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Non-FDG radionuclide imaging and targeted therapies
Published in Anju Sahdev, Sarah J. Vinnicombe, Husband & Reznek's Imaging in Oncology, 2020
Luigi Aloj, Ferdia A Gallagher
This receptor system has been implicated in the molecular mechanisms that favour development of metastases. Expression of this receptor in cancer cells favours homing to tissues that express its natural ligand, stromal derived factor 1 (SDF-1), also known as CXCL12. Small peptides targeting CXCR4 were originally developed in the late 1990s (45). Derivatives of the T140 peptide were initially modified for radiolabelling in order to obtain CXCR4-targeting radiopharmaceuticals. Biodistribution properties of these first-generation compounds proved to be unsuitable for successful application. In the early 2000s a small cyclic peptide with more favourable biodistribution properties was identified (46). This compound (GPCR04) has been utilized in preliminary clinical studies in patients with myeloma (47), glioblastoma (48), and lung cancer (49). As CXCR4 is a potential therapeutic target, the main role of these diagnostic agents in the clinic is to establish and quantify receptor expression in tumours. There is also initial clinical experience on targeting CXCR4 expression for radionuclide therapy (50,51).
Waldenström Macroglobulinemia
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The C-X-C chemokine receptor type 4 (CXCR4) gene mutation represents the second most frequent mutated gene in WM, detected in approximately 30% of patients [33]. The somatic CXCR4 mutations seen in WM closely resemble the germline CXCR4WHIM mutations described in the WHIM syndrome. The “gain-of-function” CXCR4WHIM mutations lead to permanent activation of CXCR4 receptor by its ligand CXCL-12 and results in migration and homing to the bone marrow niches of WM cell which could provide a survival advantage (Figure 82.1) [34]. The CXCR4WHIM mutation has been linked to drug resistance and impacts the response to targeted therapies such as BKT, mTOR, and PI3K inhibitors [35,36].
Chimeric VLPs
Published in Paul Pumpens, Single-Stranded RNA Phages, 2020
Comparing to the above-described RNA phage coats, the AP205 coat demonstrated unique capabilities by the toleration of foreign insertions. An impressive collection of the chimeric AP205 VLPs was generated by the fruitful collaboration of Bachmann's and Grēns’ teams (Tissot et al. 2010). The technical description of the gained chimeric AP205 VLPs is given in Table 22.1, since all structures were designed and tested as putative vaccine candidates. Generally, the six different peptides of (i) angiotensin II, (ii) outer membrane protein of S. typhi, (iii) CXCR4 receptor, (iv) HIV1 Nef, (v) gonadotropin-releasing hormone, and (vi) influenza A M2-protein were fused to either N- or C-terminus of the AP205 coat protein. The AP205-peptide fusions assembled well into VLPs, and the peptides displayed on the VLP surface were highly immunogenic in mice. Therefore, the AP205 VLPs appeared as a new and highly efficient vaccine system, suitable for complex and long epitopes of up to at least 55 amino acid residues in length. The AP205 VLPs conferred a high immunogenicity to displayed epitopes, as shown by inhibition of endogenous gonadotropin-releasing hormone and protective immunity against influenza infection in mice.
Reduced CXCR4 expression in associated with extramedullary and predicts poor survival in newly diagnosed multiple myeloma
Published in Expert Review of Hematology, 2022
Dangui Chen, Yang Zhan, Hong Yan, Hong Liang, Fusheng Yao, Haitao Xu
In a series of 19 MM patients who progressed to EMM, cytogenetic abnormality was most frequently found at diagnosis [17–19]. EMM patients underwent DNA sequencing for a targeted panel of 50 tumor suppressors and oncogenes, which revealed a high frequency of activating RAS mutations [20]. CXCR4 expression is associated with oral aquamous cell carcinoma, esophageal, gastric, colon, liver, pancreas, thyroid, ovary, prostate, lung, kidney, breast, brain, melanoma and leukemia [8]. SDF1 recruited CXCR4-positive inflammatory, vascular and stromal cells to the tumor microenvironment [21–23]. SDF1 is expressed in various human tissues, including liver, lungs, bone marrow, lymphnodes, and stromal and endothelial cells [22,23]. CXCR4 overexpression in EMM cells is associated with poor prognosis [24–26]. Bortezomib-resistant MM cells expresse less CXCR4, and plasma cells can escape from bone marrow extramedullary metastasis in MM mice and MM patients [7]. In our study, reduced CXCR4 expression in bone marrow is associated with the extramedullary subtype of NDMM. The possible reason is that the extramedullary region expressing CXCR4 tissue chemotaxis attracts CXCR4-positive myeloma cells out of the bone marrow, leading to the occurrence of extramedullary lesions.
The effect of gemcitabine combined with AMD3100 applying to cholangiocarcinoma RBE cell lines to CXCR4/CXCL12 axis
Published in Scandinavian Journal of Gastroenterology, 2021
Li Xing, Hai-Tao Lv, San-Guang Liu, Wen-Bin Wang, Teng-Fei Zhang, Jian-Hua Liu, Wei Bian
Cholangiocarcinoma is a rare malignant tumor originating from biliary epithelium, which can be classified into two major categories, based on their anatomic location, Intrahepatic cholangiocarcinoma (ICC) and Ductal cholangiocarcinoma [1,2]. Despite current treatment strategies have been developed, including surgery, chemotherapy, radiotherapy and liver transplantation, the 5-year survival rate remains low [3,4]. Moreover, for advanced cholangiocarcinoma, palliative chemotherapy with cisplatin and gemcitabine results in a median survival rate of 1 year [5]. Chemokines are chemoattracting proteins, which bind to their respective receptors and thereby activate them. Chemokine receptor 4 (CXCR4) is a CXCR, which specifically binds to chemokine ligand 12 (CXCL12). First identified on leukocytes, CXCR4 is expressed by several different cell types [6]. It is important in organogenesis, and in tissue repair and regeneration in adults. Additionally, the expression of CXCR4 was identified in hematopoietic and non-hematopoietic tissue-committed stem cells [7,8].
Zanubrutinib for the treatment of Waldenström Macroglobulinemia
Published in Expert Review of Hematology, 2020
Kenneth J. C. Lim, Constantine S. Tam
Recent studies have helped shed further light on the pathogenesis of WM through the molecular examination of acquired genetic mutations associated with WM. The identified MYD88 gene was found to encode an adaptor protein involved in Toll-like receptor and interleukin-1 receptor signaling. When these receptors are activated, the MYD88 protein undergoes homodimerization and activates downstream signaling pathways involving the phosphorylation of interleukin-1 receptor-associated kinases (IRAK1 and IRAK 4) followed by IκBα and ultimately the activation of the pro-survival nuclear factor κB (NF-κB) pathway. L265P is a gain in function mutation found in >90% of WM cases. The L265P mutation allows for spontaneous, independent MYD88 homodimerization and subsequent constitutive activation of NF-κB [2,3]. The second gene of interest in WM is the CXCR4 gene with mutations found in approximately 30% of WM cases. These mutations include frameshift and nonsense mutations of CXCR4 similar to those seen in germline mutations associated with the rare congenital immune deficiency condition WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome. Stimulation of CXCR4 by its ligand CXCL12 stimulates WM cell migration, adhesion, and homing. These WHIM-like mutations of CXCR4WHIM promote prolonged activation of CXCR4 by preventing receptor internalization which prolongs CXCR4 stimulation by CXCL12. This promotes the survival, growth, and dissemination of WM cells [4,5]. The presence of these mutations has prognostic implications to therapy and form the basis of current targeted approaches.