of the Max - MDC

Experimental
Pharmacology
Iduna Fichtner
The main area of investigations performed within the period of report concerns translational research
and was focused on the definition of biomarkers for and testing of novel anticancer agents.
Several patient-derived xenografts of leukemias, breast, colon, ovarian and lung cancers were established
and characterized regarding compliance with the clinical situation, histology and chemotherapeutic
response. These models were further analyzed concerning the involvement of target molecules
in the biology of tumors or treatment responses.
In vivo approaches were used as well to investigate the efficacy of a novel antimetastatic agent. This
has been developed with the aim to influence the interaction of tumor cells with blood and endothelial
cells by targeted liposomes. These were shown to stimulate the formation of platelet-tumor cell
complexes in the vasculature and to influence the process of metastasis.
The in vivo situation also was a precondition for investigations concerning the engraftment and differentiation
of human stem cells. Working with adult cord blood derived CD34-positive cells we could
show that a differential distribution in immunodeficient mice was obtained by pre-treating the cells
with selected cytokines or by direct cell-to-cell contact. An ongoing project especially focuses on the
potential of adult and embryonic stem cells for liver regeneration.
Use of patient derived xenografts
Patient-derived xenografts are more relevant to the clinical
situation compared with cell line – derived in vivo models
and are therefore preferred in our preclinical studies.
The formerly established panel of patient derived breast
cancer xenografts was used for the evaluation of novel therapies.
It could be shown that Tamoxifen-resistant
xenografts revealed a high sensitivity towards a Rapamycin
derivative (RAD001) suggesting that this agent could be
recommended for the second line treatment of antiestrogen-unresponsive
clinical breast cancers. Characterization
of mTOR (mammalian target of Rapamycin) pathway related
molecules revealed a distinct involvement of pAkt into
breast cancer resistance.
Ongoing studies are targeted to define the role of the estrogen
receptor beta (ERβ) in breast cancer. We could show
that the presence of that receptor isoform led to a loss of
tumorigenicity of MCF-7 cells but was not decisively involved
in the phenomenon of tamoxifen resistance. Interestingly,
ERβ expressing cells showed a distinct increase in sensitivity
towards histone deacetylase inhibitors and these compounds
induced the re-expression of ERβ in tumor cells.
Formerly established and molecularly characterized pediatric
leukemias were used for the evaluation of targeted
therapies like histone deacetylase inhibitors and a thalidomide
derivative.
In cooperation with the Evangelische Lungenklinik Berlin-
Buch fresh surgical material from non-small cell lung cancers
(NSCLC) was immediately transplanted to immunodeficient
mice. So far, 23 transplantable xenograft lines could be
established out of 101 samples obtained. The coincidence of
patient and xenograft samples was proven with genetic profiling
(Affymetriy arrays) and confirmed in relation to histology,
Ki67, E-Cadherin, EpCAM expression. Within this
project we are especially interested in the epidermal growth
factor receptor (EGFR) expression and its usefulness as predictive
marker for novel targeted therapies (Figure 1).
Though the majority of tumors were EGFR positive the
expression level was relative low. There were no functional
mutations in the EGFR detected, but 4/23 carcinomas had K-
ras and 10/23 p53 mutations.
The NSCLC xenografts were characterized for chemo sensitivity
towards a panel of five clinically used chemotherapeutic
drugs but also towards Cetuximab and Erlotinib, two
EGFR inhibitors. Ongoing studies try to find a relation
between the expression of biomarkers at genetic or protein
level with the response to therapies.
Cancer Research 143