Targeting the Tumor Microenvironment: Focus on Angiogenesis

Tumorigenesis is a complex multistep process involving not only genetic and epigenetic changes in the tumor cell but also selective supportive conditions of the deregulated tumor microenvironment. One key compartment of the microenvironment is the vascular niche. The role of angiogenesis in solid tumors but also in hematologic malignancies is now well established. Research on angiogenesis in general, and vascular endothelial growth factor in particular, is a major focus in biomedicine and has led to the clinical approval of several antiangiogenic agents including thalidomide, bevacizumab, sorafenib, sunitinib, pazopanib, temesirolimus, and everolimus. Indeed, antiangiogenic agents have significantly changed treatment strategies in solid tumors (colorectal cancer, renal cell carcinoma, and breast cancer) and multiple myeloma. Here we illustrate important aspects in the interrelationship between tumor cells and the microenvironment leading to tumor progression, with focus on angiogenesis, and summarize derived targeted therapies

Acute myeloid leukemia cells require 6-phosphogluconate dehydrogenase for cell growth and NADPH-dependent metabolic reprogramming

Acute myeloid leukemia (AML) cells are highly dependent on glycolytic pathways to generate metabolic energy and support cell growth, hinting at specific, targetable vulnerabilities as potential novel targets for drug development. Elevated levels of NADPH, a central metabolic factor involved in redox reactions, are common in myeloid leukemia cells, but the significance or biochemical basis underlying this increase is unknown. Using a small molecule analog that efficiently inhibits NADPH-producing enzymes, we found that AML cells require NADPH homeostasis for cell growth. We also found that inhibiting NADPH production through knockdown of 6-phosphogluconate dehydrogenase (6PGD) within the pentose phosphate pathway was sufficient to reduce cell growth and lactate production, a measure of metabolic reprogramming. Further, inhibition of 6PGD activity reduced NADH levels and enzymatic activity of the oxidized NADH-dependent sirtuin-1. Targeting 6PGD and NADPH production was sufficient to block growth of AML cell lines resistant to the chemotherapeutics daunorubicin and cytarabine. Importantly, stromal cell-mediated resistance to targeted inhibition of oncogenic FLT3 kinase activity by quizartinib was circumvented by 6PGD knockdown. Overall, these data suggest that the dependency of AML cells on NADPH to permit increased glycolytic flux creates a potential vulnerability of possible therapeutic benefit, since much of the enhanced production of NADPH is dependent on the activity of a single enzyme, 6PGD

The Role of AP-1 Transcription Factors in Plasma Cell Biology and Multiple Myeloma Pathophysiology

Multiple myeloma (MM) is an incurable hematologic malignancy characterized by the clonal expansion of malignant plasma cells within the bone marrow. Activator Protein-1 (AP-1) transcription factors (TFs), comprised of the JUN, FOS, ATF and MAF multigene families, are implicated in a plethora of physiologic processes and tumorigenesis including plasma cell differentiation and MM pathogenesis. Depending on the genetic background, the tumor stage, and cues of the tumor microenvironment, specific dimeric AP-1 complexes are formed. For example, AP-1 complexes containing Fra-1, Fra-2 and B-ATF play central roles in the transcriptional control of B cell development and plasma cell differentiation, while dysregulation of AP-1 family members c-Maf, c-Jun, and JunB is associated with MM cell proliferation, survival, drug resistance, bone marrow angiogenesis, and bone disease. The present review article summarizes our up-to-date knowledge on the role of AP-1 family members in plasma cell differentiation and MM pathophysiology. Moreover, it discusses novel, rationally derived approaches to therapeutically target AP-1 TFs, including protein-protein and protein-DNA binding inhibitors, epigenetic modifiers and natural products

Relapsed/Refractory Multiple Myeloma in 2020/2021 and Beyond

Despite the challenges imposed by the COVID-19 pandemic, exciting therapeutic progress continues to be made in MM. New drug approvals for relapsed/refractory (RR)MM in 2020/2021 include the second CD38 monoclonal antibody, isatuximab, the first BCMA-targeting therapy and first-in-class antibody–drug conjugate (ADC) belantamab mafodotin, the first BCMA-targeting CAR T cell product Idecabtagen-Vicleucel (bb2121, Ide-Cel), the first in-class XPO-1 inhibitor selinexor, as well as the first-in-class anti-tumor peptide-drug conjugate, melflufen. The present introductory article of the Special Issue on “Advances in the Treatment of Relapsed and Refractory Multiple Myeloma: Novel Agents, Immunotherapies and Beyond” summarizes the most recent registration trials and emerging immunotherapies in RRMM, gives an overview on latest insights on MM genomics and on tumor-induced changes within the MM microenvironment, and presents some of the most promising rationally derived future therapeutic strategies

Myeloma Bone Disease: Update on Pathogenesis and Novel Treatment Strategies

Bone disease, including osteolytic lesions and/or osteoporosis, is a common feature of multiple myeloma (MM). The consequences of skeletal involvement are severe pain, spinal cord compressions, and bone fractures, which have a dramatic impact on patients’ quality of life and, ultimately, survival. During the past few years, several landmark studies significantly enhanced our insight into MM bone disease (MBD) by identifying molecular mechanisms leading to increased bone resorption due to osteoclast activation, and decreased bone formation by osteoblast inhibition. Bisphosphonates were the mainstay to prevent skeletal-related events in MM for almost two decades. Excitingly, the most recent approval of the receptor activator of NF-kappa B ligand (RANKL) inhibitor, denosumab, expanded treatment options for MBD, for patients with compromised renal function, in particular. In addition, several other bone-targeting agents, including bone anabolic drugs, are currently in preclinical and early clinical assessment. This review summarizes our up-to-date knowledge on the pathogenesis of MBD and discusses novel state-of-the-art treatment strategies that are likely to enter clinical practice in the near future

Evaluation of Antibody Responses in Patients with B-Cell Malignancies after Two and Three Doses of Anti-SARS-CoV-2 S Vaccination—A Retrospective Cohort Study

Patients with B-cell malignancies are at a higher risk of severe SARS-CoV-2 infections. Nevertheless, extensive data on the immune responses of hematological patients and the efficacy of the third dose of the vaccine are scarce. The goal of this study was to determine standardized anti-SARS-CoV-2 S antibody levels and to evaluate differences between treatment modalities in response to the second and third vaccines among patients with B-cell malignancies treated at the University Hospital Krems and the University Hospital of Vienna. The antibody levels of a total of 80 patients were retrospectively analyzed. The results indicate a significant increase in antibody production in response to the third vaccination. The highest increases could be observed in patients in a “watchful-waiting” and “off-therapy” setting. Encouragingly, approximately one-third of patients who did not develop antibodies in response to two vaccinations achieved seroconversion after the third vaccination. “Watchful-waiting”, “off-therapy” and treatment with BTK inhibitors were indicative for increased antibody response after the third dose compared to anti-CD19 CAR T-cell and anti-CD-20 antibody treatment. In summary, the results of this study underline the pre-eminent role of the need for complete vaccination with three doses for the development of protective immunity in patients with B-cell malignancies