Selective Induction of Cancer Cell Death by VDAC1-Based Peptides

Introduction

The voltage-dependent anion channel (VDAC) is a key target for modulating cellular energy and apoptosis. VDAC1, located at the outer mitochondrial membrane, mediates the cross-talk between the mitochondria and other parts of the cell by transporting anions, cations, ATP, Ca2+ and metabolites. Substantial evidence points to VDAC1 as being a key player in apoptosis, regulating the release of apoptogenic proteins, such as cytochrome c from the mitochondria and interacting with anti-apoptotic proteins. Even in the presence of oxygen, cancer cells rely on glycolysis as the main pathway for generating energy (Warburg effect) as well as proteins, nucleotides and lipids production. Such metabolic re-programming in cancer cells also includes a marked over-expression of VDAC1. Most tumor cells have also developed apoptosis escape mechanism involving upregulation of hexokinase (HK), the Bcl-2 family as well as VDAC, which serves as the anchoring site for several anti-apoptotic proteins, including HK, Bcl-xL and Bcl-2. Mitochondrial-bound HK and Bcl2 are over-expressed in many cancer cells including Breast, Lung, Pancreas, Esophagus, Renal and Liver cancer while Bcl2 is overexpressed in Colon, Breast, Prostate, Lymphoma, Glioma, Leukemia and their over-expression in tumors is coupled with resistance to chemotherapy-induced apoptosis. Thus, complexes between VDAC1 and HK, Bcl-2 or Bcl-xL represent attractive targets for apoptosis-inducing anti-cancer therapy.

The Technology

We have developed VDAC1-based “decoy” peptides that compete with VDAC1 for the Bcl2-, Bcl-xL- and HK-VDAC1 interaction sites and consequently interrupt their anti-apoptotic activity. The lead peptide, retro-Tf-D-LP4, not only inhibits tumor growth but for the first time also offers a treatment that can reverse the unique cancerous properties back to a normal phenotype.  Our treatment method prevented energy production in the cancer cell, inhibited cell proliferation and invasion, induced cell death in the tumor and eliminated cancer stem cells from which the cancer re-develops. As such, we succeeded in inhibiting growth, invasiveness, and stemness in animal models of human mouse tumors as Glioblastoma, Lung, Liver, Breast and Melanoma metastasis to Brain or Lung.

Advantages

• Prof. Shoshan-Barmatz is a leader in the research of VDAC1.
• The lead peptide is selectively affecting multiple cancer types (both in-vitro and invivo) via cutting cell energy production and inducing apoptosis regardless of mutations and acquired survival mechanisms.
• Preclinical developed demonstrated activity at low concentrations, long stability and BBB entry.

Patent Status

Number of PCT applications were filed (PCT/IL2016/050958, PCT/IL2006/000311 and PCT/IL2007/000455). Granted patents in USA, Europe and Israel.
New provisional application No. 62/966,582 was filed January 28, 2020

Principal Investigator

Prof. Varda Shoshan-Barmatz, NIBN and the Department of Life Sciences, Ben-Gurion University of the Negev, Israel