The tumor microenvironment protecting cancer growth
Over the past decades, cancer research has increasingly recognized the importance of the cells and structures surrounding a tumor. Understanding the complex interplay between cancer cells and the tumor microenvironment has opened new possibilities for therapeutic intervention aimed at overcoming this malignant protective zone.
The abnormal metabolism of cancer cells plays a central role in shaping the tumor microenvironment. Most cancer cells rely on aerobic glycolysis as their primary energy source rather than oxidative phosphorylation. This metabolic shift allows increased glucose uptake, which fuels rapid proliferation and supports metastatic potential.
During this process, glucose is converted into lactate—a phenomenon known as the Warburg effect—resulting in an acidic, low-oxygen microenvironment. These altered conditions reduce the effectiveness of therapies such as radiation and chemotherapy, not only within cancer cells themselves but also throughout the surrounding microenvironment.
While scientific research continues to uncover new aspects of the tumor microenvironment, it is clear that this protective niche contributes to immune suppression. Elevated lactate levels support cancer cell survival, inhibit the function of tumor-associated macrophages, and facilitate immune evasion by malignant cells.
In the presence of high lactate concentrations, macrophages tend to adopt an immunosuppressive phenotype and collaborate with tumor cells to promote angiogenesis—the formation of blood vessels that supply nutrients and oxygen to the tumor. In addition, lactic acid has been shown, in experimental settings, to strongly suppress the proliferation of cytotoxic T-lymphocytes.
Targeting the tumor microenvironment to restore immune activity has demonstrated clinical potential, as illustrated by immune checkpoint inhibitors. However, the majority of cancers remain unresponsive to these therapies, underscoring the need for new classes of drugs capable of overcoming the protective qualities of the tumor microenvironment. Vidac Pharma’s novel drug candidates, which have demonstrated promising early results in preclinical and clinical settings, are designed to address this unmet need.
The main culprit – the Hexokinase-2 protein
Vidac Pharma’s drug candidates target the hexokinase (HK) enzyme, which plays a key role in the abnormal metabolism of cancer cells. Hexokinase exists in several isoforms, of which HK1 and HK2 are the most prevalent. In normal adult tissues, HK1 is widely expressed to support glycolysis during physiological conditions such as anaerobic exercise, while HK2 expression is typically limited. In contrast, many malignant tissues overexpress HK2.
Both HK1 and HK2 bind to the mitochondria—the cell’s energy-producing organelles—through interaction with voltage-dependent anion channels (VDAC), which regulate the exchange of ions and metabolites between the mitochondria and the cytosol. In cancer cells, the binding of HK2, a large protein, to VDAC promotes glycolysis and lactate production, contributing to the tumor-supportive microenvironment described above.
In addition, HK2 binding to VDAC inhibits the release of pro-apoptotic factors that, in healthy tissue, trigger programmed cell death. By blocking apoptosis, malignant cells extend their survival, a key requirement for tumor growth and persistence.
Unblocking the channels: the toposteric effect
Efforts to target the Warburg effect directly have so far yielded limited clinical success, despite the phenomenon having been recognized for over a century. This is largely because glycolysis is essential for normal cellular function. Inhibiting the active site of hexokinase enzymes would disrupt glycolysis broadly, resulting in unacceptable toxicity to healthy cells.
Vidac Pharma is developing a different approach. The Company has reported early results with a family of novel chemical entities that prevent HK2 from blocking mitochondrial VDAC channels without interfering with its catalytic role in glycolysis. Certain naturally occurring molecules, known as jasmonates, were found to induce a modification in HK2 that detaches it from its VDAC anchor, allowing it to return to the cytosol and shifting malignant cellular metabolism toward a more normalized state.
Vidac Pharma refers to this mechanism as the toposteric effect. Analogous to allosteric regulation, in which molecules bind to specific sites on an enzyme to modulate its activity, Vidac’s compounds bind to a distinct site on HK2. This interaction physically prevents HK2 from associating with VDAC channels, without inhibiting glycolysis in healthy cells.
The toposteric effect represents Vidac Pharma’s paradigm for targeting cancer metabolism while limiting impact on normal tissue. This approach has demonstrated encouraging results in vitro and in clinical studies involving patients with early carcinoma and a lymphomatous form of skin cancer.