Even in the presence of oxygen, most cancers rely on glycolysis as the main pathway for generating energy (the Warburg effect) and as a source of precursors for generating proteins, nucleotides and lipids. Such metabolic re-programming of cancer cells includes marked over-expression of the isoforms of the mitochondrial-bound glycolytic protein hexokinase (HK), required for energy production. HK also acts as an anti-apoptotic protein via a direct association with VDAC1 localized at the outer mitochondrial membrane and functioning as a gatekeeper for the entry and exit of mitochondrial metabolites, thereby controlling crosstalk between mitochondria and the rest of the cell. VDAC1 also plays a key role in mitochondria-mediated apoptosis through its participation in the release of mitochondrial pro-apoptotic proteins to the cytosol (e.g. cytochrome c, AIF, Smac/DIABLO) and via its interaction with anti-apoptotic proteins, such as members of the Bcl-2 family of proteins. Thus, VDAC1 appears to represent a convergence point for a variety of cell survival and death signals. In our studies, we observed the over-expression of VDAC1, of several of its associated proteins and of other apoptosis-modulating proteins in several cancers. These findings led to the development of a bioenergetics and apoptotic index, reflecting the metabolism and apoptosis reprogramming of the cancer cell that can be considered as a predictive and prognostic biomarker, reporting on disease progression and serving as a treatment therapeutics index.
The Technology
Analyzing the expression profiles of several proteins involved in the metabolic re-programming of cancer cells we found that in certain non-solid as well as solid tumors there is an overexpression of a number of VDAC1 associated proteins such as MAVS (the mitochondrial antiviral-signaling), SMAC/DIABLO (second mitochondria-derived activator of caspases), AIF (apoptosis-inducing factor), HK. Binary logistic regression analysis revealed the ability to predicate the probability of disease based on either VDAC1, Bcl2, SMAC/Diablo, MAVS or a combination of AIF and HK-I expression levels. Moreover, the expression profiles of these proteins point to a cancer survival strategy involving anti-apoptotic defense mechanisms and thus, a lowered susceptibility to apoptosis-mediated cell killing compounds. These protein expression profiles can serve for diagnosing cancer, predicting cancer development and selecting and monitoring response to treatment.
Applications
• Blood tests for early diagnosis, selection and monitoring of treatment in Lymphoma and Leukemia patients
• Solid tumor biopsy profiling for diagnosis and for selecting and monitoring treatment in various cancers, including lung, ovary, prostate, glioblastoma and cervix cancer and melanomas
• Developing a metabolic and apoptotic indices of certain cancers to predict cancer development, and for selecting and monitoring treatment
Advantages:
The proteins identified in our studies as highly expressed in cancer can serve as indicators of the disease state, allowing for early and accurate diagnosis of a number of different cancers and the for the establishment of a therapeutic cellular index for prognosis, for guiding treatment and for assessing effectiveness, all important steps on the road to tailored personalized therapy.
Patent Status
Pending
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