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Initiation of global Phase III clinical study by Merck KGaA of Stimuvax®

On June 22, 2009 Cancer Research Technology Limited (CRT), the oncology-focused development and commercialisation company, reported initiation of global Phase III clinical study by Merck KGaA of the therapeutic cancer vaccine Stimuvax (BLP25 liposome vaccine, L-BLP25) in patients with advanced, inoperable breast cancer (Press release, Cancer Research Technology, JUN 22, 2009, View Source [SID1234523352]). The STRIDE(a) study will determine if Stimuvax can extend progression-free survival in patients treated with hormonal therapy who have hormone receptor-positive, locally advanced, recurrent or metastatic breast cancer.

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Stimuvax is a liposomal peptide vaccine against the tumour-associated protein MUC1. The vaccine was developed by Oncothyreon (formerly Biomira) under a portfolio of patents licensed by CRT, following Cancer Research UK-funded investigations led by Prof Joyce Taylor-Papadimitriou at Guy’s Hospital, London. Stimuvax was the first investigational cancer vaccine to enter Phase III clinical testing in NSCLC with the February 2007 launch of the STARTb study, which will involve more than 1,300 patients with unresectable stage III NSCLC, who were stable or responding after chemoradiotherapy.

You can find out more about this new study by reading Merck KGaA announcement here.

Cambridge Research Institute attracts GSK backing for novel therapeutic collaboration

On May 26, 2009 Investigators at Cancer Research UK’s Cambridge Research Institute (CRI) in conjunction with Cancer Research Technology (CRT) reported that they have agreed major support from the pharmaceutical company GlaxoSmithKline (GSK) to investigate a promising new treatment in kidney, bowel and pancreatic cancer (Press release, Cancer Research Technology, MAY 26, 2009, View Source [SID1234523354]).

CRT, the Cancer Research UK owned commercialisation and development company, has secured a deal with GSK which will make use of the charity’s expertise to carry out two projects. The first project seeks to understand how the compound GSK2136773 containing the active portion of an antibody, works in laboratory models of pancreatic cancer*. The second project will use sophisticated imaging techniques** to compare the antibody’s effectiveness against current therapies in treating bowel and kidney cancer. Financial details were not disclosed.

The scientists at the Cambridge Research Institute are experienced at running high quality translational studies using the Institute’s state of the art facilities and highly developed tumour models.

Collaborations such as these with GSK’s Academic Discovery Performance Unit allow CRI researchers to study the latest therapeutics in development and make use of the charity’s expertise in progressing potential new treatments towards clinical use.

Dr David Tuveson, head of the Tumour Modelling and Experimental Medicine laboratory at Cancer Research UK’s Cambridge Research Institute – who will lead the first project – said: "We are delighted to be working with GSK and making the most of our medical and scientific expertise to push forward this project. It will enable us to determine if the domain antibody will help target pancreatic cancer – a cancer that poses some of the toughest questions for scientists because it has proven so difficult to treat."

GSK2136773 was developed by GSK. It is a domain-based biopharmaceutical that binds to and inhibits the action of the protein VEGF. VEGF drives the development of an efficient blood supply to tumours and by blocking the blood supply, a tumour’s growth can be inhibited. Domain antibodies are the smallest active part of an antibody. They can be as small as a 12th of the size of a complete antibody and it is thought that the small size means they will be able to penetrate deeper into the tumour tissue, and therefore be more effective than traditional antibody therapies.

Dr Phil L’Huillier, director of business development at Cancer Research Technology said: "This collaboration offers an opportunity for our scientists to apply their world-leading expertise in cancer to help progress potential treatments. Taking a treatment from the laboratory to the patient is one of the most challenging steps in drug development and such collaborations can make an important contribution to this process."

Cancer Research UK and GlaxoSmithKline join forces to trial new anti-cancer drug

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]).

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."

CRT, Newcastle University and KuDOS advance DNA-PK Research with a new licence

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.

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."

Preclinical Studies of CG200745, Novel Histone Deacetylase Inhibitor Discovered Using Structure-Based Drug Discovery Technologies

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.

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