Key Points C1013G/CXCR4 acts as an activating mutation in WM leading to enhanced tumor growth, and as an inducer of drug resistance. BMS936564/MDX1338, a novel anti-CXCR4 moAb, successfully targets WM cells, either C1013G/CXCR4 mutated or wild-type.

SUMMARY Extra-medullary disease (EMD) in Multiple Myeloma (MM) is associated with poor prognosis and resistance to chemotherapy. However, molecular alterations that lead to EMD have not been well defined. We developed bone marrow (BM)- and EMD-prone MM syngeneic cell lines and identified that epithelial-to-mesenchymal-tranistion (EMT) transcriptional patterns were significantly enriched in the both clones compared to parental cells, together with higher levels of CXCR4 protein; and demonstrated that CXCR4 enhanced the acquisition of an EMT-like phenotype in MM cells with a phenotypic conversion for invasion, leading to higher bone metastasis and EMD dissemination in vivo. In contrast, CXCR4-silencing led to inhibited tumor growth and reduced survival. Ulocuplumab, a monoclonal anti-CXCR4 antibody, inhibited MM cell dissemination, supported by suppression of the CXCR4-driven EMT-like phenotype. These studies suggest that targeting CXCR4 may act as a regulator of EMD through EMT-like transcriptional modulation, thus representing a potential therapeutic strategy to prevent MM disease progression.

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Key Points• Knockdown of the sialyltransferase, ST3GAL6, in MM inhibits in vivo homing and prolongs survival in xenograft mice.• In MM patients, high expression of ST3GAL6 is associated with inferior overall survival.Glycosylation is a stepwise procedure of covalent attachment of oligosaccharide chains to proteins or lipids, and alterations in this process, especially increased sialylation, have been associated with malignant transformation and metastasis. The role of altered sialylation in multiple myeloma (MM) cell trafficking has not been previously investigated.In the present study we identified high expression of b-galactoside a-2,3-sialyltransferase, ST3GAL6, in MM cell lines and patients. This gene plays a key role in selectin ligand synthesis in humans through the generation of functional sialyl Lewis X. In MRC IX patients, high expression of this gene is associated with inferior overall survival. In this study we demonstrate that knockdown of ST3GAL6 results in a significant reduction in levels of a-2,3-linked sialic acid on the surface of MM cells with an associated significant reduction in adhesion to MM bone marrow stromal cells and fibronectin along with reduced transendothelial migration in vitro. In support of our in vitro findings, we demonstrate significantly reduced homing and engraftment of ST3GAL6 knockdown MM cells to the bone marrow niche in vivo, along with decreased tumor burden and prolonged survival. This study points to the importance of altered glycosylation, particularly sialylation, in MM cell adhesion and migration. (Blood. 2014;124(11):1765-1776

• Pyk2 plays a tumor-promoting role in MM progression via modulation of the Wnt/ b-catenin signaling pathway.• Pyk2 inhibitors represent a new therapeutic option against MM.Proline-rich tyrosine kinase 2 (Pyk2) is a member of the focal adhesion kinase family that has been recently linked to tumor development. However, its role in modulating multiple myeloma (MM) biology and disease progression remains unexplored. We first demonstrated that patients with MM present with higher expression of Pyk2 compared with healthy individuals. By using loss-of-function approaches, we found that Pyk2 inhibition led to reduction of MM tumor growth in vivo as well as decreased cell proliferation, cellcycle progression, and adhesion ability in vitro. In turn, overexpression of Pyk2 promoted the malignant phenotype, substantiated by enhanced tumor growth and reduced survival. Mechanistically, inhibition of Pyk2 reduced activation of Wnt/b-catenin signaling by destabilizing b-catenin, leading to downregulation of c-Myc and Cyclin D1. Furthermore, treatment of MM cells with the FAK/Pyk2 inhibitor VS-4718 effectively inhibited MM cell growth both in vitro and in vivo. Collectively, our findings describe the tumor-promoting role of Pyk2 in MM, thus providing molecular evidence for a novel tyrosine kinase inhibitor as a new therapeutic option in MM. (Blood. 2014;124(17):2675-2686

Cutaneous T-cell lymphoma (CTCL) poses unique treatment challenges, given its range of presentations and numerous systemic therapy options. These options often lack comparative evidence or are characterized by low response rates and short remission duration in relapsed/refractory disease. The approval of mogamulizumab, a humanized, glycoengineered IgG1κ monoclonal antibody targeting the chemokine receptor type 4 (CCR4) chemokine receptor, brings a novel tool into the spectrum of treatment options for advanced CTCL and adult T-cell leukemia/lymphoma (ATLL). CCR4 is expressed in almost all cases of ATLL, and in a majority of CTCLs, particularly when blood involvement is present. In a Phase III randomized trial, mogamulizumab was associated with 28% overall response rate among patients with relapsed CTCL, median progression-free survival of 7.7 months, and median duration of remission of 14.1 months. Responses are more frequent among patients with Sézary syndrome and within the blood compartment. Common adverse effects include rash and infusion reactions, which are usually low grade. Sentinel reports indicate that exposure to mogamulizumab may result in severe or refractory graft vs host disease after allogeneic bone marrow transplantation, highlighting the need for vigilance and expert management. Further research may establish incremental efficacy of combining mogamulizumab with cytotoxic or immunomodulatory agents in CTCL, ATLL, and possibly other lymphomas and even solid tumors.

As a kinase at the crossroads of numerous metabolic and cell growth signaling pathways, glycogen synthase kinase-3 beta (GSK-3β) is a highly desirable therapeutic target in cancer. Despite its involvement in pathways associated with the pathogenesis of several malignancies, no selective GSK-3β inhibitor has been approved for the treatment of cancer. The regulatory role of GSK-3β in apoptosis, cell cycle, DNA repair, tumor growth, invasion, and metastasis reflects the therapeutic relevance of this target and provides the rationale for drug combinations. Emerging data on GSK-3β as a mediator of anticancer immune response also highlight the potential clinical applications of novel selective GSK-3β inhibitors that are entering clinical studies. This manuscript reviews the preclinical and early clinical results with GSK-3β inhibitors and delineates the developmental therapeutics landscape for this potentially important target in cancer therapy.

The role of endothelial progenitor cell (EPC)-mediated vasculogenesis in hematological malignancies is not well explored. Here, we showed that EPCs are mobilized from the bone marrow (BM) to the peripheral blood at early stages of multiple myeloma (MM); and recruited to MM cell-colonized BM niches. Using EPC-defective ID1+/- ID3-/- mice, we found that MM tumor progression is dependent on EPC trafficking. By performing RNA-sequencing studies, we confirmed that endothelial cells can enhance proliferation and favor cell-cycle progression only in MM clones that are smoldering-like and have dependency on endothelial cells for tumor growth. We further confirmed that angiogenic dependency occurs early and not late during tumor progression in MM. By using a VEGFR2 antibody with anti-vasculogenic activity, we demonstrated that early targeting of EPCs delays tumor progression, while using the same agent at late stages of tumor progression is ineffective. Thus, although there is significant angiogenesis in myeloma, the dependency of the tumor cells on EPCs and vasculogenesis may actually precede this step. Manipulating vasculogenesis at an early stage of disease may be examined in clinical trials in patients with smoldering MM, and other hematological malignancies with precursor conditions.