11 research outputs found
Targeting apoptosis signaling pathways for anticancer therapy
No full textTreatment approaches for cancer, for example chemotherapy, radiotherapy or immunotherapy, primarily act by inducing cell death in cancer cells. Consequently, the inability to trigger cell death pathways or alternatively, evasion of cancer cells to the induction of cell death pathways can result in resistance of cancers to current treatment protocols. Therefore, in order to overcome treatment resistance a better understanding of the underlying mechanisms that regulate cell death and survival pathways in cancers and in response to cancer therapy is necessary to develop molecular-targeted therapies. This strategy should lead to more effective and individualized treatment strategies that selectively target deregulated signaling pathways in a tumor type- and patient-specific manner
How to target apoptosis signaling pathways for the treatment of pediatric cancers
No full textApoptosis represents one of the most important forms of cell death in higher organisms and is typically dysregulated in human cancers, including pediatric tumors. This implies that ineffective engagement of cell death programs can contribute to tumor formation as well as tumor progression. In addition, the majority of cytotoxic therapeutic principles rely on the activation of cell death signaling pathways in cancer cells. Blockade of signaling networks that lead to cell death can therefore confer treatment resistance. A variety of genetic and epigenetic events as well as dysfunctional regulation of signaling networks have been identified as underlying causes of cell death resistance in childhood malignancies. Apoptosis pathways can be therapeutically exploited by enhancing proapoptotic signals or by neutralizing antiapoptotic programs. The challenge in the coming years will be to successfully transfer this knowledge into the development of innovative treatment approaches for children with cancer
Shifting the balance of mitochondrial apoptosis: therapeutic perspectives
No full textSignaling via the intrinsic (mitochondrial) pathway of apoptosis represents one of the critical signal transduction cascades that control the regulation of cell death. This pathway is typically altered in human cancers, thereby providing a suitable target for therapeutic intervention. Members of the Bcl-2 family of proteins as well as cell survival signaling cascades such as the PI3K/Akt/mTOR pathway are involved in the regulation of mitochondria-mediated apoptosis. Therefore, further insights into the molecular mechanisms that form the basis for the control of mitochondria-mediated apoptosis will likely open new perspectives to bypass evasion of apoptosis and treatment resistance in human cancers
Inhibitor of apoptosis proteins in pediatric leukemia : molecular pathways and novel approaches to therapy
No full textInhibitor of Apoptosis (IAP) proteins are a family of proteins with antiapoptotic functions that contribute to the evasion of apoptosis, a form of programed cell death. IAP proteins are expressed at high levels in a variety of human cancers including childhood acute leukemia. This elevated expression has been associated with unfavorable prognosis and poor outcome. Therefore, IAP proteins are currently exploited as therapeutic targets for cancer drug discovery. Consequently, small-molecule inhibitors or antisense oligonucleotides directed against IAP proteins have been developed over the last years. Indeed, IAP antagonists proved to exhibit in vitro and in vivo antitumor activities against childhood pediatric leukemia in several preclinical studies. Thus, targeting IAP proteins represents a promising molecular targeted strategy to overcome apoptosis resistance in childhood leukemia, which warrants further exploitation
Regulation of cell death in cancer - possible implications for immunotherapy
No full textSince most anticancer therapies including immunotherapy trigger programmed cell death in cancer cells, defective cell death programs can lead to treatment resistance and tumor immune escape. Therefore, evasion of programmed cell death may provide one possible explanation as to why cancer immunotherapy has so far only shown modest clinical benefits for children with cancer. A better understanding of the molecular mechanisms that regulate sensitivity and resistance to programmed cell death is expected to open new perspectives for the development of novel experimental treatment strategies to enhance the efficacy of cancer immunotherapy in the future
Hedgehog inhibitors in rhabdomyosarcoma: a comparison of 4 compounds and responsiveness of 4 cell lines
No full textRhabdomyosarcoma (RMS) are the most common soft tissue sarcoma in children and are divided into two major histological subgroups, i.e. embryonal (ERMS) and alveolar RMS (ARMS). RMS can show HEDGEHOG/SMOOTHENED (HH/SMO) signaling activity and several clinical trials using HH inhibitors for therapy of RMS have been launched. We here compared the antitumoral effects of the SMO inhibitors GDC-0449, LDE225, HhA and cyclopamine in two ERMS (RD, RUCH-2) and two ARMS (RMS-13, Rh41) cell lines. Our data show that the antitumoral effects of these SMO inhibitors are highly divers and do not necessarily correlate with inhibition of HH signaling. In addition, the responsiveness of the RMS cell lines to the drugs is highly heterogeneous. Whereas some SMO inhibitors (i.e. LDE225 and HhA) induce strong proapoptotic and antiproliferative effects in some RMS cell lines, others paradoxically induce cellular proliferation at certain concentrations (e.g. 10 µM GDC-0449 or 5 µM cyclopamine in RUCH-2 and Rh41 cells) or can increase HH signaling activity as judged by GLI1 expression (i.e. LDE225, HhA and cyclopamine). Similarly, some drugs (e.g. HhA) inhibit PI3K/AKT signaling or induce autophagy (e.g. LDE225) in some cell lines, whereas others cannot (e.g. GDC-0449). In addition, the effects of SMO inhibitors are concentration-dependent (e.g. 1 µM and 10 µM GDC-0449 decrease GLI1 expression in RD cells whereas 30 µM GDC-0449 does not). Together these data show that some SMO inhibitors can induce strong antitumoral effects in some, but not all, RMS cell lines. Due to the highly heterogeneous response we propose to conduct thorough pretesting of SMO inhibitors in patient-derived short term RMS cultures or patient-derived xenograft mouse models before applying these drugs to RMS patients
Biology-driven targeted therapy of pediatric soft-tissue and bone tumors: current opportunities and future challenges
No full textRecent advances in the understanding of the biological basis of pediatric soft-tissue and bone tumors, especially owing to the advent of “omics” technologies, have led to an exponential increase in the current knowledge on the genetic and cellular patho-mechanisms that drive these diseases. This offers the unprecedented opportunity to develop and implement targeted therapies such as monoclonal antibodies, small molecules, oncolytic viruses, and immunotherapies in standard and/or personalized treatment regimens. However, to date only a few examples document a successful translation of discoveries from the bench to the bedside. Recent international expert congresses such as the “Pediatric Cancer Translational Genomics” conference (Phoenix, Arizona, 2012), the ESF-EMBO workshop on “Molecular Biology and Innovative Therapies in Sarcomas” (Pultusk, Poland, 2012), and the AACR special meeting on “Pediatric Cancer at the Crossroads – Translating Discovery into Improved Outcomes” (San Diego, California, 2013) further emphasize the urgent need for a more rapid and especially more successful translational process. Hence, we strongly believe that a Frontiers Research Topic aiming at this aspect would fit just in time and that it would have great potential to receive numerous contributions of outstanding experts of the field. The proposed Frontiers Research Topic shall provide a platform for active and interdisciplinary discussion, summarize current state-of-the-art knowledge on all basic research and translational aspects in pediatric soft-tissue and bone tumors, and offer new perspectives of how to further promote and accelerate the translational process. We welcome high-quality original research articles, brief reports, as well as opinion, hypothesis, and review articles, and especially encourage submissions from early-career scientists
Oncogenic RAS mutants confer resistance of rhabdomyosarcoma cells to oxidative stress-induced ferroptotic cell death
No full textRecent genomic studies revealed a high rate of recurrent mutations in the RAS pathway in primary rhabdomyosarcoma (RMS) samples. In the present study, we therefore investigated how oncogenic RAS mutants impinge on the regulation of cell death of RMS cells. Here, we report that ectopic expression of NRAS12V, KRAS12V or HRAS12V protects RMS cells from oxidative stress-induced cell death. RMS cells engineered to express NRAS12V, KRAS12V or HRAS12V were significantly less susceptible to loss of cell viability upon treatment with several oxidative stress inducers including the thioredoxin reductase inhibitor Auranofin, the glutathione (GSH) peroxidase 4 (GPX4) inhibitor RSL3 or Erastin, an inhibitor of the cysteine/glutamate amino acid transporter system xc¬- that blocks GSH synthesis. Notably, addition of the iron-chelating compound ferrostatin-1 confers protection against Erastin- or RSL3-induced cytotoxicity, indicating that these compounds trigger ferroptosis, an iron-dependent form of programmed cell death. Furthermore, RMS cells overexpressing oncogenic RAS mutants are significantly protected against the dual PI3K/mTOR inhibitor PI103, whereas they are similarly sensitive to DNA-damaging drugs such as Doxorubicin or Etoposide. This suggests that oncogenic RAS selectively modulates cell death pathways triggered by cytotoxic stimuli in RMS cells. In conclusion, our discovery of an increased resistance to oxidative stress imposed by oncogenic RAS mutants in RMS cells has important implications for the development of targeted therapies for RMS
ESF-EMBO symposium "molecular biology and innovative therapies in sarcomas of childhood and adolescence" Sept 29–Oct 4, Polonia Castle Pultusk, Poland
No full textRhabdomyosarcoma (RMS) and Ewing sarcoma (ES) are among the most common pediatric sarcomas (Arndt et al., 2012). Despite sarcomas representing a highly heterogeneous group of tumors, ES and alveolar RMS (ARMS) typically share one common genetic characteristic, namely a specific chromosomal translocation (Helman and Meltzer, 2003; Lessnick and Ladanyi, 2012). These translocations generate fusion proteins, which are composed of two transcription factors (TF). Typically, one TF is a developmentally regulated factor that is essential for proper specification of a given lineage and provides the DNA-binding domain, while the partner TF contributes a transactivation domain that drives aberrant expression of target genes. Based on these common genetic characteristics, the first ESF-EMBO research conference entitled “Molecular Biology and Innovative Therapies in Sarcomas of Childhood and Adolescence” with special focus on RMS and ES was held at the Polonia Castle in Pultusk, Poland. The conference gathered 70 participants from more than 15 countries and several continents representing most research groups that are active in this field
SMAC mimetic BV6 enables sensitization of resistant tumor cells but also affects cytokine-induced killer (CIK) cells: a potential challenge for combination therapy
No full textAllogeneic hematopoietic stem cell transplantation (HSCT) is an established treatment option for high-risk hematological malignancies, and may also be offered to patients with solid malignancies refractory to conventional therapies. In case of patients’ relapse, refractory tumor cells may then be targeted by cellular therapy-based combination strategies. Here, we investigated the potential of small molecule IAP inhibitor (SMAC mimetic) BV6 in increasing cytokine-induced killer (CIK) cell-mediated cytotoxicity against different tumor targets. Four hour pre-incubation with 2.5 μMol BV6 moderately enhanced CIK cell-mediated lysis of hematological (H9, THP-1, Tanoue) and solid malignancies (RH1, RH30, TE671). However, BV6 also increased apoptosis of non-malignant cells like peripheral blood mononuclear cells and most notably had an inhibitory effect on immune cells potentially limiting their cytotoxic potential. Hence, cytotoxicity increased in a dose dependent manner when BV6 was removed before CIK cells were added to tumor targets. However, cytotoxic potential was not further increasable by extending BV6 pre-incubation period of target cells from four to 12 hours. Molecular studies revealed that BV6 sensitization of target cells involved activation of caspases. Here we provide evidence that SMAC mimetic may sensitize targets cells for CIK cell-induced cell death. However, BV6 also increased apoptosis of non-malignant cells like CIK cells and peripheral mononuclear cells. These findings may therefore be important for cell- and small molecule IAP inhibitor- based combination therapies of resistant cancers after allogeneic HSCT
