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Related Concept Videos

Regulation of Angiogenesis and Blood Supply01:24

Regulation of Angiogenesis and Blood Supply

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Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits.  Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl...
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Hypoxia01:23

Hypoxia

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Hypoxia is a medical condition characterized by an inadequate oxygen supply to body tissues. It typically manifests as a bluish discoloration of the skin and mucosae, especially in fair-skinned individuals, when hemoglobin (Hb) saturation drops below 75%.
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Adaptive Mechanisms in Cancer Cells02:53

Adaptive Mechanisms in Cancer Cells

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Cancer cells accumulate genetic changes at an abnormally rapid rate due to the defects in the DNA repair mechanisms. From an evolutionary perspective, such genetic instability is advantageous for cancer development. Mutant cell lines accumulate a series of beneficial mutations that contribute to their progression into cancer.
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Cancer Therapies02:49

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Cancer therapies are various modes of treatment, such as surgery, radiation therapy, and chemotherapy that are administered to cancer patients.
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The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
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Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
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Induction and Testing of Hypoxia in Cell Culture
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Hypoxia Inducible Factor-2α (HIF-2α) Pathway Inhibitors.

Ratika Dogra1, Ulka Vaishampayan2

  • 1Hospitalist, Internal Medicine, Mercy St Vincent Hospital, Toledo, OH, USA.

Journal of Kidney Cancer and VHL
|July 7, 2025
PubMed
Summary

Hypoxia inducible factor-2 (HIF-2) pathway inhibitors, like belzutifan, show promise in treating VHL-associated cancers, including renal cell carcinoma. These targeted therapies block HIF-2 activity, offering new hope for patients with treatment-resistant tumors.

Keywords:
LITESPARKbelzutifanhypoxiahypoxia inducible factorsvon Hippel–Lindau

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Co-immunoprecipitation Assay Using Endogenous Nuclear Proteins from Cells Cultured Under Hypoxic Conditions
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Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Hypoxia triggers adaptive cellular responses via hypoxia-inducible factors (HIFs).
  • HIF-2 is crucial in cancers, particularly Von Hippel-Lindau (VHL) disease-associated tumors.
  • HIF-2α stabilization due to VHL deficiency drives oncogenic gene expression.

Purpose of the Study:

  • To review the role of hypoxia and HIF-2 in tumorigenesis.
  • To highlight the development and efficacy of HIF-2 pathway inhibitors in cancer therapy.
  • To discuss belzutifan and emerging HIF-2α inhibitors in clinical trials.

Main Methods:

  • Literature review of hypoxia, HIF transcription factors, and HIF-2 inhibitors.
  • Analysis of clinical trial data for belzutifan in renal cell carcinoma and other VHL-related tumors.
  • Examination of emerging HIF-2α inhibitors (casdatifan, NKT-2152, DFF332).

Main Results:

  • HIF-2 inhibitors block HIF-2α/HIF-β heterodimerization, suppressing oncogenic targets (VEGF, PDGF, CAIX, Oct4).
  • Belzutifan demonstrates efficacy in monotherapy and combination treatments for renal cell carcinoma.
  • HIF-2 inhibitors are being investigated for pheochromocytoma, hemangioblastoma, and pancreatic neuroendocrine tumors.

Conclusions:

  • HIF-2 pathway inhibitors represent a promising targeted therapy for VHL-deficient cancers.
  • Belzutifan is a key drug in this class, with ongoing trials for various indications.
  • Further research and clinical evaluation are essential for managing toxicities and optimizing treatment strategies.