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New concept of cytotoxic immunoconjugate therapy targeting cancer-induced fibrin clots

  1. Top of page
  2. New concept of cytotoxic immunoconjugate therapy targeting cancer-induced fibrin clots
  3. Novel small molecule, XZH-5, inhibits constitutive and interleukin-6-induced STAT3 phosphorylation in human rhabdomyosarcoma cells
  4. Essential role of the Hedgehog signaling pathway in human glioma-initiating cells

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Page 1396–402

Immunoconjugate cancer therapy was developed to selectively target cancer tissues, thereby preventing damage to normal tissues that can occur with low molecular weight anticancer agents (ACAs). However, ACA conjugated antibodies are hindered within tumors by stroma, which block the distribution of these high molecular weight agents. In this issue, Yasunaga, Manabe, and Matsumura present a novel approach to targeted cancer therapy. The researchers sought to overcome the stromal barrier by targeting the fibrin in stroma. Evidence shows that abnormal coagulation followed by fibrin formation occurs in a variety of cancer patients. These fibrin clots in cancer last as long as the cancer cells survive and are therefore pathophysiologically unique to tumors. Yasunaga and colleagues developed an antifibrin chimeric antibody that was conjugated to ACAs using a specialized immunoconjugate linker. The immunoconjugate selectively accumulated to the fibrin in tumor stroma and released ACA, which then diffused throughout the tumor tissue, damaging both tumor cells and vessels. This technology represents a potentially potent new cancer therapy.

Novel small molecule, XZH-5, inhibits constitutive and interleukin-6-induced STAT3 phosphorylation in human rhabdomyosarcoma cells

  1. Top of page
  2. New concept of cytotoxic immunoconjugate therapy targeting cancer-induced fibrin clots
  3. Novel small molecule, XZH-5, inhibits constitutive and interleukin-6-induced STAT3 phosphorylation in human rhabdomyosarcoma cells
  4. Essential role of the Hedgehog signaling pathway in human glioma-initiating cells

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Page 1381–87

As an oncogene that confers resistance to conventional cancer therapies, signal transducers and activators of transcription 3 (STAT3) is a promising target for novel cancer treatments. It promotes cell proliferation, immune evasion, and angiogenesis. This oncogene is constitutively activated in many human cancers, including soft tissue sarcomas such as rhabdomyosarcoma. Human rhabdomyosarcoma is one of the most common soft tissue sarcomas in children and has a high relapse rate of 30%. The role of STAT3 in rhabdomyosarcoma and other soft tissue sarcomas is poorly understood. Liu and colleagues now report the successful dose-dependent inhibition of STAT3 phosphorylation in human rhabdomyosarcoma cells by a novel small molecule, XZH-5. This inhibition of STAT3 phosphorylation caused apoptosis and decreased colony formation and cell migration. XZH-5 showed selective inhibition of STAT3, blocking interleukin-6-induced, but not γ-interferon-induced, STAT3 phosphorylation. The authors call for further investigation of XZH-5’s therapeutic potential with in vivo mouse tumor model, pharmacodynamic, and pharmacokinetic studies.

Essential role of the Hedgehog signaling pathway in human glioma-initiating cells

  1. Top of page
  2. New concept of cytotoxic immunoconjugate therapy targeting cancer-induced fibrin clots
  3. Novel small molecule, XZH-5, inhibits constitutive and interleukin-6-induced STAT3 phosphorylation in human rhabdomyosarcoma cells
  4. Essential role of the Hedgehog signaling pathway in human glioma-initiating cells

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Page 1306–12

Cancer-initiating cells, or cancer stem cells, are malignant, self-renewing cells that are resistant to irradiation and anticancer drugs. In order to better characterize these cells, Takezaki and colleagues studied glioma-initiating cells in two primary human glioma cell lines from anaplastic oligodendroglioma and glioblastoma multiforme. The researchers investigated the roles of Notch, Hedgehog, and Wnt signaling pathways, all of which are involved in normal neural stem cell maintenance and appear to be involved in gliomagenesis. Notch and Wnt signaling inhibitors had little effect on cell proliferation, but Hedgehog (Hh) pathway inhibition blocked glioma-initiating cell proliferation. Further study revealed that both overexpression of Gli2ΔC, a form of Gli2 that antagonizes Gli transcription factor functions, and knockdown of the Gli downstream factor Cdc2 inhibited glioma-initiating cell proliferation. The authors conclude that the Hh[RIGHTWARDS ARROW]Gli[RIGHTWARDS ARROW]Cdc2 signaling cascade plays a critical role in the proliferation and malignancy of glioma-initiating cells. Inactivating the Hh/Gli pathway could be a potential therapeutic strategy.