An update on small molecules targeting CXCR4 as starting points for the development of anti-cancer therapeutics

Grande, Fedora; Giancotti, Gilda; Ioele, Giuseppina; Occhiuzzi, Maria Antonietta; Garofalo, Antonio

doi:10.1016/j.ejmech.2017.08.027

Cited by 36 publications

(19 citation statements)

References 50 publications

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“…The CXCL12/CXCR4 axis is an attractive target for various cancer types and several compounds belonging to different chemical classes are able to interact with the active site of CXCR4. Targeted therapies using CXCR4 antagonists represent a promising approach for the treatment of cancer [31] . Currently, plerixafor, a CXCR4 antagonist, is used as an immunostimulant to mobilize hematopoietic stem cell in hematologic malignancies and is being tested in phase I trial with pancreatic, ovarian, colorectal cancers (NCT02179970).…”

Section: Discussionmentioning

confidence: 99%

The Correlation Between Serum Chemokines and Clinical Outcome in Patients with Advanced Biliary Tract Cancer

Lee

Kim

et al. 2018

Translational Oncology

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BACKGROUND: Biliary tract cancers (BTCs) are known to have a dismal prognosis. A number of chemokines play important roles in the progress of BTCs. However, the serum levels of chemokines in BTCs have not yet been explored. METHODS: The sera of healthy donors (n = 8) and patients with BTCs who were enrolled in second line sunitinib trials (n = 27) were collected. The concentrations of three kinds of chemokines (CXCL5, CXCL8 and CXCL12) were measured using ELISA assay. The median concentrations of chemokines were compared between healthy donors and BTC patients and the role of chemokines as a prognostic biomarker was examined. RESULTS: BTC patients generally had higher serum levels of CXCL5 and CXCL12 compared to healthy donors. Patients with cholangiocarcinoma showed significantly higher levels of serum CXCL12 than patients with gallbladder cancer. In survival analysis, only CXCL12 level showed a prognostic impact on overall survival (median OS: 6.9 vs. 0.9 months in low CXCL12 vs. high CXCL12, respectively; P = .008). High CXCL5 levels were also correlated with poor survival without statistical insignificance (median OS: 6.2 vs. 2.0 months in low CXCL5 vs. high CXCL5, respectively; P = .070). CONCLUSIONS: There was a significant difference in OS according to the level of CXCL12, suggesting that serum CXCL12 levels may be a useful surrogate marker for clinical outcome in advanced BTCs.

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Section: Discussionmentioning

confidence: 99%

The Correlation Between Serum Chemokines and Clinical Outcome in Patients with Advanced Biliary Tract Cancer

Lee

Kim

et al. 2018

Translational Oncology

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“…The accumulating knowledge regarding the fundamental roles that the CXCL12/CXCR4 plays in hematological and solid malignancies has driven multiple pharma companies to develop specific CXCR4 antagonists. These may be categorized into four major groups: Non peptide CXCR4 antagonists such as AMD3100, small peptide CXCR4 antagonists such as BL-8040, antibodies to CXCR4 such as LY2624587 and Ulocuplumab and modified agonist antagonists to CXCL12 such as NOX-A12 [ 56 , 57 , 58 ]. Reviewing the characteristics of and the therapeutic indications for which each of these inhibitors is being developed, is beyond the scope of this manuscript.…”

Section: Diagnostic and Therapeutic Potential Of Cxcr4 Antagonistsmentioning

confidence: 99%

CXCR4 Based Therapeutics for Non-Small Cell Lung Cancer (NSCLC)

Wald

2018

JCM

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Lung cancer is the second most common malignancy. Unfortunately, despite advances in multimodality therapeutics for the disease, the overall five-year survival rate among newly diagnosed lung cancer patients remains in the range region of 15%. In addition, although immune checkpoint inhibitors are increasingly being incorporated into lung cancer treatment protocols, the proportion of patients that respond to these agents remains low and the duration of response is often short. Therefore, novel methodologies to enhance the efficacy of immunotherapy in lung cancer are highly desirable. Chemokines are small chemotactic cytokines that interact with their 7 transmembrane G-protein–coupled receptors, to guide immune cell trafficking in the body under both physiologic and pathologic conditions. Tumor cells highjack a small repertoire of the chemokine/chemokine receptor system and utilize it in a manner that benefits local tumor growth and distant spread. The chemokine receptor, CXCR4 is expressed in over 30 types of malignant tumors and, through interaction with its ligand CXCL12, was shown exert pleotropic pro-tumorigenic effects. In this review, the pathologic roles that CXCL12/CXCR4 play in lung cancer propagation are presented. Furthermore, the challenges and potential benefits of incorporating drugs that target CXCL12/CXCR4 into immune-based lung cancer therapeutic protocols are discussed.

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“…Thus, CXCR4 has been an attractive therapeutic target in several chronic indications, and various small molecule and peptide inhibitors were generated to target it for the management of HIV-1 infection and cancer [ 13 – 15 ]. However, these drugs often present unfavorable pharmacokinetic and toxicity profiles that limit their therapeutic application through chronic administration [ 16 ]. Nevertheless, single dose with small molecules blocking CXCR4 pathway proved useful in the mobilization of hematopoietic precursors.…”

Section: Introductionmentioning

confidence: 99%

A mouse model for evaluation of efficacy and concomitant toxicity of anti-human CXCR4 therapeutics

Costa¹,

Kudaravalli²,

Liu³

et al. 2018

PLoS ONE

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The development of therapeutic monoclonal antibodies through mouse immunization often originates drug candidates that are not cross-reactive to the mouse ortholog. In such cases, and particularly in oncology, drug efficacy studies are performed on human tumor xenografts or with “surrogate” anti-mouse ortholog antibodies if targeting tumor host cells. Safety assessment of drug candidate(s) is performed at a later development stage in healthy non-human primates. While the latter remains necessary before a drug advances into human subjects, it precludes evaluation of safety in disease conditions and drug de-risking during early development. Therefore, mouse models that allow concomitant evaluation of drug efficacy and safety are highly desirable. The C-X-C motif chemokine receptor 4 (CXCR4) is an attractive target for tumor-targeted and immuno-oncology therapeutics, with multiple mouse immunization-derived antibodies undergoing clinical trials. Given the pleiotropic role of CXCR4 in cancer biology, we anticipate continuous interest in this target, particularly in the testing of therapeutic combinations for immuno-oncology. Here, we describe the generation and validation of the first mouse knock-in of the whole coding region of human CXCR4. Homozygous human CXCR4 knock-in (hereafter designated as HuCXCR4KI) mice were viable and outwardly healthy, reproduced normally and nursed their young. The expression pattern of human CXCR4 in this model was similar to that of CXCR4 expression in normal human tissues. The human CXCR4 knock-in gene was expressed as a biologically active protein, thereby allowing normal animal development and adequate”homing” of leukocytes to the bone marrow. To further validate our model, we used an in vivo functional assay of leukocyte mobilization from bone marrow to peripheral blood by blocking CXCR4 signaling. Both an anti-human CXCR4 -specific blocking antibody and the small molecule CXCR4 inhibitor AMD3100 induced increased leukocyte counts in peripheral blood, whereas an anti-mouse CXCR4 –specific blocking antibody had no effect. This new mouse model is useful to evaluate efficacy and safety of anti-human CXCR4 -specific drugs as single agents or in combination therapies, particularly in the oncology, immuno-oncology, wound healing and chronic inflammation therapeutic areas.

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An update on small molecules targeting CXCR4 as starting points for the development of anti-cancer therapeutics

Cited by 36 publications

References 50 publications

The Correlation Between Serum Chemokines and Clinical Outcome in Patients with Advanced Biliary Tract Cancer

The Correlation Between Serum Chemokines and Clinical Outcome in Patients with Advanced Biliary Tract Cancer

CXCR4 Based Therapeutics for Non-Small Cell Lung Cancer (NSCLC)

A mouse model for evaluation of efficacy and concomitant toxicity of anti-human CXCR4 therapeutics

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