Vivolux programs are managed by NXT2B. For more information Contact nxt2b.com.
Vivolux's mission is to explore new cancer therapies. Our R&D projects are run in close collaboration with cancer institutes and academia with very encouraging outcomes.
To date, research conducted with leading academic centers has resulted in identification of two clinical candidate molecules with novel modes of actions.
The ubiquitin proteasome system (UPS) is the major intracellular protein degradation system in eukaryotic cells. The 26S proteasome complex consists of a 20S core particle (20S CP), which is associated with one or two 19S regulatory particles (19S RP). The 19S particles bind polyubiquitin-linked polypeptides and present them to the 20S degradative units. The efficient degradation of ubiquitinated substrates requires both unfolding and removal of polyubiquitin chains, a function mediated by specific deubiquitinases (DUBs). The UPS is essential to maintain normal protein composition in the cell and is increasingly recognized as a therapeutic target for the development of anticancer therapies.
The ubiquitin-proteasome system (UPS).
Proteins to be degraded are tagged with ubiquitin and trafficked to the proteasome where the chains associate with ubiquitin receptors. The proteasome DUBs USP14 and UCHL5 facilitate degradation by removing ubiquitin chains from target proteins.
Ref: D’Arcy, Wang and Linder Pharmacology & Therapeutics (2015) 147, 32-54
Inhibition of the proteasomal function leads to a disruption in the balance of proliferative and anti-proliferative signals in the cell, cell-cycle arrest and induction of apoptosis. Bortezomib (Velcade®) is a selective inhibitor of the 26S proteasome (the catalytic unit of the 20S CP). Bortezomib is in clinical use for the treatment of patients with multiple myeloma and mantle cell lymphoma. Recently, FDA also approved carfilzomib (Kyprolis) for the treatment of bortezomib-refractory multiple myeloma. As is the case with bortezomib, carfilzomib inhibits the catalytic unit of the 20S CP.
Key determinants including the development of drug resistance and dose-limiting toxicity of proteasome inhibitors call for the identification of alternative components of the UPS for novel drug targeting. In the specific case of multiple myeloma, the following points illustrate these problems:
- Despite the development of new drugs, multiple myeloma remains a non-curable disease; the median survival time is 5-6 years after diagnosis.
- About 30% of patients do not respond to current PI treatment
- Almost all patients develop resistance over time
With this unmet medical need in mind, Vivolux has performed research to identify alternative targets within the proteasome. Recently the deubiquitinases (DUBs), a diverse family of enzymes that catalyze ubiquitin removal, have attracted significant interest as targets. Pharmacological blocking of the proteasomal cysteine DUBs (i.e., USP14 and UCHL5) in particular has been shown to be especially cytotoxic to cancer cells and inhibits tumor growth in several in vivo models. VLX1570 selectively inhibits the highly conserved DUBs UCHL5 and USP14, leading to blocking of proteasome function. VLX1570 displays excellent antitumor activity in various experimental models of human cancer. Importantly the drug also shows activity against multiple myeloma cells that are resistant to bortezomib.
Link / Go to: VLX1570 Key Publications
VLX600 is preferentially active against slow/non proliferating cells in the metabolically compromised microenvironment in solid tumors, normally resistant to chemotherapy.
Traditional chemotherapy targets rapidly proliferating tumor cells, but spares slowly proliferating hypoxic cells. Nutrition/oxygenation of hypoxic cells will improve between chemotherapy sessions. These hypoxic cells, destined to die without targeted treatment, will survive and proliferate/repopulate the tumor.
The main action of conventional chemotherapy is to destroy rapidly proliferating cancer cells by targeting DNA replication and cell division. However, in solid tumors there are areas where poor vascularization leads to microenvironments deprived of oxygen and nutrition, Cells become metabolically stressed, decrease their rate of proliferation and may become dormant
Tumor cells in avascular areas suffer from deficiencies in both oxygen and nutrients. This makes these cells vulnerable to disturbance in their energy metabolism. This phenomenon provides a strategy for targeting the quiescent populations of tumor cells, which Vivolux has explored. The candidate drug VLX600 is preferentially active against quiescent cells in the deep tumor parenchyme. It is designed as a lipophilic weak base that allows it to penetrate deep into the core of spheroid tumors. The anticancer activity is associated with reduced mitochondrial respiration, leading to bioenergetic catastrophe and tumor cell death. VLX600 shows enhanced cytotoxic activity under conditions of nutrient starvation, and displays significant tumor growth.
The molecular mechanism of action of VLX600 is associated with its strong chelation of cellular iron. Iron chelation has previously been shown to inhibit tumor cell proliferation, due to inhibition of ribonucleotide reductase (an enzyme responsible for the synthesis of DNA precursors). The ability to also inhibit non-proliferating tumor cell populations has not been described for other drugs that chelate iron, and this activity of VLX600 may be due to the unique physicochemical properties of the drug allowing it to penetrate deep into the tumor parenchyme.
Vivolux is considering several different potential applications of VLX600:
- In combination with conventional anti-cancer treatments, where the targeting of quiescent cancer cells is complementary and will enhance the effect of the treatment.
- Interact synergistically with radiotherapy. It is well known that oxygen is required for radiation-induced DNA damage. Radiotherapy is therefore not effective in hypoxic cell populations of solid tumors. By reducing mitochondrial activity, VLX600 therapy has been shown to lead to a decrease in hypoxia in solid tumors. Hence, VLX600 has potential as a radio-sensitizing agent.
- As a monotherapy for tumors that are particularly dependent on mitochondrial activity and sensitive to ribonuclease reductase inhibition.
A phase 1 clinical study with VLX600 in patients with refractory advanced solid tumors has been finalized. The study was conducted in collaboration with the Mayo Clinic centers in Rochester (MN), Jacksonville (FL) and Scottsdale (AZ).
Link / Go to: VLX600 Key Publications