On May 20, 2009 Cancer Research UK and Cancer Research Technology (CRT) reported they will begin a phase I clinical trial of an anti-cancer drug from GlaxoSmithKline (GSK) (Press release, Cancer Research Technology, MAY 20, 2009, View Source [SID1234523355]).

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GSK’s 1070916A, an aurora kinase inhibitor*, is the third drug to enter Cancer Research UK’s Clinical Development Partnerships (CDP) programme**, but the first that is ready to be used in patients.

Cancer Research UK will sponsor the phase I trial, at the Institute of Oncology at St James’s University Hospital in Leeds and Barts and The London’s Experimental Cancer Medicine Centre in London. The trial will be managed by the charity’s highly experienced drug development office and will start within the next year.

The phase I trial will be carried out on around 30 to 40 patients with advanced solid tumours who have had all the treatments currently available. Cancer Research UK will have the opportunity to carry out a further phase II trial if the trial is successful.

Dr Victoria John, head of clinical partnerships at Cancer Research UK, said: "We’re delighted to be working with GSK on this promising new molecule under our CDP initiative.

"This deal brings our CDP portfolio to three and the total number of new drugs in our early preclinical and clinical pipeline to over 40, something we believe is testament to the specialist skills and capability of our drug development team."

CDP offers companies an alternative model to traditional out licensing, which enables them to retain rights to the compound throughout the development programme. The programme launched in 2006 to increase the number of new treatments for cancer patients by taking deprioritised anti-cancer agents from industry and putting them into clinical trials.

Under the terms of the partnership deal with GSK, Cancer Research UK will fund the study through early clinical development. GSK will have an option to further develop and commercialise the molecule in exchange for future payments to Cancer Research UK. Financial terms have not been disclosed.

If GSK elects not to take the programme forward, the rights to the molecule will be given to CRT to secure an alternative partner.

Dr Keith Blundy, chief executive of CRT, said: "Pharmaceutical and biotechnology companies have always had to prioritise which agents they take into clinical development, but even more so in the current economic climate.

"This deal with GSK demonstrates how Cancer Research UK and CRT can work with industry to speed up the development of anti-cancer drugs that might otherwise remain on companies’ shelves."

Professor Chris Twelves, head of Cancer Research UK’s Experimental Cancer Medicine Centre*** at the University of Leeds and St James’s Institute of Oncology, who will lead the phase I study, said: "This exciting arrangement between Cancer Research UK and GlaxoSmithKline is good news for patients. It opens up a new avenue of drug development, allowing us to investigate a compound that is almost ready for the clinic but otherwise wouldn’t be tested in patients. We look forward to beginning the trial as soon as possible."

On May 15, 2009 Cancer Research Technology Limited (CRT) reported that it has licensed the rights to its DNA-dependent protein kinase (DNA-PK)* inhibitor programme to collaboration partner KuDOS Pharmaceuticals Ltd (KuDOS) – a wholly owned subsidiary of AstraZeneca (Press release, Cancer Research Technology, MAY 15, 2009, View Source [SID1234523356]). The deal will see significant extra investment into the Newcastle University programme for further development of drugs that inhibit DNA-PK.

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DNA-PK plays a key role in the cellular repair-response to DNA damage caused by chemotherapy and radiotherapy treatments. This response often means treatments are less effective, so finding drugs that inhibit DNA repair could lead to a better outcome for patients. Results from earlier work at Newcastle University, funded by the charity Cancer Research UK, and KuDOS show that in laboratory studies the use of DNA-PK inhibitors could increase the efficacy of current chemotherapy and radiotherapy regimes.

The research is a key component of Cancer Research UK’s Drug Discovery Programme at Newcastle University directed by Professors Roger Griffin and Herbie Newell. Professor Nicola Curtin and Dr Celine Cano will head-up this study in collaboration with KuDOS. Professor Curtin said: "This exciting project will enable us to continue our work with KuDOS to rapidly progress DNA-PK inhibitors from this programme into clinical development."

As part of the two year collaboration agreement announced today, KuDOS has exercised an earlier option to a portfolio of intellectual property. The company will also receive an exclusive worldwide licence to develop the intellectual property arising from the continued programme. Both will be in return for upfront, milestone and royalty payments that will be shared between CRT and Newcastle University.

Dr Niall Martin, head of KuDOS, said: "This agreement builds on a very effective research collaboration we have had for a number of years with the Newcastle group, helping us identify and prepare exciting new drugs for clinical trials in the future. As part of this agreement, we will invest in three more full-time posts in Newcastle which will be dedicated to the project, and see further backing from Cancer Research UK and Newcastle University in addition to ongoing work in KuDOS and AstraZeneca – ensuring significant expansion of the research."

Dr Phil L’Huillier, CRT’s director of business management, said: "It’s very exciting to combine efforts with commercial partners to progress early stage scientific discoveries such as DNA-PK, which have the potential to improve cancer treatments of the future. Today’s agreement provides a very strong commitment to the development of this extremely encouraging work."

On April 29, 2009 Crystal Genomics reported Histone acetylation and deacetylation play essential roles in modifying chromatin structure and regulating gene expression in eukaryotes (Press release, CrystalGenomics, APR 29, 2009, View Source;id=596&page=10&num=27&nowpos=1252&type=&sermun=&qu=&tb_name=eng_news&rt_page=/en/news/news.php [SID1234539172]). Histone deacetylase (HDACs) regulate histone acetylation by catalyzing the removal of acetyl groups on the side chain of lysine of core nucleosomal histones. This posttranslational modification of core histone is involved in the regulation of the transcriptional activity of certain genes. It has been known that aberrant recruitment of HDAC activity is associated with the development of certain human cancers.

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In this study, we have discovered series of HDAC inhibitors by using the structure-based drug discovery technologies. The optimized compounds were evaluated by various enzyme inhibitory assays, anti-proliferation assays against cancer cell lines, FACS analysis and measurement of acetylated histone accumulation. We also carried out in vitro ADME studies including metabolic stability, CYP inhibition assays, and in vivo PK studies. The anti-tumor efficacy was also tested in the various xenograft tumor model. Many of them showed clear anti-tumor effects. Among them, CG200745 showed promising anti-tumor profiles. CG200745 inhibits histone deacetylase activity in low range nM of IC50 against class 1 and class II HDACs. The CG200745 exhibited a broad spectrum of anti-proliferative activity against various cancer cell lines at sub micromolar EC50. Mechanistically, the CG200745 induced dose -dependent increase in the accumulation of acetylated histone H4 and in apoptosis supported by annexin-V analysis in various tumor cell lines. CG200745 also showed potent antitumor effect in various xenograft tumor model.

In addition, the preclinical safety studies of CG200745 were performed in rodent and non-rodent systems for dose determination of first in human trial.

In conclusion, CG200745, novel HDAC inhibitors that are discovered through the structure based drug discovery, show potent anti-tumor activity in cell-based assays and animal studies. Currently, further PK/PD studies and preclinical safety studies of CG200745 are in progress

On April 23, 2009 AstraZeneca reported that the Committee for Medicinal Products for Human Use (CHMP), the scientific advisory committee of the European Medicines Agency (EMEA), has issued a positive opinion supporting approval of the targeted oral anti-cancer drug, IRESSA (gefitinib) (Press release, AstraZeneca, APR 23, 2009, View Source [SID1234571042]).

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The CHMP has recommended the approval of IRESSA for adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating mutations of EGFR-TK (epidermal growth factor receptor-tyrosine kinase), in all lines of therapy.

IRESSA acts by inhibiting the tyrosine kinase enzyme in the EGFR, thus blocking the transmission of signals involved in the growth and spread of tumours. A mutation in the EGFR is a characteristic occurring in 10-15% of lung cancers in Europe, and studies have shown that these types of tumours are particularly sensitive to IRESSA. There are approximately 106,000 new cases of advanced lung cancer in Europe (top 5 countries) per year.

Anders Ekblom, Executive Vice President for Development at AstraZeneca, said: "Today’s positive CHMP opinion on IRESSA is an important step towards addressing the great unmet medical need of lung cancer patients in Europe, and supports AstraZeneca’s personalised healthcare strategy to develop the right medicine for the right patient. If IRESSA is approved, for the first time patients with these types of tumours will have a better alternative to chemotherapy as a first-line treatment."

The CHMP opinion is based on a submission package including two pivotal Phase III studies, IPASS and INTEREST.

The IPASS study exceeded its primary objective, demonstrating superior progression-free survival (PFS, the time a patient lives without their cancer progressing), greater objective response rate (ORR, tumour shrinkage), improved tolerability and significant quality of life benefits for IRESSA compared to carboplatin/paclitaxel doublet chemotherapy in clinically selected first-line patients in Asia. However, the treatment effect was not constant over time, with the probability of being progression-free in favour of carboplatin/paclitaxel in the first 6 months and in favour of IRESSA in the following 16 months. This was likely due to the different effect of IRESSA in subgroups defined by EGFR tumour mutation status. PFS was significantly longer for IRESSA than doublet chemotherapy in patients with EGFR mutation positive tumours, and significantly longer for doublet chemotherapy than IRESSA in patients with EGFR mutation negative tumours.

The INTEREST study met its primary objective, demonstrating equivalent overall survival (OS) and significant quality of life benefits for IRESSA compared to standard chemotherapy (docetaxel) in the pre-treated setting. Pre-planned sub-group analyses showed a significant improvement in PFS and ORR for IRESSA over docetaxel in patients with EGFR mutation positive tumours.

AstraZeneca will be required to conduct a Follow-up Measure Study, to generate further data in a Caucasian NSCLC patient population. AstraZeneca is in discussion with the CHMP to finalise the study design and endpoints.

The CHMP positive opinion is now referred for final action to the European Commission, which grants marketing approval in the European Union.

IRESSA is already an established therapy for pre-treated NSCLC in the Asia-Pacific region, where AstraZeneca is in consultation with regulatory authorities to discuss the potential use of IRESSA in first-line therapy.

NOTES TO EDITORS:

In 2005, AstraZeneca withdrew its EU marketing authorisation application for IRESSA following data from the Phase III international ISEL study in pre-treated patients not eligible for further chemotherapy. ISEL did not meet its primary objective of a statistically significant improvement in OS for IRESSA compared to placebo, but did confirm a number of important clinical benefits for IRESSA including tumour shrinkage and a significant improvement in time to treatment failure. The refractory* nature of the ISEL population is the most likely explanation for the magnitude of the survival improvement with IRESSA compared to placebo not reaching statistical significance.

* Patients whose tumours had grown during or soon after receiving prior chemotherapy

Following delivery of the INTEREST data, AstraZeneca submitted a new regulatory package to the EMEA in May 2008; the IPASS data were added to the submission package when they became available in Q3 2008.

There is a rolling programme of approvals and licence updates for IRESSA around the world in a broad second-line population based on data from the INTEREST study.

On April 19, 2009 Cancer Research Technology Ltd (CRT) reported that its scientists will present exciting new findings showing that a potent and selective inhibitor of protein kinase D called CRT0066101, inhibits the growth of pancreatic tumours (Press release, Cancer Research Technology, APR 19, 2009, View Source [SID1234523357]).

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The research – to be presented by CRT’s Dr Christopher Ireson at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) conference today (Sunday) – was a collaborative effort between scientists at CRT’s discovery laboratories and the University of Texas MD Anderson Cancer Center. These results show for the first time that an inhibitor of PKD can slow the growth of tumours in pancreatic cancer models. In addition, experiments carried out by CRT have shown that CRT0066101 is also effective at inhibiting the growth of tumours in a lung cancer model. The scientists believe that the drug has the potential to treat other cancers too.

PKD is a relatively newly identified family of serine/threonine kinases comprising PKD1, PKD2 and PKD3. The potential of PKD as a new drug target was discovered by Enrique Rozengurt, Doreen Cantrell and Peter Parker and funded by Cancer Research UK. Following this discovery, an intensive drug discovery effort led by CRT’s Head of Medicinal Chemistry, Dr Tony Raynham, culminated in the identification of CRT0066101 as a lead candidate for pre-clinical studies. Since then, PKD has been identified as playing a central role in the development of a number of cancers. In addition to its role in the growth of tumour cells, PKD has also been shown to play a pivotal role in cell survival and angiogenesis – a process by which tumours form new blood vessels – which is central to tumour growth and spread.

CRT’s discovery laboratories director Dr Hamish Ryder said: "We focused on pancreatic and lung cancer tumours because they represent cancers with a significant unmet medical need. The CRT model of combining promising basic science with the capability of the industrially-focused discovery laboratories gives us a unique opportunity to rapidly develop potential new molecules to novel targets, and through partnering with industry, explore the potential to see if one day it might help treat cancer patients in the future".

Dr Sushovan Guha who leads the laboratory at MD Anderson Cancer Center, said: "We are very optimistic about CRT0066101’s pharmacological potential. We believe this is the first orally administered small-molecule inhibitor of PKD with significant biological efficacy in pre-clinical animal models of pancreatic cancer. My conviction is that we will show the drug can also prevent the proliferation of cancer cells by blocking their supply of blood – through neo-angiogenesis. This would mean it offers a double action treatment but this needs to be proved through further work."