Angiogenesis plays an important role in the pathogenesis and progression of multiple myeloma (MM). Recent research identified myeloma cell-secreted factors (such as vascular endotherlial cell-growth factor [VEGF] and [bFGF]) that have the potential to trigger this process. Inhibition of neovascularization by thalidomide or its analogues (immunomodulatory drugs, or IMiDs) seems to be a promising therapeutic approach for MM. In addition, the mechanisms of action of novel therapeutic molecules in MM (such as the proteasome inhibitor PS-341 and zoledronic acid) seem to be partially based on their antiangiogenic activity. Targeting angiogenesis may become an important aspect of disease control in MM.
Angiogenesis, or neovascularization, is the formation of new blood vessels from preexisting vessels. This process occurs in multiple steps and is triggered by positive angiogenic factors released by the tumor cells or induced in the microenvironment of the tumor cells. These factors stimulate the migration and proliferation of endothelial cells, resulting in the formation of new capillaries. Successful neovascularization is believed to be critical for growth and metastasis of solid tumors. Recently it became clear that neovascularisation is also part of the pathogenesis of hematologic malignancies, including MM.
Angiogenesis is involved in the pathogenesis of MM.
MM cells have the capacity to communicate with different cell types in their natural microenvironment, the bone marrow. Molecular interactions with stromal fibroblasts sustain the survival and growth of the tumor cells, and myeloma cell-mediated activation of osteoclasts results in the induction of osteolytic lesions. More recently it became evident that myeloma cells also interact with endothelial cells. Interaction between endothelial cells and myeloma cells that circulate in the blood can result in the migration and subsequent homing of the tumor cells to the bone marrow. Several recent clinical observations indicate that the presence of myeloma cells within the bone marrow compartment is associated with increased activity of endothelial cells, resulting in neovascularization. Dr. Vincent Rajkumar of the Mayo Clinic illustrated that microvessel density (MVD) in the bone marrow progressively increases from monoclonal gammopathy of undetermined significance to smoldering MM to MM and that angiogenesis has a prognostic value in MM. Superior survival for MM patients with low MVD in the bone marrow was also reported by Dr. Orhan Sezer of University Hospital Charite. He noted that bone marrow MVD significantly decreases in MM patients who achieve remission regardless of the type of chemotherapy they received. This decrease seems to be associated with prolonged progression-free survival. Dr. James Berenson of Cedars-Sinai Cancer Center mentioned that relapse after stem cell transplantation is associated with an increase in MVD.
Molecular aspects of angiogenesis in MM
Although the role of angiogenesis in the growth and metastasis of solid tumors has been clearly established, less is known about the underlying mechanisms that mediate this process in MM. Several presentations focused on the role of specific angiogenic molecules in the pathogenesis of MM. Both Dr. Rajkumar and Dr. Bellamy of the University of Arizona reported on the expression of VEGF by myeloma cell lines and myeloma plasma cells in the majority of the patients tested. Dr. Berenson demonstrated the existences of a correlation between microvessel density, VEGF expression by plasma cells, and the number of plasma cells in myeloma bone marrow samples. Dr. Kenneth Anderson of the Dana-Farber Cancer Center mentioned that VEGF might not only be important for the formation of new blood vessels in MM but also has the potential to stimulate directly the proliferation and migration of myeloma cells. His group demonstrated that production of VEGF by myeloma cells can be stimulated by activation of the CD40 molecule on the surface of the tumor cells. One study revealed that high levels of VEGF in the serum of MM patients is associated with extramedular growth of tumor cells.
Dr. Thomas Witzig of the Mayo Clinic reported on the expression of another potential angiogenic molecule in MM, fibroblast growth factor (FGF). He found that myeloma cell lines express different FGF types (FGF-2, -5, and -9) and also FGF receptors (FGFRs), indicating the possible involvement of an autocrine FGF/FGFR loop in the growth control of myeloma cells. Dr. Van Riet illustrated that human myeloma cell lines can directly trigger the neovascularization process by stimulating the migration and proliferation of human endothelial cells. He demonstrated that although VEGF-A and bFGF are both functionally involved in these steps, the major effect is caused by VEGF-A. It was found that the expression of both angiogenic factors is triggered by molecular interactions between myeloma cells and bone marrow stromal cells. He also showed that myeloma cell lines express additional angiogenesis-promoting molecules such as VEGF-B and angiopoietin-1; however, their functional role in MM remains to be determined. In one study, serum levels of different angiogenic factors (VEGF, bFGF, and hepatocyte growth factor (HGF) were measured in a group of MM patients before and after treatment. It was found that MM is associated with an increase in serum bFGF levels in advanced disease and that effective chemotherapy is associated with a significant decrease in the levels of bFGF, VEGF, and HGF.
Dr. Joshua Epstein of the University of Arkansas presented the SCID-hu model, in which human myeloma cells are injected in human fetal bones that are implanted in severe combined immunodeficiency disease (SCID) mice. In this model, myeloma cells not only grow in human bone at the site of injection but can also migrate and home to another bone implanted in the same animal. Interestingly, recombinant endostatin (a natural antiangiogenic factor) administered to tumor-bearing SCID-hu hosts had a clear antimyeloma effect that was associated with a strong inhibition of microvessel formation. Similar effects were seen with adenovirus endostatin gene therapy. It seems that survival and growth of myeloma cells in this model require active neovascularization.
Angiogenesis as a therpeutic target in MM
Several presentations illustrated the therapeutic potential of thalidomide in the treatment of MM patients. Dr. Anderson summarized the different biological effects of thalidomide that contribute to its therapeutic benefit in MM. Thalidomide not only has antiangiogenic activity but also directly induces apoptosis, or growth arrest, of myeloma cells. The major angiogenesis-inhibiting effect of thalidomide relates to its potential to abrogate the secretion of VEGF. Moreover, thalidomide stimulates the patient's immune system to kill tumor cells. Dr. Bart Barlogie of the Arkansas Cancer Research Center mentioned that thalidomide can also down regulate c-myc, an oncogene that is activated in the tumor cells of some MM patients.
Several studies indicated that thalidomide is an effective treatment for patients with advanced MM. Dr. Barlogie reported on the effect of thalidomide treatment in a group of 169 patients with advanced and refractory disease, resulting in event-free survival and overall of 60% and 20%, respectively. Dr. Rajkumar confirmed that thalidomide treatment is effective in 25% to 35% of patients with refractory disease. Similar results were reported by several other groups. In most studies, daily doses of thalidomide between 200 and 800 mg have been used. Because of the considerable toxicity, Dr. Brian Durie of Cedars-Sinai Cancer Center evaluated less toxic doses (50 to 400 mg) and observed clinical responses in 44% of patients with relapsing MM.
Several studies evaluated the clinical effect of treatment with thalidomide in combination with other therapeutic agents. It was shown that thalidomide plus dexamethosone was highly effective for patients with relapsed or refractory MM. Another study confirmed these data but also revealed that the thalidomide/dexamethosone combination does not lengthen remission duration compared with thalidomide alone. Dr. Durie mentioned that the combination of thalidomide with Biaxin or Biaxin/dexamethosone can be active for failing patients.
Dr. Donna Weber of M.D. Anderson Cancer Center demonstrated that in a group of 44 previously untreated MM patients, the response rate with thalidomide as monotherapy was approximately one half (36%) of that with the thalidomide/dexamethosone combination (69%). The promising activity of thalidomide/dexamethosone in previously untreated patients with active MM was also reported by Dr. Rajkumar.
Some novel drugs were discussed that not only target the MM cell but also act against the microenvironment, including the formation of new blood vessels. Several novel proteins were recently isolated that inhibit angiogenesis including VEGF inhibitor (VEGFI). Previous studies demonstrated that VEGFI inhibits angiogenesis and may directly induce apoptosis of tumor cells without inhibiting normal cells. Dr. Berenson demonstrated that VEGFI also directly affects the growth of human myeloma cell lines. He showed that bisphosphonates, such as zoledronic acid, not only inhibit the development of osteoclasts but also seem to be markedly antiangiogenic, possibly by affecting the production of VEGF.
Dr. Anderson gave an overview of the different biological effects of the proteasome inhibitor PS-341 on myeloma cells. This molecule directly inhibits the growth of myeloma cells, overcomes resistance to apoptosis in MM cells conferred by interleukin-6, and reduces the adhesion of tumor cells to bone marrow stroma. This impairment of binding to bone marrow stromal cells will also reduce VEGF secretion, leading to inhibition of angiogenesis. An ongoing clinical trial should explore the role of PS-341 in the treatment of MM. Dr. Anderson’s group also demonstrated that IMiD derivates of thalidomide have significantly more potent effects against myeloma cells than does thalidomide itself. These include inhibition of VEGF-induced proliferation and migration of myeloma cells and antiangiogenic activity. A Phase I study to test the safety and efficacy of the IMiD CC5013 for treatment of MM patients was recently started.
The biological and clinical importance of angiogenesis in the pathogenesis and treatment of MM was addressed by numerous speakers. The increased density of blood vessels in the bone marrow of MM patients not only is associated with the proliferation of plasma cells but seems also to correlate with the prognosis for the disease. Myeloma cells secrete molecules that have the potential to trigger formation of new blood vessels in the bone marrow. The production of these factors seems to be regulated by molecular interactions between the tumor cells and the host bone marrow microenvironment Angiogenesis may be a promising therapeutic target in MM. Treatment with thalidomide has marked activity in MM patients, even in those with refractory disease. Ongoing studies need to clarify the role of thalidomide in combination with other therapeutic agents as well as its up-front use. A new series of therapeutic molecules act against the myeloma cell and its microenvironment, including the formation of new blood vessels. These molecules either are being or soon will be evaluated in clinical trials.