Cancer Letters

Adoptive CD8+ T cell therapy against cancer:Challenges and opportunities Publication date: 10 October 2019 Source: Cancer Letters, Volume 462 Author(s): Xiaotao Jiang, Jiang Xu, Mingfeng Liu, Hui Xing, Zhiming Wang, Lei Huang, Andrew L. Mellor, Wei Wang, Sha Wu Abstract Cancer immunotherapy is a new and promising option for cancer treatment. Unlike traditional chemo- and radiotherapy, immunotherapy actives host immune system to attack malignancies, and this potentially offers long-term protection from recurrence with less toxicity in comparison to conventional chemo- and radiation therapy. In adoptive CD8+ T cell therapy (ACT), large numbers of tumor-specific T cells are sourced from patients and expanded in vitro and infused back to patients. T cells can be expanded from naturally-induced tumor-specific CD8+ T cells isolated from tumor infiltrating lymphocytes (TIL) or genetically-modified autologous circulating CD8+ T cells. The engineered T cells expressed tumor-specific antigen receptors including chimeric antigen receptors (CARs) and T cell receptors (TCRs), prepared from cultured B and T cell clones, respectively. The most successful ACT, anti-CD19 chimeric antigen receptor T (CAR-T) cell therapy directed against B cell lymphoma, is already approved for use based on evidence of efficacy. Efficacy of solid tumors is not yet forthcoming. This review summarizes current technology developments using ACT in clinical trials. In this review, differences between various ACT approaches are discussed. Furthermore, resistance factors in the tumor microenvironment are also considered, as are immune related adverse effects, critical clinic monitoring parameters and potential mitigation approaches.

Induction of endoplasmic reticulum stress and inhibition of colon carcinogenesis by the anti-helmintic drug rafoxanide Publication date: 10 October 2019 Source: Cancer Letters, Volume 462 Author(s): Federica Laudisi, Antonio Di Grazia, Veronica De Simone, Fabio Cherubini, Alfredo Colantoni, Angela Ortenzi, Eleonora Franzè, Vincenzo Dinallo, Davide Di Fusco, Ivan Monteleone, Eric R. Fearon, Giovanni Monteleone, Carmine Stolfi Abstract Colorectal cancer (CRC) remains one of the leading causes of mortality worldwide. Drug repositioning is a promising approach for new cancer therapies, as it provides the opportunity to rapidly advance potentially promising agents into clinical trials. The FDA-approved anti-helminthic drug rafoxanide was recently reported to antagonize the oncogenic function of the BRAF V600E mutant protein, commonly found in CRCs, as well as to inhibit the proliferation of skin cancer cells. These observations prompted us to investigate the potential anti-cancer effects of rafoxanide in CRC models. We found rafoxanide inhibited proliferation in CRC cells, but not in normal colonic epithelial cells. Rafoxanide's anti-proliferative action was associated with marked reduction in cyclin D1 protein levels and accumulation of cells in the G0/G1 phase. These effects relied on selective induction of the endoplasmic reticulum stress (ERS) response in CRC cells and were followed by caspase-dependent cell death. Systemic administration of rafoxanide to Apcmin/+ mice induced to develop CRCs caused ERS activation, proliferation inhibition and apoptosis induction in the neoplastic cells. Collectively, our data suggest rafoxanide might be repurposed as an anti-cancer drug for the treatment of CRC.

IL-10 knockdown with siRNA enhances the efficacy of Doxorubicin chemotherapy in EBV-positive tumors by inducing lytic cycle via PI3K/p38 MAPK/NF-kB pathway Publication date: 10 October 2019 Source: Cancer Letters, Volume 462 Author(s): Li Gao, Haige Han, Honglei Wang, Li Cao, Wen-hai Feng Abstract High levels of IL-10 expression in Epstein–Barr virus (EBV) associated tumors have been reported and it is likely to be important for maintaining EBV latency and EBV-associated tumors. The switch from the latent form of EBV to the lytic form in tumor cells can lead to tumor cell lysis. Here, we found that knockdown of IL-10 induced EBV lytic replication. Subsequently, we demonstrated that IL-10 knockdown activated BZLF1 promoter through PI3K-p38 MAPK-NF-κB signaling pathway. Interestingly, we verified that VEGF-A was required for IL-10 knockdown to activate PI3K signaling and the accompanying EBV lytic induction. Exogenous recombinant human VEGF-A induced PI3K activation and EBV lytic infection, and inhibition of VEGF-A signaling prevented the PI3K/AKT phosphorylation and EBV reactivation responded to IL-10 knockdown. Most importantly, IL-10 knockdown synergized with chemotherapeutic agent Doxorubicin to kill EBV associated tumor cells in vitro and repress EBV-positive tumor growth in vivo. Our results suggest that inhibition of IL-10 has the potential to serve as a new supplemental strategy for the treatment of EBV-associated tumors.

Humanized anti-CD271 monoclonal antibody exerts an anti-tumor effect by depleting cancer stem cells Publication date: 1 October 2019 Source: Cancer Letters, Volume 461 Author(s): Shinkichi Morita, Mai Mochizuki, Kouichi Wada, Rie Shibuya, Mao Nakamura, Kazunori Yamaguchi, Tomoko Yamazaki, Takayuki Imai, Yukinori Asada, Kazuto Matsuura, Kazuo Sugamura, Yukio Katori, Kennichi Satoh, Keiichi Tamai Abstract CD271, known as a neurotrophin receptor, is expressed in various cancers such as hypopharyngeal cancer (HPC) and melanoma. We recently reported that CD271 is a cancer-stem-cell biomarker of HPC, and that its expression is essential for cancer-cell proliferation and is correlated with a poor prognosis in this disease. Here, to develop a therapeutic antibody to CD271, we established a humanized anti-CD271 monoclonal antibody (hCD271 mA b). hCD271 mA b bound to the cysteine-rich domain 1 (CRD1) of human CD271 with high affinity (KD = 1.697 × 10−9 M). In vitro, hCD271 mA b exerted antibody-dependent cell-mediated cytotoxicity (ADCC) activity against SP2/0-CD271 (human CD271-transduced mouse cell line). Treatment with hCD271 mA b also exerted anti-tumor activity in graft models of three cell lines (HPCM2 (patient-derived xenograft cell line of hypopharyngeal cancer), MeWo-Luc (melanoma cell line), and SP2/0-CD271) in mice, resulting in smaller tumors compared to controls and reduced numbers of CD271-positive cells. Collectively, these data suggest that an antibody targeting CD271 is a promising therapeutic strategy.

Abivertinib, a novel BTK inhibitor: Anti-Leukemia effects and synergistic efficacy with homoharringtonine in acute myeloid leukemia Publication date: 1 October 2019 Source: Cancer Letters, Volume 461 Author(s): Shujuan Huang, Jiajia Pan, Jing Jin, Chengying Li, Xia Li, Jiansong Huang, Xin Huang, Xiao Yan, Fengling Li, Mengxia Yu, Chao Hu, Jingrui Jin, Yu Xu, Qing Ling, Wenle Ye, Yungui Wang, Jie Jin Abstract Ibrutinib, an inhibitor of Bruton tyrosine kinase (BTK), has shown promising pharmacologic effects in acute myeloid leukemia (AML). In this study, we report that abivertinib or AC0010, a novel BTK inhibitor, inhibits cell proliferation, reduces colony-forming capacity, and induces apoptosis and cell cycle arrest in AML cells, especially those harboring FLT3-ITD mutations. Abivertinib was also found to be more sensitive than ibrutinib in treating AML. We demonstrate that in addition to targeting the phosphorylation of BTK, abivertinib also targeted the crucial PI3K survival pathway. Furthermore, abivertinib suppressed the expression of p-FLT3 and the downstream target p-STAT5 in AML cells harboring FLT3-ITD mutations. Moreover, in vitro and in vivo data revealed synergistic activity between abivertinib and homoharringtonine (HHT), a natural plant alkaloid commonly used in China, in treating AML cells with or without FLT3-ITD mutations. Collectively, these preclinical data suggest that abivertinib may be a promising novel agent for AML, with potential for combination treatment with HHT. Clinical studies on abivertinib-involved therapy are planned.

Low-dose triple drug combination targeting the PI3K/AKT/mTOR pathway and the MAPK pathway is an effective approach in ovarian clear cell carcinoma Publication date: 1 October 2019 Source: Cancer Letters, Volume 461 Author(s): Joseph J. Caumanns, Anne van Wijngaarden, Arjan Kol, Gert J. Meersma, Mathilde Jalving, René Bernards, Ate G.J. van der Zee, G. Bea A. Wisman, Steven de Jong Abstract Advanced stage ovarian clear cell carcinoma (OCCC) is poorly responsive to platinum-based chemotherapy and has an unfavorable prognosis. Previous studies revealed heterogeneous mutations in PI3K/AKT/mTOR and MAPK pathway nodules converging in mTORC1/2 activation. Here, we aimed to identify an effective low-dose combination of PI3K/AKT/mTOR pathway and MAPK pathway inhibitors simultaneously targeting key kinases in OCCC to preclude single-inhibitor initiated pathway rewiring and limit toxicity. Small molecule inhibitors of mTORC1/2, PI3K and MEK1/2 were combined at monotherapy IC20 doses in a panel of genetically diverse OCCC cell lines (n = 7) to determine an optimal low-dose combination. The IC20 dose triple combination reduced kinase activity in PI3K/AKT/mTOR and MAPK pathways, prevented single-inhibitor induced feedback mechanisms and inhibited short and long-term proliferation in all seven cell lines. Finally, this low-dose triple drug combination treatment significantly reduced tumor growth in two genetically characterized OCCC patient-derived xenograft (PDX) models without resulting in weight loss in these mice. The effectiveness and tolerability of this combined therapy in PDX models warrants clinical exploration of this treatment strategy for OCCC and might be applicable to other cancer types with a similar genetic background.

Pro-differentiating and radiosensitizing effects of inhibiting HDACs by PXD-101 (Belinostat) in in vitro and in vivo models of human rhabdomyosarcoma cell lines Publication date: 1 October 2019 Source: Cancer Letters, Volume 461 Author(s): Francesco Marampon, Valentina Di Nisio, Ilaria Pietrantoni, Francesco Petragnano, Irene Fasciani, Bianca Maria Scicchitano, Carmela Ciccarelli, Giovanni Luca Gravina, Claudio Festuccia, Andrea Del Fattore, Mario Tombolini, Francesca De Felice, Daniela Musio, Sandra Cecconi, Paolo Tini, Marta Maddalo, Silvia Codenotti, Alessandro Fanzani, Antonella Polimeni, Roberto Maggio Abstract This study describes the in vitro and in vivo activity of PXD-101 (Belinostat), a novel hydroxamic acid-type pan-HDACs inhibitor characterized by a larger safety and efficacy, on myogenic-derived PAX3/FOXO1 fusion protein positive (RH30) or negative (RD) expressing rhabdomyosarcoma (RMS) cell lines. PXD-101 at low doses efficiently inhibited HDACs activity and counteracted the transformed phenotype of RMS by inducing growth arrest and apoptosis, affecting cancer stem cells population and inducing differentiation in RD. Notably, PXD-101 induced oxidative stress promoting DNA damages and affected the ability of RMS to assemble mitotic spindle. PXD-101 radiosensitized by inducing G2 cell cycle growth arrest, enhancing the radiation's ability to induce ROS accumulation and compromising both the ability of RMS to detoxify from ROS and to repair DNA damage. PXD-101 transcriptionally and post-transcriptionally affected c-Myc expression, key master regulator of rhabdomyosarcomagenesis and RMS radioresistance. All in vitro data were corroborated by in vivo experiments showing the cytostatic effects of PXD-101 when used alone and at low dose and its ability to promote the RT-induced killing of RMS. Taken together, our data confirm that altered HDACs activity plays a key role in RMS genesis and suggest PXD-101 as a valid therapeutic strategy particularly in combination with RT.

Higd-1a regulates the proliferation of pancreatic cancer cells through a pERK/p27KIP1/pRB pathway Publication date: 1 October 2019 Source: Cancer Letters, Volume 461 Author(s): Hyun-Jung An, Mihyeun Ryu, Hye Jin Jeong, Minho Kang, Hyung-Min Jeon, Jie-Oh Lee, Young Sang Kim, Hayyoung Lee Abstract Higd-1a/HIMP1-a/HIG1, a mitochondrial inner membrane protein, promotes cell survival under low glucose and hypoxic conditions. We previously reported that it interacts with Opa1, a factor involved in mitochondrial fusion, to regulate mitochondrial homeostasis. In the present study, we found that depletion of Higd-1a inhibited the proliferation of pancreatic cancer cells in vitro and in mice xenografts. Higd-1a knockdown did not itself lead to cell death but it caused cell cycle arrest through induction of p27KIP1 and hypo-phosphorylation of RB protein. Knockdown of Higd-1a also induced cellular senescence as shown by increased granularity and SA-β-galactosidase activity. We further showed that the mitochondrial stress induced by Higd-1a led to reduced ERK phosphorylation. Inhibition of the ERK pathway with U0126 induced p27KIP1 expression in the pancreatic cancer cells, confirming that the cell cycle retardation was the result of inhibition of the ERK pathway. Array analysis of human pancreatic cancers revealed that expression of Higd-1a was significantly elevated in pancreatic cancer tissues compared to normal tissue. Collectively, our results demonstrate that Higd-1a plays an important role in the proliferation of pancreatic cancer cells by regulating the pERK/p27KIP1/pRB signaling pathway.

Identification of a CIP4 PKA phosphorylation site involved in the regulation of cancer cell invasiveness and metastasis Publication date: 1 October 2019 Source: Cancer Letters, Volume 461 Author(s): Facundo M. Tonucci, Evangelina Almada, Carla Borini-Etichetti, Alejandro Pariani, Florencia Hidalgo, M. Jose Rico, Javier Girardini, Cristián Favre, James R. Goldenring, Mauricio Menacho-Marquez, M. Cecilia Larocca Abstract CDC42 interacting protein 4 (CIP4) is a CDC42 effector that coordinates membrane deformation and actin polymerization. The correlation of CIP4 overexpression with metastatic capacity has been characterized in several types of cancer. However, little information exists on how CIP4 function is regulated. CIP4 interacts with A-kinase (PKA) anchoring protein 350 (AKAP350) and CIP4 is also a PKA substrate. Here, we identified CIP4 T225 as the major CIP4 PKA phosphorylation site. In vitro and in vivoexperiments using hepatocellular carcinoma (HCC) and breast cancer cells showed that expression of a CIP4(T225E) phosphomimetic mutant increased cancer cell metastatic capacity and that, conversely, expression of a CIP4(T225A) non-phosphorylatable mutant reduced invasive properties. PKA inhibition decreased to CIP4(T225A) cell-levels control but not CIP4(T225E) cell migratory and invasive efficiency. Concomitantly, our studies indicate that CIP4 T225 phosphorylation promotes the formation of functional invadopodia and enhances CIP4 localization at these structures. Our findings further provide mechanistic data indicating that CIP4 T225 phosphorylation facilitates CIP4 interaction with CDC42. Altogether this study identifies a signaling pathway that involves CIP4 phosphorylation by PKA during the acquisition of a metastatic phenotype in cancer cells.

Endoplasmic reticulum-localized ECM1b suppresses tumor growth and regulates MYC and MTORC1 through modulating MTORC2 activation in esophageal squamous cell carcinoma Publication date: 1 October 2019 Source: Cancer Letters, Volume 461 Author(s): Valen Zhuoyou Yu, Josephine Mun Yee Ko, Lvwen Ning, Wei Dai, Simon Law, Maria Li Lung Abstract Esophageal squamous cell carcinoma (ESCC) is a deadly disease with dismal 5-year survival. Extracellular matrix protein 1 (ECM1) was identified as one of the most downregulated genes by transcriptomic analysis of normal esophageal/ESCC paired tissue samples. ECM1 plays oncogenic roles in cancer development in various cancer types. However, little is known about its role in ESCC. In vivo and in vitro functional assays coupled with analyses on public datasets and detailed molecular and mechanistic analyses were used to study the gene. We demonstrate that as opposed to the previously identified oncogenic role of ECM1a, ECM1b is a novel tumor suppressor in ESCC. ECM1 is significantly downregulated in ESCC and several other squamous cell carcinomas. ECM1b encodes a cellular protein that suppresses MYC protein expression and MTORC1 signaling activity. MTORC2 inactivation leads to suppressed MYC expression and MTORC1 signaling. ECM1b localizes to the endoplasmic reticulum and suppresses MTORC2 activation by inhibiting MTORC2/ribosome association. By regulating MTORC2/MYC/MTORC1 signaling, ECM1b suppresses general protein translation and enhances chemosensitivity. We provide evidence establishing a novel role of ECM1 in cancer that suggests ECM1b as a biomarker for ESCC disease management.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
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6948891480

alsfakia@gmail.com