Doctors from Belgium Explore Strategies to Overcome Resistance in Head and Neck Cancer Treatments
Nikhil Prasad Fact checked by:Thailand Medical News Team Dec 31, 2024 2 days, 23 hours, 2 minutes ago
Medical News: Head and neck cancer (HNC) remains one of the most challenging cancers to treat, with nearly 2,788 new diagnoses reported annually in Belgium, according to the Belgian Cancer Registry. These cases predominantly affect men, making it the fifth most common cancer among males and the eighth among females. Unfortunately, over 58% of cases are diagnosed at advanced stages, significantly reducing survival rates.
Doctors from Belgium Explore Strategies to Overcome Resistance in Head and Neck Cancer Treatments
Patients often undergo surgery followed by chemoradiotherapy (CRT), a combination of chemotherapy and radiotherapy, to manage unresectable tumors or cases with positive surgical margins. Despite these aggressive approaches, many tumors relapse due to either intrinsic or acquired resistance. This
Medical News report examines these resistance mechanisms and explores strategies researchers are investigating to overcome these hurdles.
Investigating the Causes of Resistance
HNC treatment efficacy often varies due to different genetic and microenvironmental factors in tumors. Intrinsic resistance refers to the natural resistance some cancers exhibit, while acquired resistance develops after repeated exposure to therapies. Researchers from the Radiotherapy and Medical Physics Departments of the Institut Jules Bordet at Université Libre de Bruxelles have summarized major resistance mechanisms in their comprehensive study.
Key Resistance Mechanisms Include:
-Efflux Pumps: These are proteins that actively pump drugs like cisplatin out of cancer cells, reducing their effectiveness. The overexpression of certain transporters, such as ATP7A/B, plays a significant role.
-DNA Damage Repair: Tumor cells upregulate repair pathways, such as homologous recombination (HR) and nucleotide excision repair (NER), to counteract DNA damage caused by treatments.
-Antioxidant Defenses: Increased levels of antioxidants like glutathione shield cancer cells from oxidative stress, a key component of radiotherapy.
-Cancer Stem Cells (CSCs): These cells resist treatments and can regenerate tumors due to their enhanced DNA repair capabilities and reduced apoptosis (programmed cell death).
-Epithelial-Mesenchymal Transition (EMT): This process allows cancer cells to become more mobile and resistant to therapy.
-Tumor Microenvironment (TME): Poor oxygenation (hypoxia) and structural barriers hinder the delivery of therapies to tumor cells.
Promising Strategies to Overcome Resistance
Researchers are actively exploring novel approaches to counteract these mechanisms and enhance treatment outcomes.
-Targeting Efflux Pumps
: Therapies aim to inhibit the overexpression of transporters like MDR1, which can enhance the intracellular concentration of drugs. Emerging drugs target these pathways to restore chemotherapy effectiveness.
-Inhibiting DNA Repair Pathways: Drugs like AZD6738 (an ATR inhibitor) and AZD1775 (a Wee1 kinase inhibitor) disrupt the DNA repair mechanisms, rendering cancer cells more sensitive to chemotherapy and radiotherapy. Clinical trials are ongoing to evaluate their efficacy in HNC patients.
-Enhancing Oxidative Stress: Compounds like dichloroacetate (DCA) and wogonin target the antioxidant defenses of cancer cells, increasing their susceptibility to oxidative damage. These approaches have shown promise in preclinical studies.
-Targeting CSCs: Markers like CD44 are being explored to develop therapies that eliminate CSCs, thereby reducing the risk of tumor recurrence. Combining CD44 inhibitors with standard therapies has demonstrated potential in preclinical settings.
-Countering Hypoxia: Hypoxia-activated prodrugs like CP-506 selectively target low-oxygen regions within tumors, enhancing the effects of radiotherapy. In addition, agents that inhibit hypoxia-inducible factor 1-alpha (HIF-1α) show promise in restoring radiosensitivity.
-Modulating EMT and TME: Inhibiting EMT-associated pathways and reducing extracellular matrix barriers are emerging strategies. These approaches aim to improve drug delivery and reduce metastatic potential.
Recent Advances in Sensitizing HNC to CRT
Researchers have developed innovative strategies to re-sensitize resistant tumors:
-Immune Checkpoint Inhibitors: Drugs like nivolumab, which target the PD-1/PD-L1 pathway, are being tested in combination with CRT to enhance immune responses against tumors.
-Autophagy Pathway Inhibitors: By disrupting cellular recycling processes, therapies like YM155 target cancer cells' survival mechanisms, increasing their susceptibility to CRT.
-Combination Approaches: Combining oxidative stress inducers with inhibitors of apoptosis has shown synergistic effects in overcoming resistance.
Generating Resistance Models
Developing resistant cell lines is crucial for testing new therapies. Researchers use prolonged exposure to increasing doses of cisplatin or fractionated radiotherapy to establish in vitro models that mimic clinical resistance. These models are invaluable for studying resistance mechanisms and testing novel treatments.
Conclusion
Resistance to CRT in HNC is a multifaceted challenge, driven by genetic, environmental, and cellular factors. Advances in understanding these mechanisms have paved the way for innovative therapies that target specific resistance pathways. Precision medicine approaches, including personalized treatment strategies and combination therapies, offer hope for improving outcomes in HNC patients.
The study findings were published in the peer-reviewed journal: Cells.
https://www.mdpi.com/2073-4409/14/1/18
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