Project: A new paradigm in breast cancer treatment: ultrasound mediated drug delivery

Breast cancer is the most frequent cancer diagnosed in women with an estimated 1.3 million new cases annually (Kamager, Dores et al, 2006). Approximately 12% of all women will develop the disease at some point in their lifetime (www.seer.cancer.gov). While prognosis of patients treated at the stage of small tumor diameter (< 2 cm) has clearly improved, there is still an unmet medical need as the vast majority of patients with advanced disease will die of their cancer. Current chemotherapy has demonstrated efficacy in this setting but is limited by systemic toxicity. It is the goal of the present consortium to bring to the clinic a drug delivery methodology comprising sonosensitive liposomes and an ultrasound device representing a high degree of innovation. With this approach a range of drugs currently used in breast cancer treatment may be transformed into more effective pharmaceutical products with the potential to improve treatment outcome of millions of breast cancer patients worldwide._x000D__x000D_A serious limitation of conventional breast cancer chemotherapy is the unspecific distribution of cytotoxic drugs resulting in reduced therapeutic efficacy and systemic side effects. By contrast, cytotoxic drugs formulated as nanoparticulate or liposomal delivery systems favour accumulation in solid tumours. There are, however, disadvantages associated with current liposome products: drug release from the liposome carrier is slow, tumour cell uptake is not improved, and the therapeutic-to-toxicity ratio is only marginally improved. During the last decades various approaches have been investigated to enhance localised drug delivery via triggered release, including combining ultrasound with ultrasound responsive drug carriers. In particular, acoustically active gas-containing liposomes or microbubbles, previously developed as ultrasound contrast agents, have received much attention. However, their large size is not compatible with efficient tumour tissue uptake and accumulation and a safe injected volume may be insufficient for a therapeutic effect._x000D__x000D_A series of studies conducted by the project participants have uncovered a clear potential for dramatically improving ultrasound sensitivity of conventional liposomes (i.e. not gas filled), and hence, for novel ultrasound sensitive or so-called sonosensitive liposomes (Figure 1 and 3, Annex). Since 2007, Epitarget has performed ten major multivariate liposomal formulation studies and several sonosensitive candidates have been identified. In a recent animal study conducted by Epitarget and Inserm it was shown for the first time that the candidate liposomes combined with therapeuic ultrasound have an inhibitory effect on tumour growth exceeding the effect of liposomes alone (Lafon et al, in prep. See Presentation Lafon et al 2010, enclosed in Annex). In contrast to gas filled carriers, these liposomes efficiently accumulate in the tumour due to the so-called Enhanced Permeability and Retention Effect (EPRE), rendering ultrasound mediated drug release and concurrent uptake into the cells possible (Figure 2, Annex)._x000D__x000D_Sonosenstive liposomes, an experimental device, and animal proof-of-principle are considered as establised upon entry into the current project. Hence, the remit of the current project is to develop an advanced device prototype and an optimised treatment regimen for breast cancer to enable entery into human clinical trails._x000D__x000D_The current project will be run as a crossfunctional collaboration between the two SMB´s Epitarget AS (CO applicant) and EDAP TMS SA, and the academic Ps Inserm U556 and U590. Epitarget AS is a Norwegian life science company dedicated to developing improved cancer therapies through particulate drug delivery. French company EDAP TMS is a global leader in medical devices based on High Intensity Focused Ultrasound (HIFU). Their CO product is Ablatherm® HIFU for thermal ablation of localised prostate cancer. The expertise of Inserm U556 in the field of therapeutic ultrasound applied to minimally invasive treatment of localized cancer is recognized worldwide. The unit has already a well-established collaboration with both Epitarget and EDAP TMS, and was instrumental in the development of the Abtlatherm® HIFU. Inserm U590 is an academic research group with expertise in preclinical and translational research, with a particular focus on breast cancer. This group has extensively published on mechanisms of action and resistance to conventional and novel agents, and has developed a number of preclinical animal models of human breast adenocarcinoma.

Acronym	ONCOSON (Reference Number: 6173)
Duration	01/04/2011 - 31/03/2014
Project Topic	The therapeutic/toxicity ratio of cytostatics is improved by inducing drug release from sonosensitive liposomes in tumor by the application of ultrasound. A drug delivery system comprising sonosensitive liposomes and an ultrasound device is developed representing a high degree of innovation.
Project Results (after finalisation)	1-Design and regulatory assistance for the development and manufacturing of a laboratory platform (CAVISTATION) dedicated to the evaluation of ultrasound mediated drug delivery for the treatment of breast cancer. _x000D_2- Implementation of the technology in a medical device designed to perform a phase I study.
Network	Eurostars
Call	Eurostars Cut-Off 5

Project partner

Number	Name	Role	Country
5	EDAP TMS SA	Partner	France
5	Epitarget AS	Coordinator	Norway
5	Inserm U556	Partner	France
5	Inserm U556	Partner	France
5	Inserm U590	Partner	France