Project: Development of Foxy-5 as a first in class anti-metastatic cancer drug
AIM_x000D_The aim of this project is to develop Foxy-5 as a first in class anti-metastatic cancer drug for the treatment of colorectal cancer. Foxy-5 is a 6 amino acid peptide fragment that mimics the effects of Wnt-5a, a signaling protein that suppresses the development of metastatic colorectal cancer. A lack of Wnt-5a expression in the primary tumour has been demonstrated, in work carried out by WntResearch, to correlate with an increased risk of cancer cell dissemination to other organs (i.e. metastasis) and reduced survival. Tumour metastasis is the predominant cause of death among cancer patients. Foxy-5 is designed to inhibit the development of metastasis by reducing the motility of cancer cells and therefore increasing survival rates in patients with colorectal cancer. _x000D__x000D_The aims of the preclinical work packages in this project are to develop Foxy-5 drug project in accordance with Good Manufacturing Practice (GMP), complete the pre-clinical toxicology and proof of concept studies. The aims of the clinical work packages are to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of Foxy-5, in patients with mixed solid tumours to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) by conducting a Phase I clinical trial. A Phase II proof of concept study will then be conducted at the MTD in colorectal cancer patients to investigate safety and efficacy of Foxy-5. _x000D__x000D_BACKGROUND_x000D_Cancer affects one in three individuals and is the leading cause of death below the age of 75 in most Western countries. Enormous efforts have been focused on improving diagnostics and therapeutics for cancer. However, the overall mortality rates reCO virtually constant. The primary tumour is rarely the cause of death of cancer patients. In fact, in the vast majority of cases, cancer-associated mortality is the result of cancer cell dissemination to other organs. The inherent problem with most current therapeutic approaches is their failure to target the dissemination process._x000D__x000D_Progression of the primary tumour, invasion of the surrounding tissue and the ability to form distant metastases depends on a series of sequential events. The metastatic process starts in a primary tumour. Upon progression of most primary tumours, the tumour cells undergo a decrease in their adhesive properties and an increase in their motility. However, not only is it the specific properties of the tumour cells themselves, but also those of the surrounding environment that are important for tumour metastasis. Interference with any of these events can delay or prevent metastatic disease. The present project focuses on the role of the Wnt-5a protein in the metastatic process. The Wnt proteins belong to a family of proteins that have been demonstrated to play a role in the formation of tumours._x000D_ _x000D_Wnt research AB, through its founder Dr. Tommy Andersson and his research group in Lund, Sweden published the first report on how the protein expression level of Wnt-5a in cancer cells correlates with the outcome of the disease, and this data revealed that low-level expression of Wnt-5a protein in primary invasive breast carcinomas is associated with higher histological grade (poor differentiation) and shortened recurrence-free survival. These findings were further confirmed with regard to disease-related death in a different breast cancer cohort. Increased proliferation was not the reason for the increased metastatic activity in these patients, but more likely it was due to an increased motile behaviour of the tumour cells. A similar role for Wnt-5a as tumour suppressor has been described in prostate and colon tissue._x000D__x000D_Dr. Andersson’s research group identified a 6 amino acid peptide fragment that mimicked the effects of Wnt-5a on breast and colon cancer cell migration. It was named hexapeptide Foxy-5. The effects of Foxy-5 on tumour metastasis were tested in vivo in a mouse model (4T1 mice cells injected into the mammary pad of normal BALB/c mice). In house results revealed that intraperitoneal injection of Foxy-5 reduced the metastatic burden in the lungs and in the liver by 70-90% in comparison to control animals._x000D__x000D_TECHNICAL APPLICATIONS_x000D_The project is comprised of 7 separate work packages:_x000D_WP1 Consortium Administration and Management (Months 0 – 36; Mar 2012 to Feb 2015)_x000D_WP2 Manufacturing upscale to GMP (Months 0 – 5; Mar 2012 to Jul 2012)_x000D_WP3 Clinical trial Phase I (Months 2 – 20; May 2012 to Oct 2013)_x000D_WP4 In vitro trials to improve cell line selection for mouse proof of concept studies (Months 1 – 9; April 2012 to Dec 2012)_x000D_WP5 Pre-clinical proof of concept study in mice (Months 8 – 25;Nov 2012 to March 2014)_x000D_WP6 Pre-clinical animal long-term toxicology study (Months 10 – 19; Jan 2013 to Sep 2013)_x000D_WP7 Clinical proof of concept study Phase II (Months 18 – 36; Sep 2013 to Feb 2015) _x000D__x000D_
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Acronym
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Foxy-5
(Reference Number: 7090)
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Duration
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01/03/2012 - 29/02/2016
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Project Topic
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Foxy-5 is a small peptide that mimics the effects of the protein Wnt-5a. Foxy-5 inhibits the development of metastasis and thereby increase survival rates in patients with breast and in particular colorectal cancer. Tumour metastasis is the predominant cause of death among cancer patients.
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Network
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Eurostars
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Call
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Eurostars Cut-Off 7
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Project partner
