Marine lichens as an innovative source of anti-cancer drugs

Informations

Funding country

France

Acronym

MALICA

URL

-

Start date

2/1/2013

End date

-

Budget

636,780 EUR

Fundings

Abstract

Cancer remains a major public health issue due to the rapid development of resistance to chemotherapy drugs and to the persistence of poorly treated cancer varieties. Therefore, the search for more specific and effective drugs, and, in particular, those based on biotechnological advances, represents an important challenge for pharmaceutical companies worldwide. In the past years, antibody drug conjugates (ADCs) have emerged as a promising targeted therapeutic strategy. These bioproducts combine the specificity of a monoclonal antibody (mAb), targeting an oncogenic or biomarker protein localized at the surface of tumor cells, and the potency of highly cytotoxic molecules, bound by a synthetic linker to the mAb. The cytotoxic agent is then released near or inside the tumor, to kill the cancer cells. Pierre Fabre Laboratories are engaged in the research and preclinical development of ADCs, already produced several monoclonal antibodies, and is now in the quest for new cytotoxic molecules. Since agents with high cytotoxic activity (100 to 1000-fold that of conventional chemotherapy drugs) are required for ADCs, enediynes, potent natural toxic agents isolated from marine animals and actinomycetes, are of particular interest. Enediynes are among the most cytotoxic natural products known and are already used as anti-tumor agents (calicheamicin is used in an ADC). Enediynes show very interesting anticancer properties by targeting DNA and inducing specific free radical damages. The specificity of their interaction with DNA, determinant of the type of damage, is molecule-dependent. One can thus expect that the isolation of novel and functionalized enediynes might lead to the discovery of new mechanisms of action. Despite this interest, only a limited number of these molecules are described and most of them are patented. Here Pierre Fabre Laboratories has decided to join its efforts with two academic partners bearing a complementary expertise in microbiology, molecular biology and natural substances chemistry targeting the identification and synthesis of novel and highly-potent enediyne molecules to be conjugated to a tumor-targeting monoclonal antibody previously developed by the company. This will potentially result in an effective anticancer drug. In MALICA, the little studied actinomycetes associated with marine lichens will be explored to find new enediynes. We will use a multidisciplinary pipeline including innovative techniques for microbial isolation, genetic screening, media optimization, high throughput cytotoxic screening, bio-guided fractionation and chemical structure analysis. Once new chemical structures are characterized, analogues suitable for ADCs will be synthesized. MALICA is a multidisciplinary and highly complementary consortium. Pierre Fabre Laboratories has a long and solid expertise in drug development, the academic partner LOMIC is an expert in marine microbiology and genomics, while partner PNSCM is an expert of lichen biology, natural products chemistry and, in particular, enediyne synthesis. A number of dissemination activities are programmed including an international workshop on lichen microbiology and natural products, and displays to the general public showing the connections between biodiversity and drug development.