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Development of oncology drug candidates to animal health: novel inhibitors of fatty acid synthase system to the melanoma canine therapeutics


In countries, such as Brazil, China and the United States, there is a continuous and frightening increase in mortality rates from skin cancer in dogs, making it an increasingly important problem for national and global animal health. The annual expenses per patient under treatment arrive on average US $ 40,000 / year, which do not reflect in important therapeutic benefit for the patients. Canine melanoma can develop in several anatomical sites such as oral cavity, paws, lips, eyes or various regions of the skin. Oral melanoma is the most commonly diagnosed form of melanoma in dogs. Although melanomas may appear in any dog, the prevalence of this disease is higher in purebred dogs, especially Schnauzers, Dobermans, Pinschers, Scottish Terriers, Irish and Gordon Setters and Golden Retrievers. Melanoma, especially in dogs, is devastating, with poor prognosis and the highest mortality rate. The antineoplastics employed in the treatment of melanoma canine are the same as those used in human therapeutic protocols. The disadvantage is the contribution to the emergence of resistance, culminating with a high number of failures in clinical practice. Thus, the development of novel drug candidate compounds for the treatment of canine melanoma becomes an urgent need. The rational design and development of a new chemical entity (NCE), called TBAT01, having as molecular target the enoyl-ACP reductase enzime, which is a crucial enzyme in the fatty acid synthase system (FAS), corresponds to a novel approach in veterinary medicine. The evaluation of cytotoxicity and selectivity of TBAT01 will be performed on a panel of melanoma cells and primary canine melanocytes. For the determination of safety doses used in in vivo tests, toxicological studies shall be carried out in accordance with the criteria established by the Organization for Economic Cooperation and Development (OECD). After the determination of the safety doses, through the no-observed side effects level (NOEL), the in vivo therapeutic effects will be evaluated in BALB / c nu / nu animals submitted to dorsal canine melanoma cell (CMGD-2) implantation. The antitumor effects will be evaluated by the set of techniques and analyzes, such as PET / CT-animal, measurement of tumor volume, tumor doubling time, tumor growth delay and the histological evaluation of dorsal tumors. It is expected that in this stage of the proposal, the preliminary proofs of concept (antitumor activity in vitro and in vivo) of the NCE will be achieved in order to provide the technological feseability of the novel antitumor compound designed for canine melanoma. (AU)

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