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The enzyme geranylgeranyl diphosphate synthase (GGDPS) is a potential therapeutic target for multiple myeloma. Malignant plasma cells produce and secrete large amounts of monoclonal protein, and inhibition of GGDPS results in disruption of protein geranylgeranylation which in turn impairs intracellular protein trafficking. Our previous work has demonstrated that some isoprenoid triazole bisphosphonates are potent and selective inhibitors of GGDPS. To explore the possibility of selective delivery of such compounds to plasma cells, new analogues with an ω-hydroxy group have been synthesized and examined for their enzymatic and cellular activity. These studies demonstrate that incorporation of the ω-hydroxy group minimally impairs GGDPS inhibitory activity. Furthermore conjugation of one of the novel ω-hydroxy GGDPS inhibitors to hyaluronic acid resulted in enhanced cellular activity. These results will allow future studies to focus on the in vivo biodistribution of HA-conjugated GGDPS inhibitors., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Geranylgeranyl diphosphate synthase (GGDPS) is the enzyme in the isoprenoid biosynthesis pathway that catalyzes the synthesis of the 20-carbon isoprenoid GGPP, which serves as the isoprenoid donor for protein geranylgeranylation reactions. Rab proteins mediate vesicle trafficking within the cell and their activity is dependent on geranylgeranylation. Our prior work has demonstrated that agents that disrupt Rab geranylgeranylation disrupt monoclonal protein trafficking in myeloma cells, resulting in induction of the unfolded protein response pathway and apoptosis. VSW1198 is a potent GGDPS inhibitor with measurable cellular activity at concentrations as low as 30 nM. Due to its potent activity against myeloma cells in vitro, we were interested in evaluating the toxicology profile, pharmacokinetic (PK) profile, tissue distribution pattern and metabolic stability of VSW1198 in preparation for in vivo efficacy studies. Single dose testing via IV administration in CD-1 mice revealed a maximum tolerated dose of 0.5 mg/kg. Doses ≥1 mg/kg resulted in liver toxicity that peaked around 6-7 days post-injection. Disruption of protein geranylgeranylation following repeat dosing of VSW1198 was confirmed via immunoblot analysis of unmodified Rap1a in multiple organs. The PK studies revealed a half-life of 47.7 ± 7.4 h. VSW1198 was present in all tested tissues with the highest levels in the liver. In both human liver microsomes and mouse S9 studies VSW1198 showed complete stability, suggesting no phase I or phase II metabolism. In summary, these studies demonstrate systemic distribution, on-target disruption of protein geranylgeranylation, and metabolic stability of a potent GGDPS inhibitor VSW1198 and form the basis for future efficacy studies in mouse models of myeloma.

CXCR2 and its ligands have been shown to play an important role in tumor angiogenesis, therapy resistance and progression. In this study, we investigated whether CXCR2 ligands are responsible for the survival advantage and metastasis of drug-resistant cells and examined the underlying mechanism(s) doxorubicin or paclitaxel resistant mammary tumor cells. Our results demonstrated that drug-resistant Cl66 cells upregulated CXCR2 ligands but downregulated expression of CXCR2. We observed delayed tumor growth but increased metastasis in mice using these drug-resistant cells. Furthermore, we observed differential upregulation of stem cell and mesenchymal markers in the doxorubicin and paclitaxel-resistant tumor cells. Abrogation of the CXCR2 signaling axis using CXCR2 ligand neutralization resulted in significant inhibition of drug-resistant cell growth. Together, our data suggest chemotherapy-specific differential regulation of CXCR2 ligands, stem cell-like and mesenchymal phenotypes, and enhanced metastasis in drug-resistant cells and targeting CXCR2 signaling, may help circumvent therapy resistance in breast cancer., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Breast cancer is one of the leading causes of cancer deaths among females. Many challenges exist in the current management of advanced stage breast cancer as there are fewer recognized therapeutic strategies, often because of therapy resistance. How breast cancer cells evade chemotherapy and the underlying mechanism remains unclear. We and others have observed that malignant cells that survive initial chemo- and radiation therapy express higher levels of CXCR2 ligands, which may provide a survival benefit leading to therapy resistance. In this report, we test the hypothesis that CXCR2-dependent signaling in malignant cells may be critical for chemotherapy resistance and targeting this signaling axis may enhance the antitumor and antimetastatic activity of chemotherapeutic drugs and limit their toxicity. We used Cl66-wt, 4T1-wt, Cl66sh-CXCR2, and 4T1sh-CXCR2 cells expressing differential levels of the CXCR2 receptor to evaluate the role of targeting CXCR2 on chemotherapeutic responses. Knockdown of CXCR2 enhances paclitaxel and doxorubicin-mediated toxicity at suboptimal doses. Moreover, we observed an increase in the expression of CXCL1, a CXCR2 ligand in paclitaxel and doxorubicin-treated mammary tumor cells, which were inhibited following CXCR2 knockdown. Knockdown of CXCR2 enhanced antitumor activity of paclitaxel in an in vivo mammary tumor model. We observed significant inhibition of spontaneous lung metastases in animals bearing CXCR2 knockdown tumors and treated with paclitaxel as compared with the control group. Our data suggest the novel role of CXCR2 and its ligands in maintaining chemotherapy resistance and provide evidence that targeting CXCR2 signaling in an adjuvant setting will help circumvent chemotherapy resistance., (©2013 AACR)

CXCR1 and CXCR2 are G-protein coupled receptors, that have been shown to play important role in tumor growth and metastasis, and are prime targets for the development of novel therapeutics. Here, we report that targeting CXCR2 and CXCR1 activity using orally active small molecule antagonist (SCH-527123, SCH-479833) inhibits human colon cancer liver metastasis mediated by decreased neovascularization and enhanced malignant cell apoptosis. There were no differences in primary tumor growth. These studies demonstrate the important role of CXCR2/1 in colon cancer metastasis and that inhibition of CXCR2 and CXCR1, small molecule antagonists provides a novel therapeutic strategy., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Importance of the Field: The incidence of malignant melanoma is increasing throughout the world and is currently rising faster than any other cancer in men and second only to lung cancer in women. Current strategies focused on systemic therapy for treatment of melanoma have shown no effect on survival. Therefore there is a pressing need for developing novel targeted therapeutics., Areas Covered in This Review: Our goal is to provide an overview regarding targeting CXCR1/2 in malignant melanoma, the rationale behind these approaches and the future perspective., What the Reader Will Gain: This review illustrates our current understanding of CXCR1/2 receptor in melanoma progression and metastasis. We describe approaches that are being developed to block CXCR1/2 activation, including low-molecular-weight antagonists, modified chemokines and antibodies directed against ligands and receptors., Take Home Message: The chemokine receptors CXCR1 and CXCR2 and their ligands play an important role in the pathogenesis of malignant melanoma. Recent reports demonstrated that CXCR1 is constitutively expressed in all melanoma cases irrespective of stage and grade, however, CXCR2 expression was restricted to aggressive melanoma tumors,. Furthermore, modulation of CXCR1/2 expression and/or activity has been shown to regulate malignant melanoma growth, angiogenesis and metastasis, suggesting CXCR1/2 targeting as a novel therapeutic approach for malignant melanoma.