Improvement of systemic cancer therapy represents one of the biggest challenges in modern medicine. Despite the key developments in precision medicine, the success of many, if not all, innovative cancer treatment options is still limited by severe adverse effects and the rapid development of therapy resistance. Metal compounds and their specific characteristics, including redox activities, versatility in ligand coordination/orientation, and synergy between metal and ligand(s), offer a multitude of possibilities to selectively target malignant cells or to exploit the tumour microenvironment for cancer-specific drug activation. Accordingly, during the last years we have intensely focused on development of novel anticancer metal compounds from bench-to-bedside on a cooperative, interdisciplinary basis within a research platform between the Institute of Inorganic Chemistry at the University of Vienna and the Institute of Cancer Research at the Medical University of Vienna. These efforts led not only to multiple high-level research publications and successful acquisition of grant money, but also to the filing of two patent applications by both involved universities. Hence, in this current proposal, we ask now for the establishment of a cooperative research cluster for Translational Cancer Therapy Research to further expedite this successful cooperation towards translational research and clinical evaluation. By this, we not only aim to bring novel drugs to clinical evaluation, but also to foster and develop their commercial potential within the two involved universities. The scientific and translational strategies in the cooperation cluster will focus on the use of metal-based compounds as well as innovative targeting vectors and nanoformulations to either develop novel compounds for efficient anticancer therapy or to enhance the therapeutic window of already clinically used chemotherapeutics and targeted compounds by tumour-specific accumulation and activation. Moreover, a major novel focus will lie on dissecting the interplay between metal drugs and the anticancer immune responses as well as the development of synergistic drug combinations with e.g. immune checkpoint inhibitors. Therefore, the cluster will focus on four major strategies within separate work packages:
WP1, Preclinical evaluation of cancer-targeted platinum and ruthenium nanoformulations (passive targeting): Within the former platform massive know-how has been accumulated with respect to passive tumour targeting of metal anticancer compounds exploiting the abnormal vascular system of the tumours by using nanoformulations such as liposomes and degradable polymers. This strategy will be extended within the cluster towards functionalized nanoformulations of the most promising drug candidates as well as bifunctional drugs e.g. leading to albumin-mediated drug accumulation in the tumour bed.
WP2, Tumour-activated prodrug development (active targeting): Here, cancer-specific properties like hypoxia and expression of specific proteases and other enzymes or the enhanced level of reactive oxygen species will be exploited for local drug activation from inactive prodrug compounds in the cancer tissue.
WP3, Design of agents for anticancer treatment with novel modes of action to overcome drug resistance. Multidrug resistance is a key impediment for prolonged therapy response. Therefore, we will develop anticancer metal compounds not affected by these resistance mechanism or bifunctional compounds releasing several bioactive groups e.g. targeting the malignant cells and inhibiting the resistance mechanisms.
WP4, Investigation of the interface between anticancer metal drugs and immunotherapy. While in earlier times, it was taken for granted that chemotherapy inhibits the patient´s immune system, it now becomes more and more evident that (at least in certain cases) systemic cancer therapy might induce a strong anticancer immune response and even a vaccination effect (immunogenic cell death). As one of the best described immunogenic drugs is the clinically approved oxaliplatin, we will systematically investigate an interaction of anticancer metal compounds and the immune system with a focus on the highly successful inhibition of immune checkpoint mechanisms. Moreover, we plan to develop tumour-specific prodrugs which are synchronously releasing the anticancer metal drug and immunosuppressive small molecules (e.g. IDO inhibitors, PD-1 inhibitors) in the malignant tissue. This should lead to a local and synergistic anticancer chemo/immune response without systemic adverse effects.
In summary, within this proposed research cluster Translational Cancer Therapy Research we plan to generate innovative, targeted anticancer strategies and to develop respective lead compounds via elaborated in vitro and in vivo assays towards early clinical studies. This should lead to further solidification of this inter-university research focus. Additionally, several strategies will be implemented for cooperation with the respective pharmaceutical industry (e.g. as Christian Doppler lab and FFG projects) to pave the way for clinical application of the developed anticancer compounds.