Original approaches to test anti-breast cancer drugs in a novel set of mouse models

Abstract

The limit therapeutic effect of traditional therapeutic approaches against breast cancer (BC) compels to search for new effective anti-BC therapies and to develop appropriate prognostic systems to predict BC patient outcome before therapy application. Therefore, first, we studied the prognostic value of several hematological and serum biochemical parameters to predict mammary carcinoma growth rate in a mouse model and the effect of IL-2 therapy. Then two therapy modes were tested in original mouse models, namely immunotherapy by means of local IL-2 and lectin aimed cytotoxic therapy. These studies are usually hampered by the lack of proper mouse models for BC. Therefore, an original system of spontaneous mouse models with various incidences of multiple mammary/ovary/uterine epithelial lesions and lymphoma in the BLRB, BYRB, and CBRB strains has been developed. The characteristics of all three strains as general mouse models for familial BC are presented.

The results of local IL-2 therapy in human BC are not clear yet. This kind of immunotherapy is first of all aimed to augment the anti-cancer response of T/NK cells. However, these cells are not frequent among BC infiltrating mononuclear cells. Our data in mouse models were in general in accordance with these findings suggesting that only a distinct proportion of MC bearing recipients, namely those with tumors with prevailed T/NK cells within tumor infiltrate, might benefit from immunotherapy. Indeed, using an original "proper subgrouping approach" both beneficial and non-beneficial recipient subgroups were found within IL-2 treated mice in spontaneous and transplanted models. Therefore, specific aim of this dissertation was to make obvious the need of a selection procedure development for recipients. Being interested in a rational design of carbohydrate-based lectin aimed therapeutics against BC we have developed synthetic glycoconjugates as diagnostic tools to identify lectins and used them for targeted delivery of a therapeutic. In particular, we developed cytotoxic melphalan bearing liposomes equipped with lipophilic tetrasaccharide SiaLex (synthetic selectin ligand) as a vector and demonstrated a promising therapeutical effect of this drug formulation in the transplantable BLRB mouse mammary carcinoma model.

Endogenous lectins, including galectins, play an important role in the in breast cancer cells during progression and in metastasis. So, they are attractive targets for lectin aimed anti-breast cancer therapy. Therefore, we studied galectin expression on MC cells from a variety of mouse models from our collection and showed that galectins are present on the MC cell surface of all mouse models tested. Moreover, galectin expression profiles detected in various mouse models in vitro and during spontaneous MC progression in vivo were similar to findings in human BC lines and specimens. These data validate our mouse model system composed of several complementary models which mimic various aspects of BC as useful tool to test novel target cytotoxic therapeutical protocols to prevent MC growth (i) directly, aimed to galectins on MC cells and (ii) indirectly, aimed to selectins expressed on endothelial cells of newly arisen tumor vascularity, or (iii) using both approaches to target "hot spots" of MC growth.