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Every minute, 34 new patients are diagnosed with cancer globally. Although over the past 50 years treatments have improved and survival rates have increased dramatically for several types of cancers, many remain incurable. Several aggressive types of blood and solid cancers form when mutations occur in a critical cellular signaling pathway, the JAK-STAT pathway; (Janus Kinase-Signal Transducer and Activator of Transcription). Currently, there are no clinically available drugs that target the oncogenic STAT3/5 proteins in particular or their Gain of Function hyperactive mutant products. Here, we summarize targeting approaches on STAT3/5, as the field moves towards clinical applications as well as we illuminate on upstream or downstream JAK-STAT pathway interference with kinase inhibitors, heat shock protein blockers or changing nuclear import/export processes. We cover the design paradigms and medicinal chemistry approaches to illuminate progress and challenges in understanding the pleiotropic role of STAT3 and STAT5 in oncogenesis, the microenvironment, the immune system in particular, all culminating in a complex interplay towards cancer progression.

Research & information: general --- Biology, life sciences --- multiple myeloma --- STAT3 --- S3I-1757 --- nanoparticle --- CD38 --- siRNA/RNAi --- polyethylenimine --- PEI --- lipopolyplex --- siRNA delivery --- glioma --- glioblastoma --- STAT5 --- AKT --- ERK1/2 --- prolactin --- androgens --- prostate cancer --- knockout --- escape mechanisms --- stem/progenitor cells --- cell hierarchy --- cancer --- CD4+ T cells --- CD8+ T cells --- myeloid cells --- immune check point --- hepatitis C virus (HCV) --- cirrhosis --- hepatocellular carcinoma (HCC) --- endoplasmic reticulum (ER) stress --- oxidative stress (OS) --- unfolded protein response (UPR) --- microRNA-122 (miR-122) --- nuclear factor erythroid 2-related factor 2 (NRF2) --- signal transducer and activator of transcription 3 (STAT3) --- hepatocyte nuclear factor 4 alpha (HNF4A) --- solid cancers --- cell cycle --- apoptosis --- inflammation --- mitochondria --- stemness --- tumor suppression --- melanoma --- autoimmune disease --- immunotherapy --- tumor-immune cell interactions --- breast cancer --- PD-L1 --- M2 macrophages --- NK cells --- STAT3 inhibitor XIII --- hedging --- transaction costs --- dynamic programming --- risk management --- post-decision state variable --- cancer progression --- cancer-stem cell --- cytokine --- therapy resistance --- metastasis --- immunosuppression --- tumor microenvironment --- proliferation --- tyrosine kinase 2 --- JAK family of protein tyrosine kinases --- signal transducer and activator of transcription --- cytokine receptor signaling --- gain-of-function mutation --- tumorigenesis --- ADAM17 --- interleukin-6 --- trans-signaling --- epidermal growth factor receptor (EGF-R) --- shedding --- metalloprotease --- tumor necrosis factor alpha (TNFα) --- inflammation associated cancer --- colon cancer --- lung cancer --- SH2 domain --- mutations --- autosomal-dominant hyper IgE syndrome --- inflammatory hepatocellular adenomas --- T-cell large granular lymphocytic leukemia --- T-cell prolymphocytic leukemia --- growth hormone insensitivity syndrome --- nuclear pore complex --- nuclear transport receptors --- nucleocytoplasmic shuttling --- targeting --- tumor-associated macrophages --- adoptive T cell therapy --- immune suppression --- STAT transcription factors --- JAK --- STAT --- T-PLL --- T-cell leukemia --- meta-analysis --- STAT5B signaling --- small-molecule inhibitors --- cancer models --- companion animals --- comparative oncology --- pharmacological inhibitor --- STAT5 signaling --- chemotherapy resistance --- myeloid leukemia --- heat shock proteins --- chaperones --- stabilization --- targeted therapy --- ovarian cancer --- hematopoietic cancers --- therapeutic targeting --- pharmacological inhibitors --- mTOR --- Bone Marrow Failure Syndromes --- lymphocytes --- lymphoma --- T-cells --- RHOA --- NGS --- MPN --- JAK2 V617F --- neoplastic stem cells --- multiple myeloma --- STAT3 --- S3I-1757 --- nanoparticle --- CD38 --- siRNA/RNAi --- polyethylenimine --- PEI --- lipopolyplex --- siRNA delivery --- glioma --- glioblastoma --- STAT5 --- AKT --- ERK1/2 --- prolactin --- androgens --- prostate cancer --- knockout --- escape mechanisms --- stem/progenitor cells --- cell hierarchy --- cancer --- CD4+ T cells --- CD8+ T cells --- myeloid cells --- immune check point --- hepatitis C virus (HCV) --- cirrhosis --- hepatocellular carcinoma (HCC) --- endoplasmic reticulum (ER) stress --- oxidative stress (OS) --- unfolded protein response (UPR) --- microRNA-122 (miR-122) --- nuclear factor erythroid 2-related factor 2 (NRF2) --- signal transducer and activator of transcription 3 (STAT3) --- hepatocyte nuclear factor 4 alpha (HNF4A) --- solid cancers --- cell cycle --- apoptosis --- inflammation --- mitochondria --- stemness --- tumor suppression --- melanoma --- autoimmune disease --- immunotherapy --- tumor-immune cell interactions --- breast cancer --- PD-L1 --- M2 macrophages --- NK cells --- STAT3 inhibitor XIII --- hedging --- transaction costs --- dynamic programming --- risk management --- post-decision state variable --- cancer progression --- cancer-stem cell --- cytokine --- therapy resistance --- metastasis --- immunosuppression --- tumor microenvironment --- proliferation --- tyrosine kinase 2 --- JAK family of protein tyrosine kinases --- signal transducer and activator of transcription --- cytokine receptor signaling --- gain-of-function mutation --- tumorigenesis --- ADAM17 --- interleukin-6 --- trans-signaling --- epidermal growth factor receptor (EGF-R) --- shedding --- metalloprotease --- tumor necrosis factor alpha (TNFα) --- inflammation associated cancer --- colon cancer --- lung cancer --- SH2 domain --- mutations --- autosomal-dominant hyper IgE syndrome --- inflammatory hepatocellular adenomas --- T-cell large granular lymphocytic leukemia --- T-cell prolymphocytic leukemia --- growth hormone insensitivity syndrome --- nuclear pore complex --- nuclear transport receptors --- nucleocytoplasmic shuttling --- targeting --- tumor-associated macrophages --- adoptive T cell therapy --- immune suppression --- STAT transcription factors --- JAK --- STAT --- T-PLL --- T-cell leukemia --- meta-analysis --- STAT5B signaling --- small-molecule inhibitors --- cancer models --- companion animals --- comparative oncology --- pharmacological inhibitor --- STAT5 signaling --- chemotherapy resistance --- myeloid leukemia --- heat shock proteins --- chaperones --- stabilization --- targeted therapy --- ovarian cancer --- hematopoietic cancers --- therapeutic targeting --- pharmacological inhibitors --- mTOR --- Bone Marrow Failure Syndromes --- lymphocytes --- lymphoma --- T-cells --- RHOA --- NGS --- MPN --- JAK2 V617F --- neoplastic stem cells