Project: Topical Skin CAncer Application

The TOSCA project aims at developing an effective and safe topical treatment for skin cancer (dermatological cancers), actinic keratosis (AK) and genital warts by combining the properties of TMX-202, which binds with high specificity a well-established target in this field, with an innovative formulation for topical treatment capable to optimize skin penetration and drug delivery. Efficacy and safety of the formulated compound will be studied and compared to currently used therapies in a suite of proof-of-concept preclinical experiments by using a unique animal model that closely mimics development of skin diseases in humans._x000D_Treatments of skin diseases fall into two broad categories: physical treatment, such as surgical or ablative methods targeted to one lesion, and topical medications. Topical treatments have the advantage to act on larger areas with many lesions and some of the available agents (Imiquimod [Aldara] and 5-fluorouracil [5-FU]) reveal and treat subclinical lesions as well. The disadvantages of medical therapies include lengthy courses of treatment with irritation and discomfort. Imiquimod 5% cream (Aldara), the current market leader, is an immune response modifier authorized for the treatment of external genital warts, AK and superficial basal cell carcinoma (BCC) lesions of 2 cm or less. Its proposed pharmacologic mechanism is the up-regulation of cell-mediated immune responses in the skin upon the activation of Toll-Like Receptor 7 (TLR7) leading to apoptosis of the tumour cells._x000D_There is a strong need for the development of more effective, specific and safe topical treatments for skin diseases, and in particular for AK, for the following reasons:_x000D_• The incidence of AK and skin diseases in general is worldwide rapidly increasing;_x000D_• The recognized benefits of early intervention on AK to prevent progression to skin cancer;_x000D_• The increased awareness of the danger associated to sun damage, AK and skin cancer;_x000D_• A need for a topical treatment because AK affects skin diffusely;_x000D_• A growing understanding among clinicians that topical treatments for AK and skin cancer may act on both clinically visible lesions and lesions that may not yet be visible;_x000D_• Patient preference for less invasive and more cosmetically acceptable treatment alternatives._x000D_TLR7 has emerged as a particularly important target for the development of drugs that modulate the innate immune system as it binds not only naturally occurring large molecules but also synthetic small molecules with classical drug-like properties (Hemmi H. et al., 2002; Lee J. et al., 2006). Drug-like properties of compounds are fundamental for their potential development as successful pharmaceutical products._x000D_TMX-202 (Telormedix background IPR) is a new chemical entity with a saturated phospholipid moiety bearing two alkyl chains of 12 carbon atoms. This compound activates TLR7 with high selectivity, inducing a prolonged but reversible production of cytokines in mice. In cellular assays, TMX-202 shows 2-3 logs enhanced potency compared to Imiquimod, the active ingredient of Aldara. Most recent preliminary experiments performed at Telormedix to evaluate TMX-202 development in skin cancer treatment evidence that: _x000D_• TMX-202 penetrates both human and pig skin;_x000D_• TMX-202 induces inflammatory cell infiltration in the skin;_x000D_• TMX-202 local/topical treatment induces low systemic pro-inflammatory cytokines compared to Imiquimod/Aldara;_x000D_• TMX-202 shows a better efficacy and tolerability in a transgenic mouse skin cancer model compared to Imiquimod/Aldara;_x000D_• Contrary to Imiquimod, TMX-202 does not interact with adenosine receptors or other pain associated receptors (Na+ channels)._x000D_Based on existing data (see Annex), TMX-202 appears suitable to further preclinical analysis to confirm its properties in animal models best suited for the study of topical treatment of skin cancer and other skin disorders such as AK and genital warts._x000D_The best animal model has been identified in an African rodent that naturally develops the suite of skin disorders to be targeted by TMX-202. Warts are causally induced by human papillomaviruses and selected animal model is naturally infected by these viruses._x000D_The CO objective of the TOSCA project is to acquire the knowledge base needed to proceed on both pre-clinical studies and clinical trials for a new highly effective topical treatment of genital warts, AK and skin cancers._x000D_A related scope is the development of an appropriate topical formulation for TMX-202. This formulation is required to obtain a proof of concept for the targeted skin diseases using the selected animal model. Standard formulations such as cream, gel and spray appear not well suited for TMX-202 as result of preliminary studies. The use of foams proposed by Foamix promises to ensure the needed solution as discussed. The in vitro assays to be done at CHARITE' – Berlin will trigger the selection of the best formulation for skin penetration properties and drug delivery.

Acronym TOSCA (Reference Number: 6872)
Duration 01/10/2012 - 31/03/2015
Project Topic TOSCA will develop a knowledge base for a new skin cancer topical treatment based on TMX-202 foam formulation. FMX, a developer of emerging foam technologies, will work with TMX to address a very promising market._x000D_ The academic Ps will contribute with unique scientific tools and expertise.
Project Results
(after finalisation)
The different formulations provided by the project Ps were investigated and the best formulation was determined. It was demonstrated that the formulation penetrated into the living tissue and that it was taken up by the dendritic (Langerhans) cells. The optimum formulation was found to be very promising for future application.
Network Eurostars
Call Eurostars Cut-Off 7

Project partner

Number Name Role Country
4 Deutsches Krebsforschungszentrum, Division "Viral Transformation Mechanisms"/Research Program Infection and Cancer Partner Germany
4 Charité - Universitätsmedizin Berlin, Clinic of Dermatology, Venereology, and Allergology / Viral Skin Carcinogenesis Group Partner Germany
4 Foamix Ltd Partner Israel
4 Telormedix SA Coordinator Switzerland