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Non-Hodgkin Lymphoma
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
Therapeutic strategies should ideally be commensurate to individual patient and disease characteristics, in the presence or absence of co-morbidities. Definitive treatment often includes rituximab or ofatumumab, in combination with bendamustine, cladribine, bortezomib or ibrutinib. It accords control of the disease, but no overall survival advantage. In relapsed and refractory disease, it is reasonable to consider high-dose chemotherapy and auto-SCT in chemosensitive patients. Investigational agents include BTK and TLR inhibitors, mTOR inhibitors, ofatumumab, a fully humanized monoclonal anti-CD20 antibody, CXCR4 antagonists such as plerixafor and a host of targeted therapies against MY88, BCL2 and CD27/CD70 signalling pathways. There is also some interest in testing adoptive cellular immunotherapy treatments, including CAR T-cell therapy.
Stem cell therapies for atrophic endometrium and Asherman's syndrome
Published in Carlos Simón, Linda C. Giudice, The Endometrial Factor, 2017
Benjamin J. Seifer, Hanyia Naqvi, Elham Neisani Samani, Graciela Krikun, Hugh S. Taylor
We have recently reported that chemoattraction of BMDSCs toward human endometrial stromal cells (hESCs) is mediated by expression of the chemokine CXCL12 and its receptor, CXCR4 (81). hESCs were shown to produce CXCL12, and BMCs were shown to express CXCR4. BMCs migrated in the direction of hESCs or toward hESC-conditioned media; a CXCR4 antagonist blocked migration of the BMCs. Moreover, E2 induced expression of CXCL12 in hESCs and CXCR4 in BMCs. An estrogen-mediated response implicates the recruitment of BMDSCs via the CXCL12-CXCR4 axis as one mechanism by which E2 treatment may induce repair and regrowth of atrophic and fibrotic endometrium. This mechanism is also likely involved in the improved pregnancy outcomes following endometrial injury, as part of a CXCL12-mediated inflammatory response (82). Thus, the CXCL12-CXCR4 axis has potential as a drug target for regeneration of the endometrium in AS, AE, and other endometrial diseases.
Therapies to Prevent or Inhibit Chemokine Receptor Expression
Published in Thomas R. O’Brien, Chemokine Receptors and AIDS, 2019
J. Scott Cairns, M. Patricia D’Souza
Strategies that capitalize on biologically inactive versions of the CXCR4 ligand SDF-1 are not as advanced as those based on RANTES derivatives. In part, this is because modifications that inactivate RANTES do not have a similar effect on SDF-1. For instance, the addition of a methionine residue at the N-terminus, a strategy that significantly diminishes the biologic activity of RANTES, enhances the intracellular signaling activity of SDF-1 (80). However, two N-terminal truncations of SDF-1, or versions in which substitutions have been made at the N-terminus, have been examined and found to lack CXCR4 signaling capacity while retaining significant binding affinity for the receptor (69). In addition, several peptides have been identified that block the interaction of HIV with CXCR4 yet are not homologous to SDF-1. T22 is an 18-amino acid peptide derived from the hemocyte debris of the horseshoe crab. It specifically blocks membrane fusion and infection by X4 viruses as well as chemotaxis in response to SDF-1 (81). ALX40-4C, a 9 D-amino acid peptide, also blocks HIV envelope and SDF-1 interactions with CXCR4 (82). More recently, a 14-amino acid peptide related to T22, termed T134, has been described (83). This peptide has improved HIV-1 inhibitory activity in vitro, as well as the ability to inhibit HIV-1 X4 variants that are resistant to AMD3100, a small molecule CXCR4 antagonist (see below). All of these peptides have a high net positive charge, suggesting that they may interact with CXCR4 through electrostatic interactions, as has been proposed for the positively charged SDF-1 core (84). Structure/function studies suggest that ALX40-4C and the SDF-1 core interact with CXCR4 at different sites (85), offering an opportunity for synergistic inhibition. It remains to be determined whether these peptides inhibit HIV by competitive blocking or, as appears to be the case with SDF-1, by receptor down-modulation.
CXCR4 as a prognostic biomarker in gastrointestinal cancer: a meta-analysis
Published in Biomarkers, 2019
Qingtao Jiang, Yun Sun, Xin Liu
The mechanism why CXCR4 expression is associated with the prognosis in GI cancer has been investigated over years. When CXCR4 interacts with its ligand CXCL12, the downstream signalling pathways like AKT and MAPK are then activated (Abe et al.2018, Bao et al.2018). Consequently, a series of tumour related biological effects including migration, proliferation and survival come into being. Though CXCR4 could promote the metastasis of cancer cells via enhancing vasculogenesis and angiogenesis, it also protects cancer cells from chemotherapy (Gilbert and Hemann 2010, Wojcechowskyj et al.2011). Therefore, it is not strange that the expression of CXCR4 in cancerous tissue would impact the prognosis of patients. A meta-analysis conducted by Xu et al. (2013) showed that increased CXCR4 expression may serve as an adverse prognostic indicator in patients with breast cancer. Another study conducted by Zhao et al. (2015) indicated high level of CXCR4 is associated with worse prognosis in terms of OS and PFS in hematological malignancy, lung cancer and so on. The important significance of CXCR4 in multiple diseases have encouraged the development of clinically viable CXCR4 inhibitors, and resulted in the US Food and Drug Administration (FDA) approval of the first CXCR4 antagonist, plerixa for patients with non-Hodgkin’s lymphoma and multiple myeloma (Karpova et al.2017).
Small molecule and peptide-based CXCR4 modulators as therapeutic agents. A patent review for the period from 2010 to 2018
Published in Expert Opinion on Therapeutic Patents, 2020
Yesim A Tahirovic, Sameshnee Pelly, Edgars Jecs, Eric J Miller, Savita K Sharma, Dennis C Liotta, Lawrence J Wilson
Since 2010, there has been a significant increase in the IP surrounding CXCR4 modulators, indicating a strong commercial interest in this therapeutic target (see Figure 1 versus Figures 2–5). The FDA approval of the first CXCR4 antagonist AMD3100 (1) highlighted the therapeutic relevance, and provided a runway for further development of new IP and several new agents reaching the clinical development stage. Within the scope of this review, there are many new small molecule and peptide patents and applications covering a wide array of structural variations and uses thereof. In the cases of the small molecules, there are AMD3100 analogs that cover a range of sub-structural types, including the clinical agent MSX-122 (9) and other discovery stage compounds. This agent (MSX-122) is currently being investigated in phase 2 clinical trials as an oral drug for the treatment of hot flashes in breast cancer-positive post-menopausal women. Other significant agents are second and third generation analogs of AMD11070 (2), which was recently revived in clinical development for treatment of various indications including melanoma and W.H.I.M. syndrome. Some of these new agents are in the pre-clinical/discovery stages (e.g. TIQ-15 (17), EMU-160 (22) and ALT-1188) and promise improved ADMET properties over AMD11070. There are also noteworthy heterocycle-based CXCR4 antagonists covering other structural types resulting in two clinical agents. One compound from Taigen, TG-0054 (32), is in phase 2 as an intravenous treatment for HSC mobilization and another from Proximagen, (34, USL311) is in phase 1 as an oral treatment for glioblastoma.
Proteomics advances for precision therapy in ovarian cancer
Published in Expert Review of Proteomics, 2019
Marilyne Labrie, Nicholas D Kendsersky, Hongli Ma, Lydia Campbell, Jennifer Eng, Koei Chin, Gordon B Mills
The standard treatment of HGSC consists of a tumor debulking surgery followed by chemotherapy treatment that is usually comprised of a combination of carboplatin and paclitaxel. In a subset of patients with advanced disease, neoadjuvant therapy is performed prior to surgery in order to reduce the tumor burden. In those cases, the neoadjuvant treatment usually consists of a combination of taxane/platin or liposomal doxorubicin/carboplatin [54]. Although most HGSC patients respond to primary therapy, resistance development and recurrence is observed in the majority of cases. Interestingly, many groups have described adaptive responses to chemotherapy and inhibition of these pathways led to increased treatment efficacy. For example, Lee et al. demonstrated that a transient expression of CXCR4 in ovarian cancer cell lines treated with cisplatin, doxorubicin, and paclitaxel allows a cell subpopulation to enter dormancy until the treatment is stopped. Moreover, they showed that CXCR4 antagonists have synergistic effects in the killing of the cancer cells when combined with chemotherapeutic agents [55]. In another study, Choi et al. used RPPA analysis to identify protein alterations that can be detected early during paclitaxel treatment. They found that S6 phosphorylation is strongly upregulated in response to paclitaxel. Interestingly, S6 is a downstream target of the mTOR pathway, which has been described as a pro-survival mechanism in many biological systems [45]. Furthermore, the inhibition of S6 phosphorylation using PI3K pathway inhibitor drugs such as BX795 or CCT128930, in combination with paclitaxel, decreased viability of ovarian cancer cells [45]. Finally, other mechanisms of adaptive response to chemotherapy were reported by other groups such as overexpression of PGC1a, a protein involved in mitochondrial biogenesis [56], as well as TRAP1. TRAP1 is proposed to contribute to the adaptive response to cisplatin through increased oxidative phosphorylation, leading to the secretion of cytokines and epithelial-to-mesenchymal transition (reviewed in [57]).