Markers for the activity of albumin-targeted platinum drugs

Theoretical framework. There is increasing evidence that cancer cells differ in their nutrient acquisition strategies from healthy tissues. Especially their enhanced consumption and degradation of plasma proteins like albumin has proven as promising target for cancer therapy. With the clinical success of drugs like Abraxane (an albumin-paclitaxel nanoparticle) and Aldoxorubicin (albumin- binding doxorubicin), the high potential of albumin as a drug carrier has been well established. Consequently, it is of great interest to develop novel albumin-targeting drugs also for other clinically used anticancer therapeutics. In order to improve the frequently applied FOLFOX (folinic acid, fluorouracil and oxaliplatin approved for colorectal cancer) scheme, we have recently developed the first albumin-binding prodrug of oxaliplatin with exciting activity against colon carcinoma in vivo. However, although the potential of albumin for targeting of cancer cells is already clinically proven, there is surprisingly little known how cancer cells differ in their albumin metabolism from healthy cells. Research questions. Aims of the here presented proposal are, on the one hand, to understand better how colon cancer cells use albumin and, on the other hand, to use this knowledge for the preclinical development of a novel albumin-targeting oxaliplatin prodrug. Approaches/ Methods. One focus will be given to the role of potential biomarkers for albumin uptake of cancer cells, which will be analyzed by diverse cell- and molecular biological tools. In addition, in order to allow the assessment of the tumoral albumin uptake in vivo in a non-invasive and quantitative manner, additionally a PET imaging platform using 89 Zr-labelled albumin conjugates will be established. This new technology will be employed to assess the albumin accumulation of individual tumor nodules before and during drug treatment and can serve as a tool, which can be also used for the selection of patients in the future. Level of innovation. Noteworthy, despite the success of albumin-targeting drugs, the knowledge in this field is still fragmentary and important tools for the investigation are missing. The here presented project will help to identify and develop novel biomarkers for albumin-targeting drugs as well as imaging probes to support the clinical development of these highly tumor-specific compounds. Primary researchers involved. This highly interdisciplinary project will be coordinated and supervised by three scientists of three Austrian research institutions: Petra Heffeter (Institute of Cancer Research of the Medical University of Vienna), Thomas Mindt (the Ludwig Boltzmann Institute Applied Diagnostics Vienna) and Christian Kowol (the Institute of Inorganic Chemistry, University of Vienna), who will closely cooperate to generate the knowledge urgently needed in this cutting edge field of cancer research.

There is increasing evidence that cancer cells differ in their nutrient acquisition strategies from healthy tissues. Especially their enhanced consumption and degradation of plasma proteins like albumin have proven as promising target for cancer therapy. With the clinical success of drugs like Abraxane (an albumin-paclitaxel nanoparticle) and Aldoxorubicin (albumin-binding doxorubicin), the high potential of albumin as a drug carrier has been well established. Consequently, it is of great interest to develop novel albumin-targeting drugs also for other clinically used anticancer therapeutics. In order to improve the frequently applied FOLFOX (folinic acid, fluorouracil and oxaliplatin approved for colorectal cancer) scheme, we have recently developed the first albumin-binding prodrug of oxaliplatin with exciting activity against colon carcinoma in vivo. However, although the potential of albumin for targeting of cancer cells is already clinically proven, there is surprisingly little known, how cancer cells differ in their albumin metabolism from healthy cells. Consequently, the aims of the here presented proposal were, on the one hand, to understand better how cancer cells use albumin and, on the other hand, to use this knowledge for the preclinical development of albumin-targeting oxaliplatin prodrugs. One focus was given to the understanding how albumin-binding drugs enter the cancer cells and where platinum(IV)-based prodrugs are activated by reduction, which was analyzed by diverse cell- and molecular biological tools. In order to allow the assessment of the tumoral albumin uptake in vivo in a non-invasive and quantitative manner, additionally PET imaging platforms using 89Zr-labelled albumin conjugates were established. Indeed, we could proof that this new technology can be employed to assess the albumin accumulation of individual tumor nodules and, thus, can serve as a tool, for the selection of patients in the future. Finally, this project led to the development of several new platinum(IV)-based anticancer drugs and the assessment of diverse parameters, which need to be considered, when designing novel albumin-binding therapeutics. This highly interdisciplinary project has been coordinated and supervised by three scientists of three Austrian research institutions: Petra Heffeter (Center for Cancer Research of the Medical University of Vienna), Thomas Mindt (the Ludwig Boltzmann Institute Applied Diagnostics of Vienna) and Christian Kowol (the Institute of Inorganic Chemistry, University of Vienna). Our close collaboration resulted in a new interdisciplinary network, which gained distinct attendance of the international scientific community as indicated not only by diverse invitations to present our work on scientific meetings but also the attraction of multiple international visiting scientists. In addition, our work won several research awards.