Download Identification of Novel Therapeutic Targets in Breast-cancer

2014 Research Grant Program Winning Abstract
Identification of Novel Therapeutic Targets in Breast-cancer-specific
Myeloid-derived Suppressor Cells
By David Escors
Cancer is responsible for more than 7 million deaths worldwide. A recent report has
shown that, particularly in the European Union, about 2.5 million people were diagnosed
with cancer in 2008, with 1.23 million deaths in 2008 and 1.75 million in 2012. The data
shows that cancer-associated deaths in the EU are in the increase. Direct associated
costs to the EU in 2009 amounted to 126 billion, to which 40% of these went to health
care. Overall, cancer costs an average of 102 per European citizen, and the highest
economic costs can be attributed to lung cancer (15%), breast cancer (12%), colorectal
cancer (10%), and prostate cancer (7%). In this project we are focusing on breast
cancer.
A major cause of the failure of anti-cancer treatments is tumor-induced immune
suppression, largely caused by the expansion of myeloid-derived suppressor cells
(MDSCs). These cells were recently described and strongly inhibit anti-tumor immune
responses. MDSCs are largely responsible for tumor-induced immune suppression and
the failure of anti-neoplasic treatments. These cells infiltrate tumors, where they inhibit
immune responses and accelerate tumor progression. Therefore, MDSCs have become
key therapeutic targets. Currently, their study is rather cumbersome because there is no
efficient in vitro system to produce them. Without any doubt, the major drawback in the
development of novel treatments targeting the immunosuppressive activities of these
cells is the impossibility of growing them in large numbers. Therefore, they have to be
isolated from tumor-bearing experimental animals, requiring more than 10 to purify about
1 to 3 million tumor-infiltrating MDSCs.
Our research team has developed a novel technology consisting of large-scale ex vivo
production of cancer-specific myeloid-derived suppressor cells (MDSCs). Our system is
based on the production of conditioning medium from cancer cells genetically modified
to express GM-CSF. In this way, we reproduce the tumor environment to drive MDSC
differentiation and proliferation from bone marrow cells. Briefly, our system possesses
three major advantages; (1) large numbers of cells allow systematic in vitro testing of
anti-neoplasic treatments. We get 50 to 60 million MDSCs from a single mouse without
inducing cancer in it; 2) these numbers allow high-throughput studies and, (3) these
MDSCs are cancer specific and equivalent to tumor infiltrating MDSCs.
Thus, our system favors the implementation of the 3 “Rs” principle in animal
experimentation (Reduction, Refinement, Replacement), since it is not necessary to
induce cancer in a large number of experimental animals.
This project proposal is divided in three main goals, each one taking approximately one
year.
1. Simulation of the tumor environment from basal-like (triple-negative), luminal-like, and
HER2 breast cancer, using representative breast cancer cell lines for gene modification.
Generation of subtype-specific breast cancer MDSCs.
2. Phenotypic, functional, epigenetic, and proteomic analyses of each type of MDSC,
and comparison with conventional dendritic cells. These control cells are highly
immunogenic. These comparisons will uncover intracellular pathways involved in MDSC
functional properties. The genes involved in the regulation of these pathways will be
cloned in lentivectors to overexpress them, or they will be silenced using specific
microRNAs. In this way, their involvement in MDSC functions will be validated, and we
will at the same time generate tools to interfere with their activities.
3. Characterization of the mechanisms of action of anti-neoplasic treatments on MDSC
functions and epigenetic/proteomic regulation. Our research groups have access to antineoplasic treatments used for breast cancer from the Hospital of Navarra. In addition, we
also have developed experimental treatments (lentivector-based gene therapy) that
stimulate anti-tumor responses. We will test their effects on MDSC functions, and the
regulatory pathways controlling their immunosuppressive function, previously identified
by high-throughput techniques.
The BD Biosciences Research Grant Program aims to reward and enable important
research by providing vital funding for scientists pursuing innovative experiments to
advance the scientific understanding of disease.
Visit bdbiosciences.com/grant to learn more and apply online.