On April 7, 2014 ImmuNovo and VUmc reproted that they have received CCMO approval for Phase I with hVEGF26-104 vaccine in combination with the RFASE based adjuvant in the Department of Medical Oncology of VUmc Amsterdam headed by Professor Dr Henk Verheul (Press release Immunovo, APR 7, 2014, View Source [SID:1234500781]).
ImmuNovo’s CEO Joost van Bree PhD: ‘We are delighted to make this important step forward.’

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More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF). The VEGF family and their receptors (VEGFR) are receiving increasingly more attention in the field of neoplastic vascularization. VEGF is a powerful angiogenic agent in neoplastic tissues, as well as in normal tissues. Under the influence of certain cytokines and other growth factors, the VEGF family appears in cancerous tissue and the adjacent stroma, and plays an important role in neovascularization.

ImmuNovo and VUmc’s Medical Oncology are working on the development of hVEGF-trunc vaccine in combination with the RFASE based adjuvant for the treatment of cancer. A pro-angiogenic phenotype can be triggered by hypoxia resulting from the increasing distance between the growing tumor cells and the capillaries or from the inefficiency of new vessels. Hypoxia induces the expression of VEGF and its receptor via hypoxia-inducible factor-1α (HIF-1α). Tumor cells feed on the new blood vessels by producing VEGF and then secreting it into the surrounding tissue. Secreted VEGF binds its receptors (VEGFR1 and VEGFR2) on the outer surface of the endothelial cell. Once VEGF binds its receptor, a sequence of events follows that lead to angiogenesis. First, activated vascular endothelial cells produce matrix metalloproteinases (MMPs). MMPs cause degradation of the extracellular matrix (ECM). Next, the endothelial cells migrate into the surrounding tissues and begin to divide. Finally, the endothelial cells differentiate in order to form a functional blood vessel. ImmuNovo is working on the development of hVEGF26-104 vaccine in combination with the RFASE based adjuvant for the treatment of cancer.

The vaccine hVEGF26-104/RFASE consists of a truncated synthetic mimic of the human VEGF protein (hVEGF26-104) emulsified in the adjuvant RFASE. hVEGF26-104 is a new chemical entity based on Pepscan’s and ImmuNovo’s joint proprietary peptide technology. hVEGF26-104 consists of a continuous sequence out of the VEGF protein (residue 26-104) that covers the β1 to β6 and α2 region of the full protein sequence. Correct formation of the cys-knot fold gives both the β1/2/α2/β3 loop (first loop) and the β5/β6 loop (second loop) the correct 3D conformation that is required for a correct mimicry of the VEGF protein surface. In its oxidized form it is used as an antigen for VEGF directing the body’s subsequent polyclonal antibody response towards the active site of the VEGF molecule. The important issue is that antibodies raised against the synthetic molecule hVEGF26-104 strongly cross-react with endogenous VEGF and after binding of the antibodies to endogenous VEGF this hormone will no longer be able to bind to its receptors (VEGFR1 and VEGFR2) and consequently will no longer exert its angiogenic effect.

To enhance the immune response, RFASE will be used as an adjuvant. RFASE belongs to the adjuvant group of sulpholipopolysaccharides.

Preclinical data has already demonstrated the feasibility of this approach.

On April 7, 2014 Myriad Genetics reported that it has submitted the first module of a premarket approval (PMA) application to the Food and Drug Administration (FDA) for the use of BRACAnalysis testing as a companion diagnostic with olaparib (Press release Myriad Genetics, APR 7, 2014, View Source [SID:1234500382]). Olaparib is an investigational, orally active poly-ADP ribose polymerase (PARP) inhibitor being developed by AstraZeneca.
In 2012, Myriad made strides in developing BRACAnalysis as a companion diagnostic by retrospectively genotyping patients in a previously completed Phase 2 study of olaparib.

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On April 7, 2014 Deciphera Pharmaceuticals reported the initiation of a Phase 1 clinical trial of its pan-RAF inhibitor LY3009120 (DP-4978), under development in collaboration with Eli Lilly (Press release Deciphera Pharmaceuticals, APR 7, 2014, View Source [SID:1234500371]). The Phase 1 trial will evaluate the safety, tolerability and initial efficacy of LY3009120 in cancer patients. Data demonstrating the preclinical activity of LY3009120 in cancer were recently presented at the New Drugs on the Horizon plenary session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) national meeting, held April 5-9, 2014 in San Diego. LY3009120 emerged from a collaboration between Eli Lilly and Deciphera Pharmaceuticals, LLC. Deciphera received a $6 million development milestone for initiation of Phase 1 studies.
LY3009120 is a small molecule kinase inhibitor that has been shown to inhibit known characterized RAF isoforms, and potentially blocks proliferation in both BRAF and RAS mutant cancer cells. LY3009120 broadly blocks signaling of cellular RAF homo/heterodimers including CRAF containing dimers, thus minimizing paradoxical pathway activation and resistance mechanisms associated with selective BRAF inhibitors. Such paradoxical pathway stimulation is associated with side effects of these selective B-RAF inhibiting drugs, including cutaneous squamous cell carcinoma and other hyperplasias. As a pan-RAF inhibitor, LY3009120 blocks aberrant cancer signaling through RAS protein mutations, known to be prevalent in approximately 30% of all human cancers.

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On April 7, 2014 CANCER RESEARCH TECHNOLOGY (CRT), the commercial arm of Cancer Research UK reported a successful outcome to their existing collaboration with Teva through the identification of a novel atypical Protein Kinase C (aPKC) inhibitor pre-clinical candidate, licensed by Teva (Press release, Cancer Research Technology, APR 7, 2014, View Source [SID1234523227]).

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The successful multi-year, cross-discipline, collaboration between CRT and Teva has produced a first-in-class, highly selective and orally-active pre-clinical candidate* inhibitor for development by Teva into possible new drug therapies for cancer patients.

The drug compound blocks the atypical class of Protein Kinase C (PKC) proteins that are differentially activated in defined subsets of cancer patients. The aPKC inhibitor pre-clinical candidate was discovered following lead optimisation of early stage compounds identified within the CRT Discovery Laboratories. Teva provided significant resource and expertise during the collaborative research term to boost existing investment by Cancer Research UK.

The aPKC isoforms PKC iota and PKC zeta are types of enzymes called serine/threonine kinases that have a key role in regulating the formation of tumours (tumourigenesis), the early steps of tumor invasion and metastasis (tumor spread) to distant tissues, and the expansion and growth of cancer stem cells, which contribute to the emergence of tumor resistance to a variety of standard cancer therapies. Inhibition of the aPKC isoenzymes is an attractive target for anti-tumour treatments. Professors Peter Parker and Neil McDonald, at Cancer Research UK’s London Research Institute, significantly contributed to understanding the structural biology of the aPKC drug targets and their validation as important players in cancer cell growth and spread.

"The fruits of this collaboration are significant. These aPKC targets may play a role in a pathway that leads to the formation and progression of cancer. The ability to inhibit this pathway may provide a new approach to the treatment of multiple cancer types in a number of different patient populations", said Dr. Michael Hayden, Teva’s President of Global R&D and Chief Scientific Officer.

Under the terms of the license, CRT receive an upfront payment, and will be eligible to receive future success-based development milestone payments and royalty payments upon reaching specified targets once the drug is marketed.

Dr Keith Blundy, Cancer Research Technology’s chief executive officer, said: "This successful outcome from our collaboration represents the pinnacle of a highly productive collaboration to discover and develop first-in-class inhibitors of aPKC.

"By working with our industry partner, Teva and academic collaborators, we’ve accessed a much wider range of specialist expertise and experience, and demonstrated our ability to execute successfully the development of novel inhibitors.

"This approach has allowed us to move fast on this project, ahead of other commercial and academic groups interested in developing atypical PKC inhibitors."