Projects / Programmes
Cellular energy metabolism as a target for cancer therapy – genetic and pharmacological approach
| Code |
Science |
Field |
Subfield |
| 3.04.00 |
Medical sciences |
Oncology |
|
| Code |
Science |
Field |
| B000 |
Biomedical sciences |
|
| Code |
Science |
Field |
| 3.02 |
Medical and Health Sciences |
Clinical medicine |
metabolism, cancer, AMPK, pharmacological therapy, in vitro modeli
Researchers (21)
Organisations (3)
Abstract
Identification and development of new pharmacological compounds and strategies for cancer treatment remains top priority for biomedical research. Unfortunately, anti-cancer therapy is often unsuccessful and although some novel treatments have emerged in the recent years, there is a clear need for improved anti-cancer therapy.
Cancer cells differ from normal cells in several key biological characteristics as described in the renowned paper “The Hallmarks of Cancer”. Recently metabolic reprogramming in cancer cells has been recognized as a new Hallmark. In fact, metabolic alterations in cancer cells were recognized already in 1920s, when Nobel laureate Otto von Warburg observed that, tumour cells maintain glycolysis even under normoxic conditions (Warburg effect). These observations were later largely disregarded or forgotten, until they were recently “rediscovered” and the re-emergence of interest in cancer metabolism opened entirely new area of research in cancer biology and oncology. Emerging data indicate that metabolic alterations in cancer cells offer the possibility of novel therapeutic approaches that selectively target cancer cell metabolism.
For example, pharmacological suppression of the Warburg effect might augment the effectiveness of conventional anti-cancer drugs. Several different entry points for modulation of cancer metabolism have already been identified. In particular, inhibitors of hypoxia-inducible factor-α (HIF-α), activators of the AMP-activated protein kinase (AMPK) and inhibitors of lactate dehydrogenase (LDH) are currently in focus of efforts to develop new anti-cancer treatments. However, molecular mechanisms linking alterations in energy metabolism to reduced or enhanced susceptibility of cancer cells to anti-cancer drugs remain understood incompletely.
The primary aim of the project will be to identify new approaches for pharmacological modulation of metabolic pathways in order to increase chemosensitivity and/or reduce viability of breast cancer cells. We will perform in vitro studies where drugs that are already approved for the therapy of non-neoplastic conditions but that may exert anti-cancer effects via modulation of metabolic pathways will be tested. Furthermore, by investigating metabolic alterations in the in vitro breast cancer cell models we will aim to identify novel targets for pharmacological treatment of breast cancer. Furthermore, we will analyse whether strategies to target metabolic pathways identified in the breast cancer cell model, may apply to other two studied cancer models, kidney and urothelial (bladder) cancer. Clearly, multiple strategies to target cancer metabolism are needed to bypass the problem of the complexity and heterogeneity of biological alterations in cancer. To develop more effective treatments, molecular mechanisms underlying metabolic alterations in cancer cells therefore need to be elucidated in more detail. This may lead to novel therapeutic strategies that will promote reprogramming the energy metabolism and, concurrently, increased susceptibility to existing chemotherapeutic modalities.
Significance for science
The “rediscovery” of the Warburg effect in conjunction with recent findings has brought significant new insights in the field of cancer metabolism. Thus, altered metabolism of cancer cells is now regarded as one of the core hallmarks of cancer. Notably, elucidation of molecular mechanisms that underpin metabolic alterations in cancer cells may lead to novel anti-cancer treatments. However, although results from recent studies have been encouraging, several issues remain to be addressed. In the proposed project we aimed to address some of open issues, namely whether and how the microenvironment and cancer cell metabolic phenotype affect chemosensitivity and cancer cell viability, whether and how the factors in the microenvironment and/or cancer cell metabolic phenotype determine the effectiveness of AMPK and HIF-? modulators as anti-cancer treatments and, finally identification of novel molecular targets and/or strategies to selectively target metabolic pathways in cancer. We established cell culture conditions that mimic in vivo conditions more closely than standard cell culture protocols. This enabled us to determine possible confounders in cell culture media that could lead to erroneous conclusions and interpretations of the results. Such approach provides basis for the extrapolation of results and translation of basic knowledge to in vivo systems and, possibly, clinical oncology. Furthermore, examination of environmental and cancer-related metabolic factors in relation to effectiveness of various AMPK and HIF-? modulators may explain some of the equivocal, opposing results in recent studies as well as provide the rationale for the use of AMPK and/or HIF-? activators and/or inhibitors. Identified mechanism that were identified in this basic project to play role in the process of tumoregenesis open possibility of novel pharmacological strategies. To summarize, this project provides a starting point to establishing more realistic approaches towards assessing cancer cell metabolism under in vitro conditions. Aside from the methodological advances, this project generated new knowledge in the field of cancer metabolism. Collectively, results of our project may open new possibilities for the development of novel strategies for anti-cancer therapy.
Significance for the country
Establishing new line of research in Slovenia. With this project we established a novel and very promising field of cancer research in Slovenia. Team members are currently employed in three different research and educational institutions in Slovenia and are actively cooperating with several foreign research groups. This project therefore brought new knowledge, expertise and methodology to Slovenia. Networking in the field of biomedicine, cancer research and metabolism. The project enabled the development and transfer of new technologies and methods, while existing collaborations allow close contact with clinicians.. The presented project is a starting point that will enable us to expand the research capabilities in the future. Cooperation with clinical doctors that was established based during this project will provide the first step towards more applicative and translational research. Close interaction between research and educational activities. This project enabled knowledge transfer through undergraduate and graduate courses in the field of medicine, biology and biochemistry (graduate MD program, graduate biology programs, doctoral program Biosciences UL, etc.). Collaborators involved in this project have already been mentors of several graduate and doctoral students in different scientific fields. Involvement of graduate students, young researchers and postdoctoral researchers in this project will enabled them hands-on approach in high-tech molecular biology, cancer research and cell metabolism methods. Raising awareness regarding the role of science in modern society. As mentioned before, cancer is a major health care problem that affects many people directly and indirectly. Cancer therefore receives a lot of attention by lay public and media alike. We will therefore disseminate major findings of the project to inform general public about our activities and their relevance.
Most important scientific results
Annual report
2014,
2015,
final report
Most important socioeconomically and culturally relevant results
Annual report
2014,
2015,
final report
