Targeting the metabolism of tumor cells is now well recognized as a powerful strategy to develop new therapeutics which could improve treatment options especially of tumor types that are resistant to standard chemo-therapy. Most of previous studies have focused on the precept that the mitochondria are dysfunctional in cancer cells and that tumors depend upon glycolysis for growth (the Warburg effect). This proposal provides a paradigm-concept shift from this view, with our discovery that the mitochondrial citrate transporter SLC25A1 (CIC) is up-regulated in many cancers, is necessary for continuous tumor outgrowth, yet supports proliferation by actually promoting mitochondrial function and by blunting glycolysis. We have also shown that CIC is necessary for the survival response that cancer cells mount in order to adapt to restriction of glucose and to mitochondrial damage. These two forms of stress inevitably ensue in the limiting microenvironment due to the irregularity of the vasculature and pose an important obstacle to the expansion of tumor cells. Thus, our data place CIC activity at the core of the mechanisms by which cancer cells acquire a proliferation advantage in these conditions. Our results specifically show that CIC promotes metabolic adaptation by enacting the switch from glycolysis to gluconeogenesis and by enhancing mitochondrial amount and activity. We have also identified two chemical inhibitors of CIC that display anti-tumor activity as single agents and are non toxic in adult mice. Based on these premises this proposal has three objectives.
In Aim 1 we will test the idea, supported by our preliminary data, that CIC maintains the homeostatic control of the tumor mitochondria by inhibiting the rates of mitochondrial degradation and by interfering with the mitochondrial division machinery. We show that through these activities CIC promotes an increase of mitochondrial amount during stress conditions that, in the absence of CIC, would instead lead to mitochondrial depletion, thus depriving tumor cells of their power engine.
In Aim 2 we will use NMR spectroscopy and metabolic profiling to confirm our preliminary findings that CIC promotes metabolic plasticity by influencing mitochondrial and cytoplasmic pathways of energy production, thus enacting adaptation to stress.
In Aim 3 we will exploit pre-clinical mouse models to study the chemo-therapeutic potential of CIC inhibitor compounds. This will be achieved by employing canonical cancer cell lines as well as patient-derived tumor biopsies expanded as conditionally reprogrammed cells (CRC). The emphasis of these in vivo studies will be on lung cancer based on the important observations that high CIC expression levels predict the poorest prognostic outcome in patients affected by this disease and that CIC promotes the rapid outgrowth of lung cancer cells in vivo. The ultimate goal of these studies is to obtain proof of principle that CIC inhibitors will allow the more effective treatment of well-defined and clinically relevant lung cancer sub-types that are otherwise difficult to target with currently available chemo-therapy.

Public Health Relevance

Lung cancer is one of the most deadly forms of cancers and new treatment options for this disease are desperately needed. We found that CIC is a negative prognostic factor and a therapeutic target in lung cancer and we have identified two inhibitors of CIC activity that display anti-tumor activity as single agents. Our studies will foster the understanding of the mechanisms involved in the progression of lung cancer, and have the potential to generate novel and more effective therapies for patients affected by this disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA193698-01
Application #
8859263
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Espey, Michael G
Project Start
2015-04-21
Project End
2020-03-31
Budget Start
2015-04-21
Budget End
2016-03-31
Support Year
1
Fiscal Year
2015
Total Cost
$355,706
Indirect Cost
$126,956
Name
Georgetown University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Yun, Jieun; Espinoza, Ingrid; Pannuti, Antonio et al. (2015) p53 Modulates Notch Signaling in MCF-7 Breast Cancer Cells by Associating With the Notch Transcriptional Complex Via MAML1. J Cell Physiol 230:3115-27
Waye, Sarah; Naeem, Aisha; Choudhry, Muhammad Umer et al. (2015) The p53 tumor suppressor protein protects against chemotherapeutic stress and apoptosis in human medulloblastoma cells. Aging (Albany NY) 7:854-68
Albanese, Chris; Avantaggiati, Maria Laura (2015) The SLC25A1-p53 mutant crosstalk. Aging (Albany NY) 7:519-20