STAT3 activation appears in over 70% of all human cancers


STAT3 plays an important regulatory role in a variety of cancers and is a key factor in non-cancer diseases, such as autoimmune diseases. As a result, STAT3 Therapeutics’ approach to drug development has a broad applicability. We are currently working on developing drugs in four key markets where STAT3 is shown to be an issue, including:

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Head and Neck Squamous Cell Carcinoma

Hyperactivated STAT3 plays an important regulatory role in 95% of all head and neck cancers, independent of HPV status.1 For patients with recurrent or metastatic head and neck squamous cell cancer, median survival is poor. The STAT3 pathway has the potential to make a significant impact as a therapeutic target for those suffering from head and neck cancers.

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Non-Small Cell Lung Cancer

Lung cancer is the most lethal cancer worldwide and remains a challenging disease. It is responsible for the high cancer mortality rates in the US and worldwide. Over half of lung cancer patients die within one year of being diagnosed due to late-stage detection and the scarceness of late-stage treatment options. About 80% of patients with non-small cell lung cancer (NSCLC), a class of lung cancer that constitutes 80–85% of the cases, develop stage IV disease.2 Not surprisingly, the 5-year survival rate for lung cancer patients is only 16.6%.3

Accumulating evidence over the last two decades suggests a critical role for STAT3 as a point of convergence for various signaling pathways that are dysregulated in the disease.4 Persistent phosphorylation of STAT3 has been demonstrated in 22%-65% of non-small cell lung cancers (NSCLC).5 This STAT3 activation is mediated by receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR) and MET; cytokine receptors, such as IL-6; and non-receptor kinases, such as Src. Over expression of total, or phosphorylated, STAT3 in resected NSCLC leads to poor prognosis.

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Glioblastoma

Glioblastoma multiforme (GBM) is the most aggressive form of cancer that begins within the brain, and patients typically receive a dismal prognosis and limited therapeutic options. STAT3 is a critical mediator of tumorigenesis, tumor progression, and suppression of anti-tumor immunity in GBM. In a high percentage of GBM cells and tumor microenvironments, persistent activation of STAT3 induces cell proliferation, anti-apoptosis, glioma stem cell maintenance, tumor invasion, angiogenesis, and immune evasion. This makes STAT3 an attractive therapeutic target and a prognostic indicator in GBM. Targeting STAT3 affords an opportunity to disrupt multiple pro-oncogenic pathways at a single molecular hub.6

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Melanoma

Studies using keratinocyte-specific STAT3-deficient mice have revealed that STAT3 plays an important role in skin homeostasis, including keratinocyte migration, wound healing, and hair follicle growth. Use of both constitutive and inducible keratinocyte-specific STAT3-deficient mouse models have demonstrated that STAT3 is required for both the initiation and promotion stages of multistage skin carcinogenesis. Further studies using a transgenic mouse model with a gain of function mutant of ​STAT3 (STAT3 C) expressed in the basal layer of the epidermis revealed a novel role for STAT3 in skin tumor progression. Studies using similar STAT3-deficient and gain-of-function mouse models have indicated its similar roles in ultraviolet B (UVB) radiation-mediated skin carcinogenesis.7

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References
  1. Darnell JE. (2005) Validating Stat3 in cancer therapy. Nat. Med. 11:595–6.
  2. American Cancer Society Cancer facts and figures. 2014.
  3. Centers for Disease Control and Prevention National Center for Health Statistics. CDC WONDER On-line database, compiled from compressed mortality file 1999-2010 series 20 No. 2P, 2013.
  4. Role of STAT3 in lung cancer; Pranabananda Dutta, Nafiseh Sabri, Jinghong Li, Willis X Li
    JAKSTAT. 2014; 3(4): e999503. Published online 2015 Jan 20. doi: 10.1080/21623996.2014.9996.2014.999503
    PMCID: PMC4580090
  5. Harada, D., Takigawa, N., & Kiura, K. (2014). The Role of STAT3 in Non-Small Cell Lung Cancer. Cancers, 6(2), 708–722.
  6. The role of STAT3 in glioblastoma progression through dual influences on tumor cells and the immune microenvironment; https://www.sciencedirect.com/science/article/pii/S0303720717300047?via%3Dihub

  7. Everardo Macias, Dharanija Rao, and John DiGiovanni, “Role of Stat3 in Skin Carcinogenesis: Insights Gained from Relevant Mouse Models,” Journal of Skin Cancer, vol. 2013, Article ID 684050, 10 pages, 2013. doi:10.1155/2013/684050