nexavar (sorafenib) and the hormone antagonist Arimidex (anastrozole) are forecast to break the $1bn sales barrier. In 2010, the antimetabolite Gemzar (gemcitabine) is predicted to have sales of about $1.7bn, the microtubule modulator Taxotere (docetaxel) more than $2bn and the protein kinase inhibitor Gleevec (imatinib) in excess of $3bn.

With the high incidence and prevalence of cancer and the diversity of causes, there remains great potential for novel drugs targeting specific pathways implicated in cancer - such as Aurora kinases.

Aurora kinases

Aurora kinases are key enzymes involved in mitosis and are overexpressed in a range of malignancies including breast, prostate, colorectal, ovarian and thyroid cancer. There are three Aurora kinases, all localised in different areas within the cell and with diverse functions during mitosis.

Aurora A kinase localises on the duplicated centrosomes and has functions in centrosome separation and spindle bipolarity.

Aurora B kinase forms part of what is known as the "chromosomal passenger protein complex". This complex is essential throughout mitosis, regulating chromosome condensation, the mitotic spindle checkpoint, the formation of the indentation that occurs in the cell before separation (known as cleavage furrow formation) and cytokinesis.

Recently discovered Aurora C is specifically expressed at high levels in the testis and localises to the centrosomes in anaphase and telophase. It has also been implicated as a chromosomal passenger protein.

In normal cells, Aurora kinases are expressed at low levels in G1 followed by a steady increase towards mitosis. Malignant cells, in contrast, express Aurora kinases regardless of their cell cycle phase. Overexpression of Aurora A kinase has been associated with abnormal centrosome amplification, giving rise to aneuploid cells containing multiple centrosomes. This results in chromosome misalignment during mitosis and failure of cytokinesis.

Aurora A kinase can contribute to uncontrolled proliferation of the cancerous cell by directly enhancing the degradation of the protein that inhibits unrestrained cell division in normal cells (tumoursuppressor p53).

Overexpression of Aurora B kinase can also add to genetic instability by inducing abnormalities in chromosome alignment or by affecting the spindle checkpoint and cytokinesis.

As yet, little is known about the role Aurora C may play in cancer.

Aurora kinase inhibitors

Anticancer therapy aims to inhibit the proliferation of malignant cells and to kill them effectively. Selectively targeting cancer cells that overexpress certain proteins, like Aurora kinases, avoids the cytotoxic effects in normal cells, associated with many currently available drugs.

The inhibition of Aurora kinases therefore represents a highly significant therapeutic strategy.

According to Thomson Pharma, there are currently 21 Aurora kinase inhibitors in development with four in phase I and three in phase II clinical trials.

Phase II clinical trials

MK-0457

MK-0457 (VX-680) is a small molecule being developed by Merck & Co, under licence from Vertex Pharmaceuticals. In preclinical studies, MK-0457 potentiated cell death in colon cancer, lymphoma and leukaemia cell lines and tumour growth was inhibited in in vivo animal models. In phase I/II trials in patients with haematological cancers, MK-0457 was well tolerated and cell death was induced in leukaemia patients.

Phase II trials are currently ongoing in patients with haematological and colorectal cancers.

PHA-739358 and AT-9283

Also in phase II trials for patients with haematological neoplasm and solid tumours are PHA-739358 (Nerviano Medical Sciences) and AT-9283 (Astex Therapeutics). In mice tumour models, PHA-739358 inhibited tumour growth by about 80 per cent. PHA-739358 was found safe in a phase I trial in solid tumour patients and phase II trials were initiated in February 2007 in patients with haematological malignancies.

Efficacy in animal models was observed for AT-9283. No clinical data is available yet but phase I/II trials were initiated at the end of 2006.

Phase I clinical trials

AZD-1152

AstraZeneca's AZD-1152 inhibits Aurora B kinase and inhibition of colorectal and lung tumour growth of between 69 per cent and 100 per cent were reported. A combination of AZD-1152 with gemcitabine could enhance chemotherapeutic agents by augmented cell growth inhibition. In an ongoing phase I trial, AZD-1152 was well tolerated and three of 19 patients achieved stable disease to date.

MLN-8054

In lung, colorectal and prostate tumours, preclinical efficacy has been observed for MLN-8054, being developed by Millennium Pharmaceuticals. Phase I trials are currently assessing safety and tolerability of MLN-8054 in patients with advanced solid tumours and lymphoma.

R-763

Merck Serono's R-763 has shown therapeutic potential in haematological cancer. In leukaemia animal models, tumours regressed by between 78 and 87 per cent after one dose. It also appeared to be well tolerated. Haematological cancer patients were enrolled in February for a phase I trial.

MK-6592

In March, a phase I trial in solid tumour patients started for another Aurora kinase inhibitor from Merck & Co - MK-6592.

Other potential therapies

Sunesis Pharmaceuticals' SNS-314 is expected to enter phase I trials by mid-2007. SNS-314 was effective in animal models of colon, breast, prostate, lung, ovarian and skin cancer with up to 96 per cent tumour growth inhibition.

Phase I trials are also expected for SuperGen's MP-235, which had good selectivity for Aurora A kinase and demonstrating antiproliferative effects in pancreatic cell lines. SuperGen is also investigating MP-529 for oral administration. Like MP-235, MP-529 is more selective for Aurora A kinase and reduced cell proliferation in pancreatic, as well as lung cancer.

Currently undergoing lead optimisation are the Aurora kinase inhibitors Ab-038 (Ambit Biosciences) and CHR-3520 (Chroma Therapeutics). Several programmes to identify Aurora kinase inhibitors are in progress such as those from Axxima Pharmaceuticals and EntreMed. EntreMed's ENMD-981693
was shown to induce tumour regression.

Additionally, Cyclacel Pharmaceuticals is investigating oral Aurora kinase inhibitors with CYC-116 being the lead compound.Merck & Co has other compounds in its programme, including VE-465 and VX-689.

Therapeutic potential

Aurora kinase inhibitors are promising anticancer agents against a novel target. Their effectiveness in inducing cell death and tumour regression has been demonstrated in several cancer types. Aurora kinases are implicated in pathways leading to production of new tumour growth and there is evidence that their overexpression is associated with malignancy. Directly targeting Aurora kinases may prevent
side effects.

Aurora kinase inhibitors have been well tolerated in preclinical and clinical studies. Although the effectiveness and tolerability of this class of drugs needs to be established in clinical trials, it represents an important addition to cancer research with potential in future anticancer therapy.

Ulrike Jahnke is editor in the drug information department at Thomson Scientific. This article is based on data taken from the Thomson Pharma database (www.thomsonpharma.com)

"With the high incidence and prevalence of cancer and the diversity of causes, there remains great
potential for novel drugs"

 

19th June 2007

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