Abstract
Background
Acidic pH and low oxygen levels Due to the Warburg effect have been shown to impart resistance to certain anti-cancer therapies for solid tumors, such as radiation and a variety of chemotherapeutic drugs. Cancer immunotherapy represents one of the most exciting advancements in recent cancer therapy. However, despite these achievements, the numbers of patients with effective cure are very low for patients with solid tumors. Recent studies pointed out that the main cause for this low efficiency is the Tumor microenvironment (TME), with metabolic changes, and immune evasion that renders solid tumor eradication a real challenge. Drugs targeting the inhibitory TME are urgently needed in combination with Immunotherapy, as well as other conventional therapies like chemotherapy and cancer targeted growth blockers.
Methods
In this study we used an inhibitor of Hexokinase-2 binding to the mitochondrial VDAC1 channel (VDA-1275), that is shown to block cancer cell proliferation, induce apoptosis in cancer cells, and change TME from a protumor to a pro-immunological environment. Our studies demonstrate a significant tumor growth inhibition and survival prolongation, combined with a strong safety profile in-vivo. In addition, a powerful synergistic anti-cancer effect was demonstrated, using a 3D cell culture with human hepatic cancer cell organoids, when VDA-1275 was combined with low levels of Cisplatin or Sorafenib, as examples for chemotherapy and targeted therapy treatments, respectively.
Results
Our results suggest that VDA-1275 is a novel compound that effect cancer cells directly and indirectly by changing the TME to a pro-immunogenic environment.
Conclusion
VDA-1275 may be used as a standalone drug, or in combination therapy that will allow more effective and safe treatment of patients with solid tumors. We coined the word and concept of “Toposteric” effect as the use of small molecules or peptides which interact with a receptor or ligand binding site avoiding the possibility of a pro-pathological harmful anchoring without affecting its active site.