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Targeted Therapy for Cancer Stem Cells
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Rama Krishna Nimmakayala, Saswati Karmakar, Garima Kaushik, Sanchita Rauth, Srikanth Barkeer, Saravanakumar Marimuthu, Moorthy P. Ponnusamy
Wnt has become a substantial new target for drug development to treat cancer because of its signaling cascade that plays a central role in regulating significant functions of malignant epithelial cells. Wnt ligands and signals drive the Wnt signaling pathway through canonical (β-catenin dependent) or non-canonical (β-catenin independent) paths. The Wnt ligand binds to various transmembrane receptors, such as Frizzled (FZD), Receptor tyrosine kinases (RTKs) and Receptor tyrosine kinase-like orphan receptor (ROR) 1 or ROR2. The pathway is activated with the binding of Wnt ligand to its receptor, followed by the activation of β-catenin. In the absence of Wnt ligand, β-catenin undergoes phosphorylation by a destruction complex containing glycogen synthase kinase 3b (GSK3b), adenomatous polyposis coli (APC) and axin, followed by degradation of β-catenin.
CAR-T cell therapy for triple-negative breast cancer and other solid tumors: preclinical and clinical progress
Published in Expert Opinion on Investigational Drugs, 2022
Chiara Corti, Konstantinos Venetis, Elham Sajjadi, Lorenzo Zattoni, Giuseppe Curigliano, Nicola Fusco
Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is implicated in the neuronal growth that takes place in the central nervous system (CNS). Although ROR1 is limitedly expressed in healthy adult tissues, it appears to be highly and uniformly expressed in both hematologic malignancies and solid tumors, including TNBC (~22%) [50,60,61]. Modification of the CAR spacer design and increase of the affinity of ROR1-CARs have displayed ability in enhancing T-cell effector functions [62]. More recently, in a three-dimensional in vitro model of TNBC, 4–1BB co-stimulated ROR1-CAR-T cells were shown to infiltrate and migrate through TNBC cultures and cause significant antitumor responses [60]. In this sense, ROR1-CAR-T cells have entered the clinic through a phase I study (NCT02706392) (Table 1). In the early-phase assessment, from the 4 TNBC patients treated with ROR1-CAR-T cells, 2 individuals showed stable disease and one participant had a partial response after the second infusion, persisting for 14 weeks [63]. No safety signals were observed. A strategy to avoid possible off-tumor toxicity has been implemented relying on the engineering of ROR1-CAR-T cells with synthetic Notch receptors that are specific for EpCAM or B7-H3, which are expressed on ROR1+ tumor cells but not on ROR1+ stromal cells. Synthetic Notch receptors can induce ROR1 expression selectively within the tumor, thus sparing normal tissues [63].
Investigational treatments for chronic lymphocytic leukemia: a focus on phase 1 and 2 clinical trials
Published in Expert Opinion on Investigational Drugs, 2020
Elżbieta Iskierka-Jażdżewska, Tadeusz Robak
Cirmtuzumab is a humanized anti-ROR1 monoclonal antibody. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an onco-embryonic antigen presented on CLL cells but not on normal adult tissues. It has been found to be a receptor for Wnt5a, which can enhance CLL-cell proliferation and survival by promoting the activation of Rac1. Chen et al. report that cirmtuzumab can inhibit leukemia cell activation of both NF-κB and STAT3 in patients with CLL [85]. In addition, Yu et al. note that CLL cells of patients treated with ibrutinib display activated Rac1 and that cirmtuzumab may enhance the activity of ibrutinib in the treatment of patients with CLL or other ROR1 + B-cell malignancies [86,87]. The combination of cirmtuzumab (given for 12 months), with ibrutinib (given in standard dose) has been evaluated in a phase I study of 12 patients with CLL [88]. Therapy was well tolerated (with no discontinuations for toxicity and no dose limiting toxicities) and effective (with ORR of 67% and 2 CR after 16–48 weeks of treatment). Of note, typical ibrutinib-induced lymphocytosis was diminished, with only a 50% mean rise in absolute lymphocyte count which rapidly returned to baseline. A randomized phase II study comparing combined cirmtuzumab and ibrutinib with ibrutinib alone is ongoing (NCT03088878) (Table 3).
Elevated expression of HDAC6 in clinical peritoneal dialysis patients and its pathogenic role on peritoneal angiogenesis
Published in Renal Failure, 2020
Yingfeng Shi, Jun Ni, Min Tao, Xiaoyan Ma, Yi Wang, Xiujuan Zang, Yan Hu, Andong Qiu, Shougang Zhuang, Na Liu
Except for the IL-6/STAT3/VEGF signaling pathway, Wnt/β-catenin is another important angiogenic pathway involved in peritoneal angiogenesis. Padwal et al. proved that Wnt/β-catenin signaling contributes to peritoneal membrane injury and regulates the level of VEGF in the presence of receptor tyrosine kinase-like orphan receptor (Ror2) [45]. Both of Dickkopf-related protein (DKK)-1 (inhibitor of Wnt) and ICG-001 (inhibitor of β-catenin) could attenuate peritoneal angiogenesis and reduce VEGF [11]. Interestingly, HDAC6 was reported to regulate β-catenin by deacetylation, leading to β-catenin phosphorylation and activation of downstream signal molecules [46]. Further research indicated that HDAC6-induced β-catenin deacetylation (K345) is essential for Wnt signal transduction [47]. So, we consider that HDAC6 may be associated with β-catenin deacetylation and activate Wnt/β-catenin-mediated angiogenic pathway during peritoneal angiogenesis.