Evaluation of a CXCR4 antagonist in a xenograft mouse model of inflammatory breast cancer
Balraj SinghKendra R. CookCecilia MartínEugene HuangKailash MosalpuriaSavitri KrishnamurthyMassimo CristofanilliAnthony Lucci
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CXCR4 antagonist
Primary tumor
Matrigel
CXCR4 antagonist
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Abstract Introduction: Tumor metastasis is the primary reason for mortality of cancer patients. The ability to model the microenvironment of the primary tumor and the secondary and tertiary sites is critical for advancing the treatment options for the invasive cancers. There is currently no 3D tumor model that mimics the in vivo vascular geometry and the microenvironment for monitoring progression of tumors. In this study, we report on the development of a 3D tumor model comprising of vascular cells in communication with tumor cells leading to invasion and metastasis at secondary and tertiary sites. Materials and Methods: Vascularized tumor networks comprising primary, secondary and tertiary tumor sites were developed using in vivo images and fabricated using soft lithography. Human mammary microvascular endothelial cells (hMMEC) were cultured in the vascular channels while a GFP-labeled metastatic breast cancer cell (MDA-MB-231) and a GFP-labeled non-metastatic cell (MCF-7) mixed with and without human fibroblast cell line BJ-5ta was cultured in the primary tumor site in a 3D environment using Matrigel™. The tumor networks were perfused with endothelial cell media and the growth, migration, invasion and metastasis of the tumor cells from the primary site to secondary and tertiary site was monitored for 28 days using time lapse microscopy. Results and Discussion: The aggressively metastatic MDA-MB-231/BJ-5ta tumor at the primary site was found to proliferate rapidly resulting in breakdown of the Matrigel and invasion across the endothelial cells. Secondary sites were localized with pockets of tumor colonies within 48 hours and by 120 hours had metastasized to the tertiary site. By 14 days, the primary site tumor formed a necrotic core while the tumor cells at secondary and tertiary were viable. In contrast, the non-aggressive MCF-7/BJ-5ta tumors were able to proliferate within the Matrigel scaffolding but did not break down beyond the primary site until 14 days. Culture of tumor cells without the presence of fibroblast or endothelial cells resulted in a significant difference in the invasion and metastasis pattern highlighting the importance of the native tumor microenvironment. Conclusions: We have developed a 3D, heterogenic model of invasive tumor growth and metastasis which closely mimics the in vivo microenvironment of solid tumors. This model can be used to investigate tumor progression and their underlying mechanisms using a combination of real-time techniques as well as ‘omic’ methodologies for screening and evaluation of the therapeutics. Acknowledgements: We gratefully acknowledge financial support from NIH (#HHSN261201400037C). References: B. Prabhakarpandian et al., J Control Release 2015; 201:49-55 Citation Format: Ashley Smith, Charles Garson, Shantanu Pradhan, Elizabeth Lipke, Robert Arnold, Balabhaskar Prabhakarpandian, Kapil Pant. In vitro vascularized model for tumor growth and progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4108.
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Background: Hematopoietic stem cell (HSC) transplantation is a treatment option for hematological malignancies. Current mobilization regimes frequently result in inadequate numbers of HSC for transplant therefore alternative methods of mobilization are required. Objective: The chemokine receptor CXCR4 and ligand SDF-1 are integrally involved in HSC homing and mobilization. Disruption of the SDF-1/CXCR4 axis by the CXCR4 anatagonist, plerixafor, is shown to improve HSC mobilization. Methods: The molecular and in vivo pharmacology of plerixafor and subsequent clinical development is reviewed. Results/conclusion: Preclinical studies demonstrate that plerixafor is a selective antagonist of CXCR4 and can rapidly mobilize HSC. Clinical trials demonstrated improved HSC mobilization when plerixafor was included in the mobilization regimen. These data suggest the potential for a significant role for plerixafor in hematological disease.
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Previous chemotherapy and radiation exposure can make adequate stem cell mobilisation prior to autologous transplant extremely difficult in paediatrics. Plerixafor, a selective reversible CXCR4 antagonist interferes with CXCR4 interaction with Stromal cell‐derived factor 1 alpha (SDF‐1). Combination with granulocyte‐colony stimulating factor (G‐CSF) amplifies G‐CSF affects in mobilising haematopoietic stem cells. Whilst licensed for use with G‐CSF for enhancement of mobilisation of haematopoietic stem cells in adults, paediatric data for use of plerixafor remain limited. We present a retrospective review of outcomes seen with plerixafor and G‐CSF to mobilise stem cells heavily pre‐treated paediatric patients with cancer. Pediatr Blood Cancer 2015;62:1477–1480. © 2015 Wiley Periodicals, Inc.
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CXCR4 is a G-protein-coupled receptor involved in a number of physiological processes in the hematopoietic and immune systems.The SDF-1/CXCR4 axis is significantly associated with several diseases, such as HIV, cancer, WHIM syndrome, rheumatoid arthritis, pulmonary fibrosis and lupus.For example, CXCR4 is one of the major co-receptors for HIV entry into target cells, while in cancer it plays an important role in tumor cell metastasis.Several promising CXCR4 antagonists have been developed to block SDF-1/CXCR4 interactions that are currently under different stages of development.The first in class CXCR4 antagonist, plerixafor, was approved by the FDA in 2008 for the mobilization of hematopoietic stem cells and several other drugs are currently in clinical trials for cancer, HIV, and WHIM syndrome.While the long-term safety data for the first generation CXCR4 antagonists are not yet available, several new compounds are under preclinical development in an attempt to provide safer and more efficient treatment options for HIV and cancer patients.
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Abstract The chemokine receptor, C-X-C chemokine receptor type 4 (CXCR4) and its ligand, C-X-C motif chemokine 12, are key mediators of hematopoietic cell trafficking. Their roles in the proliferation and metastasis of tumor cells, induction of angiogenesis, and invasive tumor growth have been recognized for over 2 decades. CXCR4 is a promising target for imaging and therapy of both hematologic and solid tumors. To date, Sanofi Genzyme’s plerixafor is the only marketed CXCR4 inhibitor (i.e., Food and Drug Administration-approved in 2008 for stem cell mobilization). However, several new CXCR4 inhibitors are now being investigated as potential therapies for a variety of fluid and solid tumors. These small molecules, peptides, and Abs include balixafortide (POL6326, Polyphor), mavorixafor (X4P-001, X4 Pharmaceuticals), motixafortide (BL-8040, BioLineRx), LY2510924 (Eli Lilly), and ulocuplumab (Bristol-Myers Squibb). Early clinical evidence has been encouraging, for example, with motixafortide and balixafortide, and the CXCR4 inhibitors appear to be generally safe and well tolerated. Molecular imaging is increasingly being used for effective patient selection before, or early during CXCR4 inhibitor treatment. The use of radiolabeled theranostics that combine diagnostics and therapeutics is an additional intriguing approach. The current status and future directions for radioimaging and treating patients with CXCR4-expressing hematologic and solid malignancies are reviewed. See related review - At the Bench: Pre-Clinical Evidence for Multiple Functions of CXCR4 in Cancer. J. Leukoc. Biol. xx: xx–xx; 2020.
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Mobilized blood has supplanted bone marrow (BM) as the primary source of hematopoietic stem cells for autologous and allogeneic stem cell transplantation. Pharmacologically enforced egress of hematopoietic stem cells from BM, or mobilization, has been achieved by directly or indirectly targeting the CXCL12/CXCR4 axis. Shortcomings of the standard mobilizing agent, granulocyte colony-stimulating factor (G-CSF), administered alone or in combination with the only approved CXCR4 antagonist, Plerixafor, continue to fuel the quest for new mobilizing agents. Using Protein Epitope Mimetics technology, a novel peptidic CXCR4 antagonist, POL5551, was developed. In vitro data presented herein indicate high affinity to and specificity for CXCR4. POL5551 exhibited rapid mobilization kinetics and unprecedented efficiency in C57BL/6 mice, exceeding that of Plerixafor and at higher doses also of G-CSF. POL5551-mobilized stem cells demonstrated adequate transplantation properties. In contrast to G-CSF, POL5551 did not induce major morphological changes in the BM of mice. Moreover, we provide evidence of direct POL5551 binding to hematopoietic stem and progenitor cells (HSPCs) in vivo, strengthening the hypothesis that CXCR4 antagonists mediate mobilization by direct targeting of HSPCs. In summary, POL5551 is a potent mobilizing agent for HSPCs in mice with promising therapeutic potential if these data can be corroborated in humans.
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