Project: Pre-clinical drug development of TR4 for the treatment of human carcinomas
The TROJANDRUG project aims to carry out the first pre-clinical drug development using innovative capabilities and expertise previously unavailable in Cyprus. The proposed consortium has been assembled to provide the proper pre-clinical setting that will enable the TR4 cancer drug molecule developed by Trojantec, to cross the barrier from pre-clinical phase and into the clinical trial phase, the first of its kind in Cyprus. The project consortium recognizes the need for initiatives that foster synergies between industry and academia and among EU countries, and considers the role and input of each P as integral to the successful execution of the project. The project Ps further acknowledge that without critical EU funding provided through national funding schemes as well as from the collaborating Ps, this innovate proposal will not be successful as Cyprus is only just beginning to develop such novel pharmaceutical core capabilities._x000D__x000D_The cancer inhibiting potential of the TR4 fusion protein is based on increasing available evidence, which suggests that the same molecular pathways regulating the self-renewal of stem cells are also being employed in cancer progression. The Notch signaling is an evolutionary-conserved pathway in vertebrates and invertebrates that is involved in many developmental processes, including cell-fate decisions, apoptosis, and stem-cell proliferation, differentiation and self-renewal. The Notch pathway has been associated also with several human cancers, including acute T-cell lymphoblastic leukaemia, cervical, prostate, neuroblastomas, lung, breast cancer and is strongly implicated in tumourigenesis. Today due to the strong evidence of a role for Notch signaling in many forms of cancers, this pathway is an attractive target for many pharmaceutical companies for the development of novel anti-Notch therapeutics. _x000D__x000D_We have genetically engineered a fusion protein, TR4, consisting of the truncated version Mastermind-like (MAML), which behaves in a dominant negative (DN) fashion and inhibits Notch activation, and the cell penetrating peptide Antennapedia (ANTP). Our results indicate that targeting Notch signaling with the ANTP-DNMAML translocates into the cell nucleus and suppresses Notch activation. In addition, we show that attenuation of Notch signaling with the recombinant ANTP DNMAML reverts the transformed phenotype, inhibits the anchorage dependent growth, induces self contact inhibition and apoptosis in high metastatic epithelial human breast cancer cells. More significantly, we provide direct evidence that that inhibiting Notch signaling at the transcriptional level with the ANTP-MAML protein suppresses the expression of downstream Notch targets, induces tumor cell apoptosis, and inhibits or eliminates human tumor growth in nude mice (see Partial TR4 preliminary data in the Annexes). These findings support the premise that TR4 regulation is a promising therapeutic strategy for human cancers. Trojantec and its Ps plan to develop the necessary research capabilities to investigate the dynamics of the TR4 fusion protein in an in vivo setting and help characterise the therapeutic interactions of the drug molecule in an animal tumour model. These mechanisms of interaction will be investigated via the application of innovative imaging modalities such as in vivo flow cytometry and whole body reflectance imaging with the aim of guiding Trojantec’stechnology closer to the market and completing the necessary pre-clinical studies in order to optimise and validate the TR4 fusion protein as novel therapy for cancer disease._x000D_
|
Acronym
|
TROJANDRUG
(Reference Number: 8520)
|
|
Duration
|
09/12/2013 - 09/02/2016
|
|
Project Topic
|
We have generated a fusion protein, TR4, that inhibits the Notch pathway at the transcriptional level and reduces tumor growth in experimental animals. We are carrying out pre-clinical studies to support the premise that TR4 is a potential therapeutic agent for the treatment of human cancers.
|
|
Network
|
Eurostars
|
|
Call
|
Eurostars Cut-Off 10
|
Project partner
