Treating cancer with VDAC1-based siRNA; Reprograming metabolism and reversing oncogenic properties
Introduction
Cancer cells acquire a common set of properties, including unlimited proliferation, metabolic re-programing, cell survival strategies and anti-apoptotic mechanisms. These processes involve changes in key oncogenes and non-oncogenes essential for cancer cell survival. The ultimate goal in cancer therapy is therefore, to either reverse these properties and/or to target them as tumor-specific liabilities. The multifunctional mitochondrial protein VDAC1 is a mitochondria gatekeeper and a convergence point for various cell survival and death signals. VDAC1 acts at a “bottleneck” position, controlling the metabolic and energy functions of mitochondria and the cell. Most cancer cells undergo metabolic reprograming known as the “Warburg effect”, a phenomenon that also provides tumors with precursors for the biosynthesis of nucleic acids, phospholipids, fatty acids, cholesterol and porphyrins. VDAC1 is over-expressed in many cancer types and thus represents an attractive target for cancer therapy.
The Technology
A single VDAC1 modified siRNA tested in multiple mouse cancer models, resulted in rewired metabolic properties and inhibited cell proliferation, EMT, invasion, angiogenesis and stemness, leading to the appearance of normal-like cells. Knockdown of VDAC1 expression in 30 tested cell lines reduced cellular ATP levels and inhibited the growth of cancerous but not non-cancerous cells, regardless of their origin or mutational status. Similar results were also demonstrated in-vivo using lung cancer (LC), breast cancer (BC) and glioblastoma multiform (GBM) mouse models. Silencing VDAC1 expression via specific si-hVDAC1, resulted in a multi-pronged attack on cancer hallmarks, reversing oncogenic properties via cancer-reprogrammed metabolism, resulting in inhibited cell proliferation, tumor growth, invasiveness, tumor-associated macrophage (TAM) presence and decreased angiogenesis. In a Triple Negative Breast cancer model, knockdown of VDAC induced the re-expression of Her2. PLGA-encapsulated si-VDAC1 given i.v. targeted tumors in the brain or lung. VDAC1 depletion also targeted radio- and chemo-resistant cancer stem cells, leading to their differentiation into mature cells that cannot replicate, thereby preventing tumor recurrence. A preliminary safety study of multiple administration of siRNA-PLGA nanoparticles showed no signs of toxicity.
Advantages
- VDAC1 silencing via reprograming cancer cell metabolism alternated expression of a wide array of genes associated with key functions and pathways involved in tumor survival
- VDAC1 depletion can substitute for several anti-cancer modalities, increase sensitivity to other anti-cancer treatments and thus be used in combinations therapy
- VDAC1 silencing in mice models also eliminated cancer stem cells and reprogramed tumor cells to advanced differentiated states, thus it may also prevent tumor recurrence
Patent Status
Family 1: Granted patents in Israel, UK, France, Germany and the US (International patent application No. PCT/IL2006/001176 )
Family 2: Pending applications in Israel, Europe, Hong Kong and the US (International patent application No. PCT/IL2016/051215)
Family 3: Pending applications in Israel, Europe and the US (International patent application No. PCT/IL2019/051181)
Partnering
Licensing out for further development
Principal Investigator
Prof. Varda Shoshan-Barmatz, NIBN and the Department of Life Sciences, Ben-Gurion University of the Negev, Israel