The concept of “starving cancer” involves disrupting how cancer cells acquire and process nutrients to fuel their uncontrolled growth. Understanding these metabolic vulnerabilities offers potential avenues for new treatments. This article explores how these principles apply to bladder cancer, focusing on its metabolic characteristics and investigational therapies.
How Bladder Cancer Feeds Itself
Cancer cells exhibit distinct metabolic behaviors compared to healthy cells, allowing them to proliferate rapidly. The “Warburg effect” is a prominent characteristic, where bladder cancer cells show increased glucose uptake and a preference for glycolysis, even with oxygen. This process, aerobic glycolysis, converts glucose into lactate, providing building blocks for new cells. Bladder cancer cells demonstrate this heightened glucose absorption and lactate generation.
Beyond glucose, bladder cancer cells also rely on specific amino acids and lipids for growth. Glutamine, an abundant amino acid, is a significant source of carbon and nitrogen for bladder cancer cells, supporting their survival and proliferation by replenishing intermediates in the tricarboxylic acid (TCA) cycle. Studies show bladder cancer cell lines depend on glutamine, with its deprivation affecting cell proliferation by influencing STAT3 activation and reactive oxygen species (ROS) levels.
Lipid synthesis is heightened in bladder cancer cells to support rapid cell division and maintain cell membrane integrity. Altered lipid compositions can affect their growth, proliferation, and drug resistance. For instance, the protein PIN1 drives bladder cancer growth by triggering cholesterol synthesis, a lipid essential for cancer cell proliferation.
Targeting Bladder Cancer’s Energy Supply
Researchers are exploring various strategies to disrupt bladder cancer cells’ energy supply. One approach involves glucose restriction, either through dietary interventions or by inhibiting glucose transporters. Studies show that increased glucose concentrations can enhance bladder cancer cell proliferation, while reduced levels can decrease it. Inhibitors like 2-deoxy-D-glucose (2DG) target hexokinase 2 (HK2), an enzyme in the first step of glycolysis, reducing cell viability, proliferation, and tumor growth in preclinical models of bladder cancer.
Amino acid deprivation is another strategy, particularly targeting glutamine pathways. Since bladder cancer cells often depend on glutamine for survival, inhibiting its metabolism or transport can impede their growth. Glutaminase inhibitors, which block the conversion of glutamine to glutamate, are being tested in clinical trials for various cancers. Arginine deprivation, using enzymes like pegylated arginine deiminase (ADI-PEG 20), has also shown promise in inducing cell stress and apoptosis in bladder cancer cells lacking argininosuccinate synthetase 1 (ASS1).
Targeting key enzymes within metabolic pathways is a broad research area. Glycolysis inhibitors, such as those targeting lactate dehydrogenase A (LDH-A), can selectively induce cell death in bladder cancer cells, as these cells have little capacity to compensate for inhibited aerobic glycolysis. Enolase-1 and PKM2 are glycolytic enzymes overexpressed in most bladder tumors; inhibiting them can lead to novel therapeutic strategies. Mitochondrial inhibitors are also being explored, as mitochondria play a multi-faceted role in supporting bladder cancer cell survival and proliferation. Silencing mitochondrial proteins like voltage-dependent anion channel 1 (VDAC1), overexpressed in bladder cancer, can reprogram metabolism, reducing energy and metabolite generation required for cell growth.
Emerging Research and Therapies
Current research in metabolic targeting for bladder cancer focuses on translating these foundational insights into actionable therapies. Ongoing clinical trials are exploring promising drug candidates and novel combinations. For instance, some trials investigate anti-PD-1 monoclonal antibodies alongside metabolic modulators for solid tumor malignancies, including bladder cancer.
Metabolic therapies are also being integrated with conventional treatments to enhance their effectiveness. For example, inhibiting fatty acid synthesis with drugs like orlistat can reverse bladder cancer resistance to PD-1 therapy. Simvastatin, a statin, has been shown to increase the sensitivity of bladder cancer cells to doxorubicin, a chemotherapy drug. This highlights how manipulating metabolic pathways can make existing treatments more potent.
Combining metabolic interventions with immunotherapy is an active area of investigation. Resistance to immune checkpoint inhibitors (ICI) can be influenced by lactate concentrations in the tumor microenvironment, which promote the survival of immune suppressive cells. Research suggests that combining LDH-A inhibitors with anti-PD-1 therapy can significantly reduce tumor volume in bladder cancer mouse models, surpassing the effects of anti-PD-1 therapy alone. While these approaches show promise, challenges remain in identifying which patients will benefit most and in managing potential side effects.
Key Considerations for Patients
Patients considering metabolic therapies should approach these options with caution and under strict medical supervision. Attempting extreme dietary changes or using unproven supplements without professional guidance carries significant risks, including potential nutritional deficiencies or adverse health effects. These investigational approaches are not standalone cures and should not replace standard-of-care treatments for bladder cancer, which typically include surgery, chemotherapy, radiation, or immunotherapy.
Metabolic interventions are currently being studied as investigational or adjunctive therapies, meaning they are explored in conjunction with established treatments to improve outcomes. Patients should discuss all potential treatment options, including participation in clinical trials, with their healthcare team. This ensures that decisions are evidence-based and tailored to their specific condition, minimizing risks and maximizing potential benefits. Open communication with medical professionals is important for understanding the potential side effects and risks associated with any metabolic intervention.