The tumor microenvironment as target and regulator of anticancer (metal) drug response

Survival of cancer even at an advanced stage is increasing based on improved diagnosis and therapy. Besides the novel forms of systemic cancer therapy, including targeted compounds and immunotherapy, also classical chemotherapy e.g. with platinum drugs is still a mainstay distinctly contributing to cure or at least improved patient survival. Supported by the novel high-end technologies and the massive increase of know-how concerning the nature of cancer, also chemotherapy gets more precise and effective. Additionally, it becomes increasingly obvious that also for metal-based chemotherapy precise target mechanisms exist and not only the direct cytotoxic activity against the tumor cells but also e.g. immune effects are important for a successful therapy response. However, still positive outcomes are not achieved in every patient and side effect, though nowadays much better manageable, are still one of the key limiting factors of cancer cure. Consequently, our cooperative project network aims to improve the quality of platinum-based systemic cancer therapy in several directions. First, we want to analyze the fate and the impact of clinically used and experimental platinum compounds down to the single cell level of the cancer tissue comprising in addition to the tumor cells also blood vessels, stroma and immune components. For this single cell analyses, high-end analytical techniques are available in this consortium and will be optimized in course of this project. Second, concerning novel remedies, the focus will lie on manipulating not only the cancer cells but also the direct environment of the tumor (as the surrounding tissues like stromal cells, immune cells etc. is often abused and altered by the tumor to support its needs). This should allow improved tumor control and reduced therapy failure by resistance development often caused by alterations in both tumor cells and microenvironment. Moreover, besides enhancing the anticancer effect, we aim to reduce the side effects by activating the cytotoxic activity of the metal drugs specifically inside the malignant tissue. Strategically, already successfully used platinum drugs are altered (oxidized) in a way that leads to 1) reduced toxicity in the health tissue, and 2) the ability to chemically attach up to two additional chemical moieties (including other drugs supporting the platinum compound or delivery structures allowing to enhance accumulation in the malignant tissue) to the molecule. Consequently, only in the chemically altered environment of the malignant tissue, these per se non-toxic compounds (prodrugs) should fall apart and release their cell killing activities. In order to fulfill such a challenging task successfully, multidisciplinary cooperations like in this consortium are essential, including synthetic chemists (generating the novel remedies), analytical chemists (able to precisely determine the fate of the remedies on their impact on the organism), as well as cancer biologists and toxicologists (to test the compounds activities and adverse effects using diverse models systems). In detail, our strategies comprise the development of anticancer platinum prodrugs specifically targeted to the tumor (via binding to the main blood protein albumin which is efficiently degraded by the tumor but much less by health cells) and releasing in the malignant tissue besides the cytotoxic chemotherapy (cisplatin, oxaliplatin) also immune-stimulating agents. Therapy response/failure will be traced back to the contribution of metabolic factors and the tumor architecture down to the single cell level with a specific focus on the role of fibroblasts and immune cells. This should not only deliver novel, highly efficient chemotherapeutic metal drugs with improved tolerability and the respective high-end analytical approaches/protocols to dissect their mode-of-action, but also improve the know-how concerning determinants of response/failure of already widely used chemotherapeutic regimes.

Solid tumors are complex tissues containing besides cancer cells also extracellular matrix and diverse cell types of non-malignant origin. Although the importance of the cellular interplay is more and more recognized, the impact of metal-based therapy on the tumor microenvironment and its role in the anticancer response is still surprisingly under-investigated. Consequently, this research group aimed at further dissecting and exploiting the interface between the therapeutic intervention and the complex and versatile characteristics of solid tumors as multicellular tissue. In more detail, we addressed the following research questions: 1) What is the role of the immune system in the anticancer activity of new tumor-specifically activated metal drugs? 2) What is the role of cancer-associated fibroblasts and their secreted molecules in the tumor responsiveness to these novel prodrugs? 3) How does platinum-based therapy impact on the lipidome of cancer cells and their lipid-based communication with the microenvironment? 4) Which cell type is responsible for activation of our novel prodrugs (on a single cell level) and are the drugs accumulating in intratumoral drug depots? 5) Can we develop novel prodrugs, which not only release drugs in a tumor-specific manner but also tune the tumor microenvironment for enhanced therapeutic efficacy? These questions were studied using a wide range of methods spanning from analytical and synthetic chemistry to preclinical drug development in vitro and in vivo in form of an interdisciplinary platform between researchers from the Center for Cancer Research (Medical University of Vienna) and scientists from the Faculty of Chemistry (University of Vienna). In more detail, five teams (lead by Petra Heffeter, Walter Berger, Gunda Koellensperger, Christian Kowol, and Evelyn Rampler), 14 PhD fellows and 6 Master students worked together to establish new analytical techniques, extended scientific data sets and anticancer drugs to further elaborate and utilize tumor microenvironmental factor for optimized cancer therapy. This led to more than 37 joint research articles in internationally peer-reviewed top journals, attraction of diverse (follow-up) grants and joint foundation of a spinoff company. This great success is also reflected by multiple invitation to present our platform at international conferences as well as 13 research and presentation awards. Moreover, the novel discoveries and progresses were regularly conveyed to the public in frame of e.g. the cancer school of the Comprehensive Cancer Center, the Long Night of Research and on social media. Consequently, the involvement into this research platform distinctly promoted the career of multiple participants including a venia docendi and a promotion to full professorship.