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Vol. 1, 1361-1365, December 2002     Molecular Cancer Therapeutics
© 2002 American Association for Cancer Research

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Synopsis of a Research Roundtable Presented on Cell Signaling in Myeloma: Regulation of Growth and Apoptosis—Opportunities for New Drug Discovery

Kenneth C. Anderson and William S. Dalton1

The Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Department of Adult Oncology, Harvard Medical School, Boston, Massachusetts 02115 [K. C. A.], and H. Lee Moffitt Cancer Center, University of South Florida, Tampa, Florida 33612 [W. S. D.]


   Abstract
Top
 Abstract
Introduction
 Growth Control, Survival, and...
 Novel Treatment Approaches
 Recommendations for Future...
 References
 
A wide variety of alterations affect important cell-signaling pathways involved in growth, survival, and migration of myeloma cells. Several of these pathways have been identified, and a number of potential anticancer agents are in development to block specific cell signaling proteins. The fifth experts’ roundtable in multiple myeloma was convened in May 2001 to focus on this important issue. The roundtable brought together myeloma experts, researchers involved in cell signaling, industry scientists, and investigators studying other hematologic malignancies, with the single purpose of challenging current thought and increasing the collective knowledge in the evolving field of cell signaling and multiple myeloma. The session was cochaired by Dr. William S. Dalton of the H. Lee Moffitt Cancer Center and Dr. Kenneth C. Anderson of the Dana-Farber Cancer Institute. Sponsored by the Dana-Farber Cancer Institute, the roundtable was funded by the Multiple Myeloma Research Foundation and McCarty Cancer Foundation of Canada.


   Introduction
Top
 Abstract
 Introduction
Growth Control, Survival, and...
 Novel Treatment Approaches
 Recommendations for Future...
 References
 
MM2 is a plasma cell malignancy characterized by migration and localization to the bone marrow from where cells disseminate and facilitate formation of bone lesions. Despite all available therapies, MM is generally considered incurable and will affect ~14,000 individuals in the United States in 2002 (1, 2). MM typically displays a low proliferative rate and ultimately develops resistance to currently available therapeutic agents. Apoptosis is the primary means by which most chemotherapy and radiotherapy modalities kill cancer cells (3). This cytotoxic response uses signal transduction pathways common in physiological mechanisms of programmed cell death or apoptosis. A block in programmed cell death is believed to be a major contributing factor to the drug resistance observed in MM. To prevent apoptosis, tumor cells acquire mechanisms to prevent cell death. Some of these mechanisms are mediated by extracellular growth and survival factors and the tumor microenvironment (4, 5).

Tumor progression is a multistep process determined by events intrinsic to the tumor cell and microenvironment. Environmental factors that contribute to the pathogenesis and progression of human malignancies include soluble factors, such as cytokines, hormones, and growth factors; interaction of the tumor with extracellular matrix molecules; and interactions of the tumor with healthy extracellular cells and tissues. The presence of growth factors, such as IL-6, the most important growth factor in MM, may block cell death associated with chemotherapies and radiotherapies (3, 5).


   Growth Control, Survival, and Apoptosis
Top
 Abstract
 Introduction
 Growth Control, Survival, and...
Novel Treatment Approaches
 Recommendations for Future...
 References
 
Translocations and Mutations.
Although for most normal B-cell differentiation and for many B-cell malignancies critical signals are transduced by the B-cell receptor, this is probably not the case for myeloma, a plasma cell malignancy. It is most likely that in the terminal stages of plasma cell differentiation, other signals coming from the microenvironment are more important mediators of growth and survival. Like their normal counterpart, myeloma cells are naturally long lived, and presumably genetic mutations are not required to increase this life span. In keeping with this, the translocations and point mutations that have been identified primarily appear to promote growth, rather then survival. The key oncogenes involved are cyclin D1, cyclin D3, FGFR3, c-maf, mafB, and c-myc3 (6, 7).

Primary translocations are mediated by switch combinations and, to a lesser extent, somatic hypermutations. Translocations mediated by these mechanisms occur in 75% of patients with MM. With disease progression, secondary translocations that result from general chromosomal abnormalities are observed. In contrast to primary translocations, secondary translocations can be very complex. Recent research highlights the important role of FGFR3 in primary translocations and c-myc in secondary translocations in myeloma. FGFR3 is translocated in ~25% of myeloma cell lines and ~20% of primary tumors.4 Overexpression of FGFR3 in a murine bone marrow transplant model results in enhanced cellular proliferation in response to IL-6 and complete independence from IL-6 in some situations (8). The reasons for enhanced cellular proliferation are still unclear; however, up-regulation of STAT3 and Bcl-XL appears to explain the reduced apoptosis that is observed. Thus, FGFR3, STAT3, and Bcl-XL are all potential targets for myeloma therapy.5 An FGFR inhibitor (SU5402) developed by SUGEN, Inc. inhibits growth of MM lines in vitro in an FGFR3-specific fashion and represents a potential therapy for myelomas bearing this translocation.5

IL-6 and STAT Activation.
Most conventional chemotherapies for MM exert their effects, at least in part, via disruption of the IL-6-dependent cell growth pathway. In MM, the interaction between tumor and BMSCs triggers production of cytokines, such as IL-6 (5). Elevated IL-6 levels observed in patients with MM contribute to chemo-resistance and treatment failure by mechanisms that increase tumor growth and survival (9). Moreover, IL-6 inhibits dexamethasone-induced tumor apoptosis (5). Dexamethasone-induced apoptosis in MM is associated with down-regulation of growth-related signaling pathways, such as MAPK and p70rsk. MAPK is a relatively late event during IL-6 signaling, and more upstream gp130-associated kinases, such as members of the Janus family of kinases (JAK1, JAK2, JAK3) and the STAT family of proteins (STAT1, STAT3), may be important targets3 (4).

STAT3 mediates IL-6 activities. When IL-6 is engaged by the high-affinity receptor, it activates STAT3. Receptors of both gp80 and gp130 are expressed when cells are in the activated B-cell stage. When induced by IL-6, these cells become plasma cells, and both gp80 and gp130 are shut off. Therefore, IL-6, by way of activating STAT and downstream events, actually down-regulates both receptors. This is the first evidence of negative regulation of gp130 in any system. This implies that IL-6 negatively controls its own receptor expression. In contrast, there is no down-regulation in myeloma cells, which exhibit continued proliferation and STAT3 activation in response to IL-6, possibly attributable to up-regulation of the IL-6 receptor (10, 11). Therefore, IL-6 signaling is different in B cells as compared with malignant cells, and the difference is in receptor regulation. The challenge is to determine which point downstream of IL-6 leads to negative regulation of gp130.6

Although STATs are activated by numerous physiological signals, their constitutive expression in a wide variety of human cancer cells is linked to persistent activation of tyrosine kinases leading to continued STAT signaling and cell proliferation (12). In a number of tumor models, inactivation of STATs is associated with a loss of survival or cell proliferation. Because normal cells are fairly tolerant of inhibition of STAT signal transduction, STATs are an attractive target for cancer therapy. STAT activation is an important event in endothelial cell proliferation and may contribute to angiogenesis, a critical process in tumor growth (13). Therefore, modulation of STAT function may be important not only in directly inhibiting tumor growth but also as an antiangiogenic strategy.7

Cell Adhesion and Survival.
It is possible that cell adhesion creates an antiapoptotic environment that allows for the progression of hematopoietic tumors, particularly myeloma (14). Although intrinsic factors like overexpression of constitutively active receptors may be important, extrinsic factors such as the microenvironment may also participate in the pathogenesis of MM. In addition to soluble factors like IL-6, there are other means by which the environment can influence cancer cells, e.g., through direct cell contact. A number of cell adhesion molecules are involved in cell signaling, and some of these signaling events can influence cell survival. When myeloma cells adhere to fibronectin, they become resistant to chemotherapeutic agents, such as doxorubicin and melphalan, as well as radiation therapy. The protective effects of adhesion to fibronectin can be avoided if ß1 integrins are blocked (15).

FAS-induced apoptosis is also inhibited by ß1 integrins, and inhibition occurs at a very proximal event demonstrated by a blocking of procaspase 8 activation. A number of inhibitors can block FAS-induced apoptosis. One of these inhibitors is c-FLIPL. Theoretically, the more FLIPL that is present, the more resistance there will be to FAS-induced apoptosis attributable to inhibition of procaspase 8. When myeloma cells are adhered to fibronectin, there is a dramatic increase in cytoplasmic FLIPL concentration (3). In contrast, virtually no FLIPL is detected when cells are in suspension. Therefore, by adhering to fibronectin, myeloma cells are protected from FAS-induced apoptosis. This may allow myeloma cells to escape immune surveillance and contribute to myeloma progression (3).


   Novel Treatment Approaches
Top
 Abstract
 Introduction
 Growth Control, Survival, and...
 Novel Treatment Approaches
Recommendations for Future...
 References
 
Despite the availability of a growing number of biological, chemotherapeutic, and combination regimens, the prognosis of MM remains poor. Therefore, numerous researchers are investigating novel approaches to treatment.

Proteasome Inhibitors.
Proteasome inhibitors represent novel anticancer agents for the treatment of MM because of their effects on multiple pathways in the pathogenesis of the disease. These include regulation of cell cycle progression by blocking degradation of ubiquinated cyclins and cyclin-dependent kinase inhibitors, induction of tumor apoptosis, and suppression of gene transcription by preventing activation of NF-{kappa}B (5). The effects of the proteasome inhibitor PS-341 on myeloma proliferation were evaluated using myeloma chemosensitive and chemoresistant cell lines and human myeloma cells (16). PS-341 suppressed tumor cell proliferation and induced apoptosis, even in myeloma cells resistant to chemotherapy and dexamethasone. In fact, PS-341 overcame IL-6-induced protection against dexamethasone-induced apoptosis and suppressed IL-6-induced growth through inhibition of MAPK. PS-341 also suppressed paracrine tumor growth by blocking NF-{kappa}B-dependent IL-6 secretion from BMSCs and decreasing myeloma cell adherence to BMSCs (5). Remarkably, PS-341 with or without chemotherapy had no effect on normal bone marrow and blood leukocytes. Thus, PS-341 reduces NF-{kappa}B activity in myeloma and is cytotoxic to myeloma cells without an affect on normal cells.8

Inhibitors of Angiogenesis.
Angiogenesis is essential for the sustained growth of solid tumors (17). Tumors that lack adequate vasculature do not grow beyond a limited size. However, tumors that undergo neovascularization acquire the ability to grow rapidly and generally exhibit increased metastatic potential. Bone marrow angiogenesis is critical for the progression of several leukemias. Angiogenesis is accomplished by the enhanced production and release of VEGF that occurs during contact between myeloma and stromal cells (18). Coculture studies indicate stromal cell-derived IL-6 is the major stimulus for VEGF, which in turn amplifies the response by autocrine stimulation of IL-6 production. Thus, angiogenesis inhibitors that target VEGF or the VEGF receptor have the potential to inhibit myeloma in two ways. They can: (a) inhibit angiogenesis; or (b) block the ability of VEGF to stimulate vascular endothelial cells to produce IL-6. SU5416 and SU6668 are novel small molecule antiangiogenic agents that inhibit VEGF signaling through receptor tyrosine kinases essential to angiogenesis, including the VEGF receptor Flk-1/KDR (19, 20). Both agents have been evaluated for antitumor activity in preclinical models as single agents and in combination with standard cytotoxic agents and radiation. SU5416 is a selective inhibitor of Flk-1/KDR. In a Phase II trial of SU5416 in patients with acute myelogenous leukemia, there was an overall response rate of 30% by day 28 of therapy. Phase II trials in patients with MM are currently ongoing.9

SU6668, which is structurally related to SU5416, is currently in Phase I trials. SU6668 also inhibits Flk-1/KDR, although its activity against this receptor is ~10-fold less than that of SU5416. The more broadly acting SU6668 reduced tumor vascularity, which was accompanied by increased tumor cell death, decreased proliferation, and a concomitant rise in VEGF gene transcription in mice (21). In the A431 human epidermoid tumor model, p.o. therapy with SU6668 completely regressed tumors that had grown to between 500 and 2000 mm3. When therapy was stopped, tumors remained regressed in the majority of the mice. In the few animals in which tumors regrew, reinitiation of therapy with SU6668 regressed tumors a second time with no evidence of resistance. SU6668 is about to enter Phase I studies against a variety of hematologic malignancies, including MM.9

Antisense Strategies.
Apoptosis involves two pathways: (a) one that is mitochondria independent; and (b) one that is mitochondria dependent. The mitochondria-dependent pathway is involved in chemotherapy-induced apoptosis. To overcome mitochondrial-dependent resistance, an antisense oligonucleotide can be used to turn down the Bcl-2 protein. Preclinical and clinical studies suggest that oblimersen sodium, a Bcl-2 antisense oligonucleotide (G3139; Genta) that down-regulates Bcl-2 in human tumors, synergizes with cytotoxic and immunotherapeutic agents against various hematologic malignancies and tumors (22). Results from a Phase I study using oblimersen sodium were published last year. Patients in the study had low-grade malignancy and were heavily pretreated.10 One patient had a complete response and has retained this response for 4 years. There was disease stabilization in eight other patients. In the patients who displayed a response to therapy, a significant down-regulation of Bcl-2 in bone marrow, lymphocytes, and lymph node samples was documented. In seven of eight responders, down-regulation of the Bcl-2 protein was also documented. Reduction in platelet count was the dose-limiting toxicity, which occurred at approximately the same dose associated with unacceptable toxicity with other antisense oligonucleotides. The toxicity is reversible in ~4–5 days after discontinuation of treatment. This dose is much higher than the dose required to reduce B cells to the therapeutic level required. The results of this study confirmed that down-regulation of a protein through an antisense approach is clinically viable.10 Phase III studies were initiated in 2001 for advanced MM at 65 centers in the United States, Canada, and Great Britain (23).

FTase and Geranylgeranyl-Transferase I Inhibitors.
The fact that proteins such as Ras, Rac, and Rho A require farnesylation or geranylgeranylation for inducing malignant transformation prompted many investigators to develop FTIs and geranylgeranyl-transferase I inhibitors as novel anticancer drugs (24). FTIs antagonize oncogenic signaling, reverse malignant transformation, inhibit human tumor growth in nude mice, and induce tumor regression in transgenic mice without toxicity. One study evaluated the effects of FTIs in patients with MM, nonsmall cell lung cancer, and colorectal cancer. Preliminary biochemical data from four patient samples demonstrated that ex vivo exposure to the FTI inhibited FTase activity. Therefore, at clinically relevant doses, FTIs are capable of blocking farnesylation of critical proteins involved in myeloma progression. A Phase II clinical trial is currently ongoing in myeloma.11

Purine Analogues.
The purine analogue 8-Cl-Ado demonstrates cytotoxicity against MM both in vitro and in vivo (25). It mediates programmed cell death against MM cell lines resistant to traditional chemotherapeutic agents.12 8-Cl-Ado induces formation of a classical chromatin ladder, poly (ADP-ribose) polymerase cleavage, accumulation of cells in the sub-G1 cell cycle fraction, increased activity of caspases 8 and 9, and a decrease in mitochondrial membrane potential. This compound is effective against a broad spectrum of both solid tumors and hematologic malignancies. Although it kills normal lymphocytes in vitro, it produces very little hematopoietic toxicity in animal models. 8-Cl-Ado is phosphorylated through the adenosine kinase pathway to the monophosphate and ultimately to the triphosphate derivative (8-chloro ATP), which is thought to be the cytotoxic metabolite (25). In myeloma cells, ~40% is converted to the monophosphate derivative, ~40% into the triphosphate, and the remainder to the diphosphate.12 Adenosine kinase is required for cell killing. The primary effects of 8-Cl-Ado are on mRNA synthesis (50% inhibition) and to a lesser degree on RNase. There is no effect on tRNA. In contrast to other purine analogs, 8-Cl-Ado does not affect DNA synthesis. Eight-Cl-Ado may be an effective agent in drug-resistant myeloma.

Tyrosine Kinase Inhibitors.
Tyrosine kinases represent a family of enzymes that are critical for cell growth, proliferation, and survival (19). These include FGFRs and VEGFRs, both of which are considered central to local autocrine and paracrine mechanisms that support and perpetuate myeloma growth and proliferation. FGFR3 is a major target for tyrosine kinase inhibition, because it is overexpressed in MM patients having the t(4;14) gene translocation (19). Small molecule inhibitors of enzyme targets are being investigated in programs directed against, among others, tyrosine kinases known or thought to be important in cell signaling in transformed cells.13 Certain pyrido [2,3-d] pyrimidines are potent selective inhibitors of c-Src kinases and FGFRs, whereas quinazolines primarily block VEGFRs and FGFRs (19, 26). The transforming tyrosine kinase Bcr-Abl is considered an ideal target to validate the clinical utility of protein kinase inhibitors as therapeutic agents in chronic myelogenous leukemia that may be applicable to MM (27, 28). These observations suggest that small molecule inhibitors of signal transducing transforming proteins may have clinical potential and represent effective and novel approaches to treatment of neoplastic disease, including MM.13


   Recommendations for Future Research
Top
 Abstract
 Introduction
 Growth Control, Survival, and...
 Novel Treatment Approaches
 Recommendations for Future...
References
 
Cell growth and apoptosis are essential, yet opposing, cellular processes. Cross-talk between these signaling pathways regulates the growth and survival of tumor cells. Characterization of the mechanisms regulating myeloma growth and resistance to apoptosis in vitro provides a framework for understanding potential ways to specifically inhibit cell growth and/or trigger apoptosis.3 An understanding of the apoptotic pathways is instrumental to the development of new therapies that will enable us to pinpoint where to attack tumor cells.14 Defining the signaling pathways mediating growth and survival, as well as angiogenesis, may help derive new and effective treatment strategies in MM.3 Approaches to blocking signal transduction pathways mediated by IL-6 and other cytokines may enhance cytotoxic drug activity (3).

In addition to signaling pathways, further research is needed to identify ways that the microenvironment, including cell adhesion, influences how cells respond to immune surveillance. Interactions between tumor cells and environmental factors may help to explain not only the pathogenesis of malignant disease but also the protective mechanisms contributing to the selection and outgrowth of drug-resistant tumors (3).

Studies of signal transduction will lead the way into the next generation of anticancer agents. It is unlikely that new alkylating agents or new anthracyclines will have a huge impact on myeloma therapy. We need to further investigate what goes on in the normal cell and understand how it differs from a malignant cell to develop a new generation of anticancer compounds.7 Further definition of the heterologous network of growth, survival, and apoptotic factors may provide clues to the development of better treatments of MM and other myeloid malignancies.15


   Acknowledgments
 
We thank the roundtable participants: Dr. Julian Adams, Millenium Pharmaceuticals (Cambridge, MA); Dr. Kenneth Anderson, Dana-Farber Cancer Institute (Boston, MA); Dr. James R. Berenson, Cedars-Sinai Medical Center and University of California, Los Angeles, School of Medicine (Los Angeles, CA); Dr. P. Leif Bergsagel, Weill Medical College of Cornell University (New York, NY); Dr. Finbarr E. Cotter, FRCP, FRC Path, Department of Experimental Hematology, St. Bartholomew’s and the Royal London School of Medicine (London, UK); Dr. Dharminder Chauhan, Dana-Farber Cancer Institute (Boston, MA); Dr. Selina Chen-Kiang, Weill Medical College of Cornell University (New York, NY); Dr. William S. Dalton, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida (Tampa, FL); Dr. David A. Frank, Dana-Farber Cancer Institute, Harvard Medical School (Boston, MA); Dr. Diane F. Jelinek, Department of Immunology, Mayo Graduate and Medical Schools, Mayo Clinic (Rochester, MN); Dr. Alan J. Kraker, Pfizer Global Research and Development, Ann Arbor Laboratories (Ann Arbor, MI); Dr. Dirk B. Mendel, Sugen, Inc. (South San Francisco, CA); Dr. Nikhil Munshi, University of Arkansas for Medical Sciences (Little Rock, AR); Dr. Kenneth Nilsson, Department of Genetics and Pathology, Laboratory of Tumor Biology, Rudbeck Laboratory, University of Uppsala (Uppsala, Sweden); Dr. Klaus Podar, Dana-Farber Cancer Institute, Harvard Medical School (Boston, MA); Dr. Steven T. Rosen, Northwestern University School of Medicine and Cancer Center at Northwestern University (Chicago, IL); Dr. Said Sebti, H. Lee Moffitt Cancer Center (Tampa, FL); and Dr. A. Keith Stewart, Princess Margaret Hospital (Toronto, Ontario, Canada).


   Footnotes
 
1 To whom requests for reprints should be addressed, at H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL 33612. Phone: (813) 615-4260; E-mail: dalton{at}moffitt.usf.edu. Back

2 The abbreviations used are: MM, multiple myeloma; IL, interleukin; FGFR, fibroblast growth factor receptor; BMSC, bone marrow stromal cell; STAT, signal transducer and activator of transcription; JAK, Janus-activated kinase; MAPK, mitogen-activated protein kinase; VEGF, vascular endothelial growth factor; NF, nuclear factor; FTase, farnesyltransferase; FTI, farnesyltransferase inhibitor; c-FLIPL, cellular-FLICE-like inhibitory protein-long; 8-Cl-Ado, 8-chloro-adenosine. Back

3 D. Chauhan. Apoptotic and survival proteins as novel therapeutic targets in multiple myeloma. Presented at: Cell Signaling in Myeloma: Regulation of Growth and Apoptosis. Banff, Alberta, Canada: May 3–4, 2001. Back

4 P. L. Bergsagel. FGFR3 signaling in t(4;14) myeloma. Presented at: Cell Signaling in Myeloma: Regulation of Growth and Apoptosis. Banff, Alberta, Canada: May 3–4, 2001. Back

5 A. K. Stewart. FGFR-3 signaling in myeloma and therapeutic intervention. Presented at: Cell Signaling in Myeloma: Regulation of Growth and Apoptosis. Banff, Alberta, Canada: May 3–4, 2001. Back

6 S. Chen-Kiang. IL-6 and TNF signaling in plasma cells. Presented at: Cell Signaling in Myeloma: Regulation of Growth and Apoptosis. Banff, Alberta, Canada: May 3–4, 2001. Back

7 D. Frank. STAT signal transduction in tumor development. Presented at: Cell Signaling in Myeloma: Regulation of Growth and Apoptosis. Banff, Alberta, Canada: May 3–4, 2001. Back

8 J. Berenson. New inhibitors of NF-{kappa}B signaling and angiogenesis in myeloma. Presented at: Cell Signaling in Myeloma: Regulation of Growth and Apoptosis. Banff, Alberta, Canada: May 3–4, 2001. Back

9 D. Mendel. Small molecule tyrosine kinase inhibitors as antiangiogenic agents for the treatment of hematologic malignancies. Presented at: Cell Signaling in Myeloma: Regulation of Growth and Apoptosis. Banff, Alberta, Canada: May 3–4, 2001. Back

10 F. E. Cotter. Antisense strategies for malignancy. Presented at: Cell Signaling in Myeloma: Regulation of Growth and Apoptosis. Banff, Alberta, Canada: May 3–4, 2001. Back

11 S. Sebti. Farnesyl transferase and geranylgeranyltransferase I inhibitors in cancer therapy: important mechanistic and bench-to-bedside issues. Presented at: Cell Signaling in Myeloma: Regulation of Growth and Apoptosis. Banff, Alberta, Canada: May 3–4, 2001. Back

12 S. Rosen. 8-Chloro adenosine-mediated cytotoxicity in multiple myeloma. Presented at: Cell Signaling in Myeloma: Regulation of Growth and Apoptosis. Banff, Alberta, Canada: May 3–4, 2001. Back

13 A. J. Kraker. Effects of inhibitors of tyrosine kinase on phosphorylation, in vitro cell growth, and in vivo tumor growth. Presented at: Cell Signaling in Myeloma: Regulation of Growth and Apoptosis. Banff, Alberta, Canada: May 3–4, 2001. Back

14 K. Nilsson. Regulation of growth and apoptosis in human multiple myeloma cell lines: Presented at: Cell Signaling in Myeloma: Regulation of Growth and Apoptosis. Banff, Alberta, Canada: May 3–4, 2001. Back

15 K. Anderson. Introduction and overview. Presented at: Cell Signaling in Myeloma: Regulation of Growth and Apoptosis. Banff, Alberta, Canada: May 3–4, 2001. Back

Received 4/29/02; revised 10/11/02; accepted 10/17/02.


   References
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 Abstract
 Introduction
 Growth Control, Survival, and...
 Novel Treatment Approaches
 Recommendations for Future...
 References
 

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