Abstract A108: Induction of mitochondrial dysfunction as a strategy for targeting tumor cells in hypoxic microenvironment.
Authors: Zhang Xiaonan , Fryknäs Mårten , Hernlund Emma , Fayad Walid , De Milito Angelo , Olofsson Maria Hägg , Linder Stig 
Published: August 2014

A fundamental problem in cancer drug discovery is to identify compounds that eliminate dormant malignant cells responsible for tumor relapse. Abnormal vascularization of solid tumors leads to the generation of tissue microenvironments that are chronically starved of oxygen and nutrients. Cells residing in such environments are slowly growing or quiescent and display altered phenotypic characteristics when compared to cells located in more vascularized regions. Such non-dividing cells are often resistant to mainstay standard chemotherapies that rely on DNA replication and cell division to elicit their anti-tumor effect. The altered phenotype of quiescent cells enables them to survive chemotherapeutic regimes and reseed nascent tumors following secession of chemotherapy. Indeed resistance to agents such as doxorubicin, cisplatin and vinblastine has been correlated with poor vasculature, tumor relapse and poor patient survival. Thus there is a need to alter the scope of cancer drug discovery and focus more on screening for agents that can exploit the altered phenotype of quiescent metabolically stressed cells to eliminate tumors.

Cell-based screening for novel anticancer drugs is typically performed using monolayer cultures of tumor cells, however such monolayer cultures do not represent the characteristics of 3-D solid tumors, frequently leading to the failure of subsequent in vivo models. The multicellular tumor spheroid model is of intermediate complexity between in vivo tumors and in vitro monolayer cultures and is more suitable for drug screening and evaluation. Spheroids are known to be more resistant to drug effects compared to monolayer cultures. Resistance is due not only to pharmacokinetic obstacles limiting drug penetrance to inner layers, but also to multi-cellular interactions leading to altered expression of genes and proteins regulating drug response. An additional benefit of growing cells three- dimensionally is the opportunity to explore the core regions’ potential vulnerability related to hypoxia and nutrient defiency and to reflect the heterogeneous milieu in tumor microregions relative to the supply. Poorly vascularized and perfused tumor microareas in many aggressive cancers have limited access not only to oxygen but also to glucose. Core regions are also associated with acidic pHsince these tumor cells change their metabolism towards increased glycolysis, resulting in increased lactic acid production.

We here employed spheroid cultures of HCT116 colon cancer cells to screen a diverse chemical library with the aim to find compounds with cytotoxic activity in core, hypoxic, regions. The screen identified a compound (VLX600) demonstrating anti-cancer activity with a large therapeutic window both in vitro and in vivo. Here we characterized the mechanism of action and potential of VLX600 as anti-cancer therapy.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A108.

Citation Format: Xiaonan Zhang, Mårten Fryknäs, Emma Hernlund, Walid Fayad, Angelo De Milito, Maria Hägg Olofsson, Stig Linder. Induction of mitochondrial dysfunction as a strategy for targeting tumor cells in hypoxic microenvironment. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A108.