CAFs and albumin-targeting drugs

Colorectal cancer (CRC) is the third most common cancer worldwide, therefore finding effective treatment strategies with minimal side effects is still highly desirable. The majority of patients are still receiving standard chemotherapies based on 5-fluorouracil and oxaliplatin, which is associated with severe side effects and resistance development. Consequently, new strategies to improve the tumor specificity of anticancer therapy are urgently needed. One approach is the use of targeted drug delivery systems, which exploit the specific conditions and needs of the malignant tissue. The solid tumor is a complex tissue containing diverse cell types of healthy and malignant origin. Cancer-associated fibroblasts (CAFs) are an abundant component of the tumor microenvironment promoting cancer cells with nutrients, e.g. via attracting the plasma protein albumin. It is already known that cancer cells have increased albumin uptake to satisfy their immense nutritional requirements. Consequently, albumin came into the focus of interest as a drug delivery vehicle. One such example is KP2156, a compound which is currently investigated in the laboratory of Petra Heffeter (Center for Cancer Research, Medical University of Vienna). KP2156 is the platinum-based prodrug that releases active unmodified oxaliplatin upon reduction in the tumor, thereby eliminating adverse effects on healthy tissue. This proposal focuses on the role of CAFs in the tumor accumulation and distribution of that novel platinum-based prodrug, which are delivered into the tumor tissue using albumin as a carrier. Consequently, this project aims to establish novel imaging techniques based on imaging mass cytometry (ICM). ICM is a kind of mass spectrometry enables to high-dimensional characterization of single cells. For that together with our collaboration partners, we will develop metal-labeled antibodies for CAFs and albumin. It means that the proteins of our interest will be labeled with heavy metal isotopes so that they are detectable by ICM at the same time. Then, we will exploit the ICM to study of simultaneous drug uptake, its distribution and effect in CAFs vs. cancer cells. The methods will first be established on 3D cell cultures called spheroids to be finally applied to already available histological samples from mouse models as well as on models derived from patient-samples of CRC. We hypothesize that these novel approaches of ICM would contribute to preclinical studies of resistance mechanisms against metal-based drugs. Moreover, we hypothesize that these novel approaches of ICM would contribute to select the appropriate patient collective for albumin-targeted therapeutics in general.