The proteasome inhibitor bortezomib (BTZ) is successfully applied in the treatment of multiple myeloma, but its efficacy is restricted by the wide-spread occurrence of resistance. Metabolic alterations play an important role in cancer development and aid in the cellular adaptation to pharmacologically changed environments. Metabolic changes could therefore play an essential role in the development of drug resistance. However, specific metabolic pathways that can be targeted to improve bortezomib therapy remain unidentified. We elucidated the metabolic mechanisms underlying bortezomib resistance by using mass spectrometry-based metabolomics and proteomics on BTZ-sensitive and BTZ–resistant multiple myeloma cell lines as well as in a set of CD138+ cells obtained from multiple myeloma patients. Our findings demonstrate that a rewired glucose metabolism sustains bortezomib resistance. Mechanistically, this results in higher activity of both the pentose phosphate pathway and serine synthesis pathway, ultimately leading to an increased anti-oxidant capacity of BTZ-resistant cells. Moreover, our results link both serine synthesis pathway activity and expression of 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of serine synthesis, to bortezomib resistance across different BTZ-resistant multiple myeloma cell lines. Consistently, serine starvation enhanced the cytotoxicity of bortezomib, underscoring the importance of serine metabolism in the response to BTZ. Importantly, in CD138+ cells of clinically bortezomib refractory multiple myeloma patients, PHGDH expression was also markedly increased. Our findings indicate that interfering with serine metabolism may be a novel strategy to improve bortezomib therapy and identify PHGDH as a potential biomarker for BTZ resistance.

Objective: To determine the expression of folate receptor β (FRβ) in synovial biopsy tissues and peripheral blood lymphocytes from rheumatoid arthritis (RA) patients and to identify novel folate antagonists that are more selective in the targeting and internalization of FRβ than methotrexate (MTX).Methods: Immunohistochemistry and computer‐assisted digital imaging analyses were used for the detection of FRβ protein expression on immunocompetent cells in synovial biopsy samples from RA patients with active disease and in noninflammatory control synovial tissues. FRβ messenger RNA (mRNA) levels were determined by reverse transcription–polymerase chain reaction analysis. Binding affinities of FRβ for folate antagonists were assessed by competition experiments for³H‐folic acid binding on FRβ‐transfected cells. Efficacy of FRβ‐mediated internalization of folate antagonists was evaluated by assessment of antiproliferative effects against FRβ‐transfected cells.Results: Immunohistochemical staining of RA synovial tissue showed high expression of FRβ on macrophages in the intimal lining layer and synovial sublining, whereas no staining was observed in T cell areas or in control synovial tissue. Consistently, FRβ mRNA levels were highest in synovial tissue extracts and RA monocyte‐derived macrophages, but low in peripheral blood T cells and monocytes. Screening of 10 new‐generation folate antagonists revealed 4 compounds for which FRβ had a high binding affinity (20–77‐fold higher than for MTX). One of these, the thymidylate synthase inhibitor BCG 945, displayed selective targeting against FRβ‐transfected cells.Conclusion: Abundant FRβ expression on activated macrophages in synovial tissue from RA patients deserves further exploration for selective therapeutic interventions with high‐affinity–binding folate antagonists, of which BCG 945 may be a prototypical representative.

Folate receptors and transporters and one-carbon metabolism continue to be important areas of study given their essential roles in an assortment of diseases and as targets for treatment of cancer and inflammation. Reflecting this, every 2 years, the Folate Receptor Society organizes an international meeting, alternating between North America and Europe, where basic and translational scientists, clinical oncologists and rheumatologists from both academia and industry convene in an informal setting. The 7th International Symposium on Folate Receptors and Transporters was held in Sant’Alessio Siculo (ME), Taormina, Italy from 1st to 5th of October 2018, organized by Dr. Mariangela Figini from Fondazione IRCCS Istituto Nazionale dei Tumori, Milan. Following the format of previous meetings, more than 50 scientists from 9 different countries attended the 2018 meeting to share ongoing developments, discuss current research challenges and identify new avenues in basic and translational research. An important feature of this meeting was the participation of young investigators and trainees in this area, two (A. Dekhne and N. Verweij) of whom were awarded fellowships to attend this meeting as a recognition of the high scientific quality of their work. This report provides a synopsis of the highlights presented in the following sessions: Barton Kamen Lecture; Targeting one-carbon metabolism in cytosol and mitochondria; Structure and biology of the one-carbon solute transporters; Physiology and pathophysiology of folate receptors and transporters; Folate receptors for targeting tumors and inflammatory diseases; Conventional and new anti-folate drugs for treating inflammatory diseases and cancer; Imaging; Ongoing clinical trials; and Chimeric Antigen Receptor cell therapies of cancer.

Macrophages play a key role in the pathophysiology of rheumatoid arthritis (RA). Notably, positive correlations have been reported between synovial macrophage infiltration and disease activity as well as therapy outcome in RA patients. Hence, macrophages can serve as an important target for both imaging disease activity and drug delivery in RA. Folate receptor β (FRβ) is a glycosylphosphatidyl (GPI)-anchored plasma membrane protein being expressed on myeloid cells and activated macrophages. FRβ harbors a nanomolar binding affinity for folic acid allowing this receptor to be exploited for RA disease imaging (e.g., folate-conjugated PET tracers) and therapeutic targeting (e.g., folate antagonists and folate-conjugated drugs). This review provides an overview of these emerging applications in RA by summarizing and discussing properties of FRβ, expression of FRβ in relation to macrophage polarization, FRβ-targeted in vivo imaging modalities, and FRβ-directed drug targeting.

Current treatment strategies for rheumatoid arthritis (RA) consisting of disease-modifying anti-rheumatic drugs or biological agents are not always effective, hence driving the demand for new experimental therapeutics. The antiproliferative capacity of proteasome inhibitors (PIs) has received considerable attention given the success of their first prototypical representative, bortezomib (BTZ), in the treatment of B cell and plasma cell-related hematological malignancies. Therapeutic application of PIs in an autoimmune disease setting is much less explored, despite a clear rationale of (immuno) proteasome involvement in (auto)antigen presentation, and PIs harboring the capacity to inhibit the activation of nuclear factor-κB and suppress the release of pro-inflammatory cytokines such as tumor necrosis factor alpha and interleukin-6. Here, we review the clinical positioning of (immuno) proteasomes in autoimmune diseases, in particular RA, systemic lupus erythematosus, Sjögren’s syndrome and sclerodema, and elaborate on (pre)clinical data related to the impact of BTZ and next generation PIs on immune effector cells (T cells, B cells, dendritic cells, macrophages, osteoclasts) implicated in their pathophysiology. Finally, factors influencing long-term efficacy of PIs, their current (pre)clinical status and future perspectives as anti-inflammatory and anti-arthritic agents are discussed.