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Inhibition Of Constitutive Stat3 Pathway In Breast Cancer Cells By A Novel Low-Molecular-Weight Compound
Background: The constitutive activation of signal transducer and activator of transcription 3 (Stat3) is frequently detected in breast cancer specimens from patients with advanced diseases . Constitutive Stat3 signaling participates in oncogenesis by stimulating cell proliferation, promoting angiogenesis, and resistance to apoptosis induced by conventional chemotherapy. Blocking constitutive Stat3 activation by dominant-negative Stat3 mutants induced apoptosis and inhibited cell growth, demonstrating that constitutive Stat3 signaling is crucial to the survival of cancer cells and inhibiting Stat3 is a promising therapeutic approach. Giving that Stat3 is frequently activated and contributes to breast cancer progression and survival, there is a critical need to develop potent Stat3 inhibitors. We have identified a novel non-peptide, cell-permeable small molecule with promising inhibitory efficacy of blocking Stat3 functions and opened a new opportunity to pharmacologically target Stat3 . Objective/Hypothesis: Since the dimerization of Stat3 via SH2 domain is a decisive event for its activation, we hypothesize that small molecule compounds that bind to the SH2 domain of Stat3 will directly block the dimerization of Stat3 and inhibit Stat3 activity. We further hypothesize that blocking Stat3 by small molecule compounds should sensitize breast cancer cells to cytotoxic agents-induced apoptosis and have anti-tumor activity. Specific Aims : 1. Determine the inhibitory efficacy of Stat3 inhibitor in combination with cytotoxic agents in breast cancer cells expressing constitutively active Stat3. 2. Evaluate the efficacy of Stat3 inhibitor in combination with cytotoxic agents in a nude mouse tumor model. Study Design : We will examine the synergistic effects of Stat3 inhibitor in combination with commonly used anti-breast cancer cytotoxic agents in vitro and the molecular mechanism in induction of apoptosis by Stat3 inhibitor. We will further examine the anti-tumor activity and synergistic effects of Stat3 inhibitor in combination with cytotoxic agents in nude mice breast tumor model. Potential Outcomes and Benefits of the Research : Blocking constitutive Stat3 signaling by drug-like Stat3 inhibitor would provide a novel pharmacological approach for breast cancer treatment. We anticipate that the proposed studies will pave the way for future clinical studies of Stat3 inhibitor as an entirely new class of cancer therapy with the ultimate goal of breast cancer therapy.
The constant activation (persistently turned on) of Signal transducer and activator of transcription 3 (Stat3) is frequently detected (45%) in breast cancer patients with advanced diseases. Constantly activate Stat3 activities in nonmalignant human mammary epithelial cells can induce tumor formation of these cells in mice suggesting activated Stat3 can promote breast cancer progression. Activated Stat3 induces tumor progression by stimulating cancer cell growth , promoting angiogenesis, and resistance to cell death induced by conventional chemotherapies. Inhibiting activated Stat3 in cancer cells dramatically induced cell death, demonstrating that constant Stat3 signaling is crucial for the survival and growth of tumor cells. It also indicates that Stat3 is a highly important and true therapeutic target for breast cancer, because once Stat3 pathway is inhibited, cancer cells die quickly. Because Stat3 is frequently activated in breast cancer and contributes to breast cancer progression and survival, there is an urgent need to develop inhibitors that block Stat3. To date, no Stat3-specific Small molecule drugs are available. We have developed a new pharmacological small molecule compound that selectively inhibits Stat3 and opened a new opportunity to inhibit Stat3 in breast cancer. Our first aim is to investigate the combination effects of our pharmacological Stat3 inhibitor with commonly used anti-breast cancer chemotherapeutic drugs. Our second aim is to investigate the anti-tumor activity and combination effects of this Stat3 inhibitor with chemotherapeutic drugs using breast cancer cells and a mouse tumor models. We predict that our new pharmacological Stat3 inhibitor will sensitize and significantly enhance anti-breast cancer drugs to induce cell death of breast cancer cells and tumors in mouse model. Such an approach should reduce side effects to normal cells that are associated with conventional, aggressive chemotherapeutic drugs and improve the overall responses. Our long-range goal is to develop potent pharmacological drugs that inhibit Stat3 in breast cancer as a promising therapeutic approach. We anticipate that these proposed studies will pave the way for future clinical studies of pharmacological Stat3 inhibitor, alone or in combination with anti-breast cancer chemotherapeutic drugs, as an entirely new class of anti-cancer therapy, with the ultimate goal of therapy for breast carcinoma.