New Proposal for Combined Therapy Proves Effective Against a Notoriously Resistant HER2+ Breast Cancer Subtype

Note: This article discusses research that was performed in cells and in mice in the lab. Therefore, the results do not necessarily apply to humans. Nonetheless, they are promising. The research looked into treatment of a specific HER2+ breast cancer subtype known as p95HER2. The scientists found that this type of tumor might be successfully treated with a combination of chemotherapy and the targeted drug Herceptin. Clinical trials with volunteer patients will be needed to see if this holds true.

“Research led by Joaquín Arribas, Principal Investigator of the Vall d´Hebron Institute of Oncology´s (VHIO) Growth Factors Group, Director of Preclinical Research at VHIO, and ICREA Professor, has shown the combined strategy of chemotherapy plus trastuzumab (a selective therapy against HER2 receptors), as effective in reducing tumors of a specific HER2+ breast cancer subtype known as p95HER2. Recently published in the Journal of the National Cancer Institute (JNCI), this study signposts new therapeutic promise for patients with p95HER2-positive breast tumors, since, up until now, this subgroup has proven highly resistant to therapy. Funded through support received from the Spanish Association against Cancer (AECC), this research has also been carried out in collaboration with Atanasio Pandiella from the Cancer Research Center of Salamanca (CIC) and other organizations including the Breast Cancer Research Foundation (BCRF).”


The Antimelanoma Activity of the Histone Deacetylase Inhibitor Panobinostat (LBH589) is Mediated by Direct Tumor Cytotoxicity and Increased Tumor Immunogenicity

“Melanoma is the deadliest skin cancer, and its incidence has been increasing faster than any other cancer. Although immunogenic, melanoma is not effectively cleared by host immunity. In this study, we investigate the therapeutic, antimelanoma potential of the histone deacetylase inhibitor (HDACi) panobinostat (LBH589) by assessing both its cytotoxic effects on melanoma cells as well as enhancement of immune recognition of melanoma. Utilizing murine and human melanoma cell lines, we analyzed the effects of LBH589 on proliferation and survival. In addition, we analyzed the expression of several immunologically relevant surface markers and melanoma differentiation antigens, and the ability of LBH589-treated melanoma to activate antigen-specific T cells. Finally, we assessed the in-vivo effects of LBH589 in a mouse melanoma model. Low nanomolar concentrations of LBH589 inhibit the growth of all melanoma cell lines tested, but not normal melanocytes. This inhibition is characterized by increased apoptosis as well as a G1 cell cycle arrest. In addition, LBH589 augments the expression of major histocompatibility complex and costimulatory molecules on melanoma cells leading to an increased ability to activate antigen-specific T cells. Treatment also increases expression of melanoma differentiation antigens. In vivo, LBH589 treatment of melanoma-bearing mice results in a significant increase in survival. However, in immunodeficient mice, the therapeutic effect of LBH589 is lost. Taken together, LBH589 exerts a dual effect upon melanoma cells by affecting not only growth/survival but also by increasing melanoma immunogenicity. These effects provide the framework for future evaluation of this HDAC inhibitor in melanoma treatment.”


Nuclear PTEN Controls DNA Repair and Sensitivity to Genotoxic Stress

“Loss of function of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor gene is associated with many human cancers. In the cytoplasm, PTEN antagonizes the phosphatidylinositol 3-kinase (PI3K) signaling pathway. PTEN also accumulates in the nucleus, where its function remains poorly understood. We demonstrate that SUMOylation (SUMO, small ubiquitin-like modifier) of PTEN controls its nuclear localization. In cells exposed to genotoxic stress, SUMO-PTEN was rapidly excluded from the nucleus dependent on the protein kinase ataxia telangiectasia mutated (ATM). Cells lacking nuclear PTEN were hypersensitive to DNA damage, whereas PTEN-deficient cells were susceptible to killing by a combination of genotoxic stress and a small-molecule PI3K inhibitor both in vitro and in vivo. Our findings may have implications for individualized therapy for patients with PTEN-deficient tumors.”


Nuclear PTEN Controls DNA Repair and Sensitivity to Genotoxic Stress

“Loss of function of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor gene is associated with many human cancers. In the cytoplasm, PTEN antagonizes the phosphatidylinositol 3-kinase (PI3K) signaling pathway. PTEN also accumulates in the nucleus, where its function remains poorly understood. We demonstrate that SUMOylation (SUMO, small ubiquitin-like modifier) of PTEN controls its nuclear localization. In cells exposed to genotoxic stress, SUMO-PTEN was rapidly excluded from the nucleus dependent on the protein kinase ataxia telangiectasia mutated (ATM). Cells lacking nuclear PTEN were hypersensitive to DNA damage, whereas PTEN-deficient cells were susceptible to killing by a combination of genotoxic stress and a small-molecule PI3K inhibitor both in vitro and in vivo. Our findings may have implications for individualized therapy for patients with PTEN-deficient tumors.”


Nuclear PTEN Controls DNA Repair and Sensitivity to Genotoxic Stress

“Loss of function of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor gene is associated with many human cancers. In the cytoplasm, PTEN antagonizes the phosphatidylinositol 3-kinase (PI3K) signaling pathway. PTEN also accumulates in the nucleus, where its function remains poorly understood. We demonstrate that SUMOylation (SUMO, small ubiquitin-like modifier) of PTEN controls its nuclear localization. In cells exposed to genotoxic stress, SUMO-PTEN was rapidly excluded from the nucleus dependent on the protein kinase ataxia telangiectasia mutated (ATM). Cells lacking nuclear PTEN were hypersensitive to DNA damage, whereas PTEN-deficient cells were susceptible to killing by a combination of genotoxic stress and a small-molecule PI3K inhibitor both in vitro and in vivo. Our findings may have implications for individualized therapy for patients with PTEN-deficient tumors.”


Diabetes Plus Anticancer Drug Combination Targets Melanoma Cells Unresponsive to Standard Treatments


Researchers at the Wistar Institute in Philadelphia, Pennsylvania, recently developed a combination approach to target melanoma tumor cells that are particularly resistant to both chemotherapy and targeted therapies, such as vemurafenib. A combination of anti-melanoma drugs with an anti-diabetes drug was better able to target all of the cells in a tumor than the anti-melanoma drugs alone. The combination therapy even proved effective against cells that are usually resistant to therapy and are thought to be responsible for at least some of the resistance patients develop to melanoma treatment. Continue reading…