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INTERNATIONAL CONGRESS OF

CancerGenetics

• HIF targeting in cancer therapy

• Leila Rostamizadeh,^1,* Kobra Rostamizadeh,² Seied Rafi Bahavarnia,³ elena levantini,⁴
  1. Department of Molecular Medicine, Faculty of Advanced Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran
  2. Department of Psychiatry and Behavioral Sciences, Department of Pharmacology, School of Medicine, University of Washington, Seattle, WA, USA
  3. Screening laboratory, Blood Transfusion Organization, Tabriz, Iran
  4. Pisa Research Area, National Research Council (CNR) Pisa, Italy
  
  
  
• Introduction: Cancer is a heterogeneous disease influenced by intrinsic mutation burden and factors within the tumor microenvironment (TME) that are involved in its initiation, progression, and responses to therapy. None of the current cancer treatment modalities utilized for cancer management are entirely efficacious, and their efficacy is limited by drug resistance, non-specific targeting, tumor heterogeneity, TME factors, and metastasis. Addressing these challenges requires the development of innovative therapeutic strategies capable of overcoming these barriers. Numerous endeavors have been undertaken to enhance treatment efficacy and ameliorate patient outcomes.
• Methods: Accumulating evidence suggests that both cellular and acellular components of the TME can influence tumor initiation, growth, invasion, metastasis, and response to therapies. The increasing recognition of the TME's role in cancer progression and therapy resistance has led to a paradigm shift in cancer research and treatment. Rather than solely targeting tumor cells, a broader strategy is being developed, including the indirect targeting of the TME to enhance anti-tumor responses. This shift acknowledges the multifaceted nature of primary and secondary resistance to therapies, which arise not only from tumor intrinsic factors but also from the complex crosstalk between cancer cells and their intermingled TME. As a result, emerging approaches integrate TME-targeted therapies, immunotherapy, and combination treatments, to enhance the therapeutic landscape and hold promise for improving outcomes for cancer patients. While immunotherapy exerts durable and effective responses, only a minority of patients respond at present. Combining various treatment modalities with targeted TME agents has considerable potential to significantly enhance treatment efficacy and improve outcomes for cancer patients.
• Results: In this context, several agents and approaches have been developed to target both cellular components, such as chemokines (CCL2/CCR2), and immune checkpoints (PD-1 and CTLA4), and non-cellular components like collagen and metalloproteinase in the extracellular matrix (ECM), as well as hypoxia-induced factor (HIF) and vascular endothelial growth factor (VEGF) within the TME.
• Conclusion: Targeting HIF, in particular, has demonstrated remarkable anti-cancer responses in both preclinical and clinical studies. This review explores therapeutic interventions targeting HIF and their impact on anti-cancer responses, with a special emphasis on lung cancer, the leading cause of cancer death, without disregarding valuable insights from other oncological fields.
• Keywords: HIF, Therapy, Targeting, Tumor microenvironment (TME)