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A multi-targeted approach to treating bone metastases
C H A P T E R
54 A multi-targeted approach to treating bone metastases Daniel F Camacho1, Kenneth J Pienta2 1
Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA 2 Brady Urological Institute, Baltimore, MD, USA
INTRODUCTION Bone metastases are a major cause of morbidity and ultimately mortality for thousands of patients suffering from cancer worldwide each year. It is conservatively estimated that 280,000 U.S. adults had bone metastases at the end of 20081. In the vast majority of cases, cancer continues to be an incurable disease once it has spread from its primary site to osseous sites2. The traditional paradigm for treating metastatic cancer focuses on designing therapies to kill replicating tumor cells, but it has now been demonstrated that targeting the bone microenvironment can improve therapeutic benefit. Cancer cells exist within a complex environment requiring the cooperation, or at a minimum, the undermining, of normal functions of multiple normal cell types. Deeper understanding of the role of the tumor microenvironment has led to a paradigm shift in the treatment of bone metastases and continuing evolution of treatment requires a further understanding of the vicious cycle in which tumor cells interact with normal host cells of the bone microenvironment.
A MODEL FOR SUCCESSFUL CANCER METASTASIS TO BONE The spread of tumor cells to the bone follows the paradigm established by Stephen Paget in 1889 of seed and soil: the tumor cell (seed) invades the marrow space (fertile soil) to successfully form metastatic lesions3–5. We have extended this paradigm and have described metastasis in terms of successful migration from a point of origin to a distant site utilizing ecological principles (Figure 54.1). Cancer cells must successfully leave the primary tumor environment (emigration), travel to a new site (migration), land and establish themselves (immigration), and, finally, flourish in their new environment (naturalization)6. Each of these steps requires the acquisition of properties or traits that are usually tightly regulated in non-cancerous cells to maintain host homeostasis. Early in the life of a tumor, cells grow at an uncontrollable rate7. As the cancer grows, it must be supplied by new blood vessels or cells start to die from a lack of nutrient supply8. Hence, hypoxia creates a “famine” environment for the tumor, analogous to the potato famine in Ireland which started emigration to new countries6. Emigration, however, is only the first step in successful migration. Tumor cells, like migrants, must survive a journey to a distant destination and must find a hospitable place to land, establish themselves, and flourish. To accomplish successful metastasis to the bone marrow, cancer cells hijack several properties exhibited by normal cells that use the circulation and bone marrow as their natural environment. Hypoxia, as occurs in a tumor cell mass, leads to the upregulation of HIF-1a. Increased expression of this factor activates several cellular programs that mimic those expressed by hematopoietic progenitor cells (HPCs). This includes increased expression of CXC chemokine receptor 4 (CXCR4), the receptor for stromal derived factor-1 (SDF-1, CXCL12). Multiple tumor types, including breast, prostate, and multiple myeloma exhibit osteotropism through mimicry of HPCs which use this receptor to migrate to the bone marrow through chemoattraction to the CXCL12 secreted by osteoblasts9–11. Moreover, CXCL12 signaling through CXCR4 triggers an immigrant phenotype by triggering the adhesion of these cells to bone marrow endothelial cells Bone Cancer. DOI: 10.1016/B978-0-12-416721-6.00054-6 Copyright © 2015 Elsevier Inc. All rights reserved
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FIGURE 54.1 Metastasis mimics the behavior of invasive species in ecosystems. The generalized steps necessary for a species to invade a new ecologic niche are directly analogous to the steps of cancer metastasis (modified from Chen and Pienta91). The transport, establishment, and spread of invasive species can be compared to the intravasation of cancer cells into the blood stream (emigration), where they are transported to a target organ (migration) where they extrasavate (immigration). The cancer cells then enter a dormant period (lag period for invasive species) before growing, and displacing the host cells (native species). This results in damage to the local organ and eventually the host patient.
and osteoblasts through activation of CD164 and avb2 integrin12–14. The high frequency of prostate cancer cell metastasis to bone, which occurs in virtually all patients, may be explained by the fact that these prostate cancer cells also bind to annexin-2, an adhesive-localization molecule used by HPCs15–17. Once established in the bone, metastatic cells flourish (naturalize) by utilizing a supporting framework of multiple host cells (Figure 54.2). An understanding of the biologic underpinnings of these interactions has allowed the development of several therapeutic strategies that target more than simply the cancer cells. Importantly, these strategies target supportive host cells as well as the complex interactions between the cancer cells and the host environment in addition to the crosstalk between the different host cells co-opted to support tumor growth (Figure 54.2 and Table 54.1).
TARGETING OSTEOCLAST FUNCTION Osteoclasts are active in bone remodeling and offer targets for interruption of the bone destruction associated with metastases. These cells are known to be activated by a variety of growth factors, many of which are secreted by cancer cells (e.g. PTHrP, IL-6, IL-8, IL-11, TNF, and M-CSF)18. The activation of osteoclasts leads to the catalysis of the bone matrix and subsequent release of multiple growth factors and cytokines which are capable of stimulating metastatic growth in the bone, thereby establishing the vicious cycle of further cancer growth and further bone destruction19,20. Bisphosphonates are pyrophosphate analogs which bind exposed bone matrix and block bone resorption by inducing osteoclast apoptosis. Furthermore, nitrogen-containing bisphosphonates halt osteoclast function and activation by inhibiting farnesyl diphosphate synthase in the biosynthetic mevalonate pathway21,22. Poisoning of osteoclast function has been used in multiple tumor types, including prostate, breast, lung, and multiple myeloma to decrease the morbidity of skeletal metastases23–25. For example, zoledronic acid has been shown to decrease skeletal-related events such as fractures in many groups of cancer patients, including those with androgen-independent prostate cancer, lung cancer, renal cancer, and multiple myeloma26. The receptor activator of nuclear factor-kB ligand (RANKL), its receptor (RANK), and its natural decoy receptor osteoprotegerin (OPG) are the final effector molecules of osteoclastic bone resorption27. Interruption of this axis allows for the inhibition of osteoclast function. RANKL inhibition leads to osteoclast apoptosis. The fully human monoclonal antibody denosumab is directed against RANKL and is approved for the treatment of osteoporosis or for delaying skeletal-related events in patients with bone metastases secondary to breast or prostate cancer28. The Src pathway is also known to regulate normal osteoclast function29. Several agents offer promise in inhibiting this pathway for therapeutic benefit in the context of metastatic cancer. Dasatinib is a tyrosine kinase inhibitor that is approved for the treatment of chronic myelogenous leukemia and Philadelphia-chromosome positive acute lymphoblastic leukemia30. Dasatinib has been shown to inhibit the proliferation, survival, and activity of osteoclasts by blocking signaling through c-fms in vivo31. The use of this agent for treating cancer metastases is currently under clinical evaluation. III. BONE METASTASES
Targeting Osteoclast Function
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FIGURE 54.2 Tumor cell–bone microenvironment interactions. The relationship between the tumor cell and the surrounding tissue is complex. Bone extracellular matrix, stromal cells, osteoblasts, osteoclasts, hematopoietic progenitor cells, endothelial cells, and cells of the immune system coordinate a sophisticated series of interactions with cancer cells to promote tumor cell survival and proliferation. The ability of targeted therapies to interrupt the vicious tumor-supportive environment is critical to treatment. See text for a description of agents.
TABLE 54.1 Treating bone metastases: agents and their presumed targets within cells of the bone microenvironment Cell type
Target
Example agents (Ref)
Osteoclast
Pyrophosphate (bone matrix)
Bisphosphonates26, samarium38, strontium39, Alpharadin44
RANKL
Denosumab28
SRC
Dasatinib30
Osteoblast
Proteosome
Bortezomib32–37
Endothelial cell
VEGF
Bevacizumab47,48, VEGF-TRAP, lenalidomide45, thalidomide46
VEGFR
Sunitinib, vatalanib, sorafenib, cabozantinib52
avb3/5 integrin
Cilengitide53, Abegrin57, CNTO9554,55
Hematopoietic progenitor cell
Stromal-derived factor-1
Filgrastim85, AMD310086
Immunologic activation
Macrophages
Carlumab82,83, MLN1202, bisphosphonates84, pantoprazole84
T cells (CTLA-4, PD-1)
Ipilimumab64–67, nivolumab69
Complement (CD55)
105AD771
Dendritic cells
Sipuleucel-T58–60, Lapuleucel-T61, GVAX62, PROSTVAC63,64
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54. A multi-targeted approach to treating bone metastases
TARGETING OSTEOBLAST FUNCTION Osteoblasts play a key role in the bone metastatic microenvironment. Several growth factors (e.g. insulin-like growth factor 1, insulin-like growth factor 2, and TGF-b) produced by osteoblasts act as chemoattractants for cancer cells, as well as promote tumor growth and proliferation32. Other factors produced by osteoblasts (TNF-a, IL-1b) reduce cancer cell growth32. A strategy of clinical importance is to turn on osteoblast function to ameliorate the inappropriate osteolytic activity as seen in diseases such as multiple myeloma33. In bone metastasis where there is a predominantly lytic component, osteoblast activity is inappropriately repressed34–36. The proteasome inhibitor bortezomib has been demonstrated to activate osteoblast activity and is an effective therapy in both multiple myeloma and mantle cell lymphoma37, suggesting that this agent may be a useful addition in treating lytic lesions induced by other cancers33–36.
TARGETING BONE MATRIX Another approach for creating an inhospitable microenvironment for tumor cells in the bone involves the use of systemic radioisotopes38,39. Radioisotopes are effective therapeutic agents for the management and palliation of bone-specific disease due to the high levels of radioisotope retention by bone metastases; retention of these substances is high in damaged bone, less in normal bone tissue, and is not seen outside of bone. The most common radioisotopes used are strontium-89 and samarium-153, which are both beta-emitting isotopes38,39. The mechanism of radiotherapy-induced palliation is associated with the combination of the radioisotope with the calcium component of hydroxyapatite in damaged bone. Radioisotopes have been successfully utilized to palliate pain in patients with bone metastases40,41. Adding systemic radioisotopes to chemotherapy regimens for patients with advanced prostate cancer appeared to increase response rates and survival42,43. Recently, the alpha-emitting radioisotope radium-223 has been investigated in the advanced prostate cancer setting44. Alpha-emitting radioisotopes deliver more energy through a shorter tissue range in comparison to beta-emitting radioisotopes, and so offer the advantage of less toxicity to normal marrow44. In the phase III ALSYMPCA trial, which focused on symptomatic, bone-metastatic mCRPC patients, Radium-223 (Alpharadin®) was shown to be the first bone-targeted radiopharmaceutical to demonstrate a survival benefit and it was recently approved by the FDA to treat prostate cancer bone metastases44.
TARGETING ENDOTHELIAL CELL FUNCTION Cancer metastases, even those in the bone marrow microenvironment, require blood vessels for growth8. Multiple strategies are being pursued to block blood vessel proliferation, including the blockade of the interaction of VEGF with its receptors. This can be done by decreasing VEGF production, through antibodies to VEGF (i.e. bevacizumab), antibodies to the VEGF receptors to themselves, or by inhibiting the tyrosine kinase activity of the receptors. The secretion of VEGF by tumor cells as well as many of the supporting cells of the microenvironment can be inhibited by agents such as thalidomide and lenalidomide45,46. These agents have demonstrated significant activity in multiple myeloma. The efficacy of directly blocking the growth factor with the anti-VEGF antibody bevacizumab in prostate cancer did not appear to be effective, but this may be due to the addition of the drug to late in the disease course47,48. Several small molecule inhibitors of tyrosine kinase activity have demonstrated activity in clinical trials in multiple cancers that metastasize to bone49–51. Cabozantinib is a c-MET and VEGFR2 inhibitor currently under investigation for advanced prostate cancer52. Another strategy targets integrin binding to block the sprouting of new blood vessels into the tumor microenvironment53–57. Tumor-related blood vessels sprout into the extracellular matrix through a process that is mediated by the integrins avb3 and avb5 which bind to a variety of ECM molecules including vitronectin54. Integrins avb3 and avb5 bind molecules containing the amino acid sequence Arg-Gly-Asp (RGD), allowing endothelial cells to attach to the extracellular matrix54. EMD121974 (Cilengitide), a cyclized pentapeptide containing the amino acid sequence RGD, is in clinical trials for patients with advanced prostate cancer53. Two different antibodies that block the avb3 and avb5 integrins, Abegrin and CNTO95, are also under clinical development for patients with bone metastases54–57. III. BONE METASTASES
Targeting Tumor Associated Macrophages
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ENHANCING IMMUNE RESPONSE Inhibition of cancer growth by host immune response enhancement is being pursued with a variety of therapies, each targeting different immune components or processes. Current immune targets include antigen presenting cells, immune regulatory mechanisms, and the complement system. Sipuleucel-T (APC8015, Provenge®) was approved by the FDA in 2010 as an option for patients with metastatic castrate-resistant prostate cancer58. Provenge® therapy involves the exposure of autologous antigen presenting cells to PA2024 with subsequent reintroduction to the patient59. PA2024 is a fusion protein consisting of prostatic acid phosphatase (PAP), an antigen expressed specifically in prostate tissue and in 95% of prostate cancers, in addition to GM-CSF, which promotes presentation of the protein to APCs60. Sensitization of immune cells to PAP is thought to result. Similarly, Lapuleucel-T (APC8024, Neuvenge®) is an autologous active cellular immunotherapy, currently in clinical trials, that activates APCs with a HER-2 based antigen to treat breast cancer patients61. Other therapies aim to stimulate antigen presenting cells. GVAX is an immunotherapy that is comprised of two irradiated prostate cancer cell lines that have been genetically modified to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF), which encourages the development of APCs62. GVAX cancer vaccines are currently in phase III clinical trials for treatment of prostate cancer and in various stages of clinical study in leukemia, myeloma, melanoma, as well as breast and colorectal cancers. A non-cellular vaccine, PROSTVAC, is a pox-based virus against PSA which also contains three costimulatory molecules important for APC stimulation: B-lymphocyte activation antigen B7-1 (B7.1), intercellular adhesion molecule 1 (ICAM-1), and lymphocyte function-associated antigen 3 (LFA-3)63,64. PROSTVAC is currently in phase III trials. Another important approach is the induced dysregulation of immune regulatory mechanisms which impede antitumoral response, two of which include the CTLA-4 and the PD-1 pathways. Blockade of the T-cell inhibitory receptor CTL-associated antigen-4 (CTLA-4) using the monoclonal antibody ipilimumab provides one method for boosting and extending T-cell response and is under active clinical investigation to elicit anti-tumor immunity. Ipilimumab, approved for use in melanoma, is currently in phase III clinical trials for metastatic prostate cancer (NCT00861614 and NCT01057810)64 and in other cancers65–67. Blockade of Treg cells is actively being pursued68. PD-1 (CD279) signaling in T cells is responsible for tolerance and exhaustion of T cells69. Anti-PD-1 antibodies are in various phases of clinical investigation with the goal of inhibiting immune activation against tumor cells. Nivolumab (BMS-936558) is one such antibody which binds PD-1 and blocks is interaction with its two receptors69. Nivolumab has yielded favorable outcomes in the treatment of melanoma, renal cell cancer, and non-small cell lung cancer in phase I and II trials, and other anti-PD-1 drugs are expected to follow suit in the near future69. An alternative approach within the concept of targeting the immune system is to target the complement system. CD55 is a membrane-bound complement regulatory protein overexpressed in a variety of cancers which protects cells against complement-mediated lysis70. Currently, an anti-idiotypic monoclonal antibody, 105AD7, is in clinical trials as a cancer vaccine that mimics the tumor-associated antigen CD55 and has demonstrated the applicability of vaccine-targeted approaches in cancer treatment71. These strategies could be used in conjunction with chemotherapy as well as primary cell therapy early in the disease course.
TARGETING TUMOR ASSOCIATED MACROPHAGES Many malignant tumors are infiltrated with cancer-promoting tumor-associated macrophages72. Macriphages are an essential component of the innate immune system and are derived from myeloid progenitor cells in the bone marrow compartment. These progenitor cells develop into pro-monocytes and are released into the circulation where they differentiate into monocytes. Monocytes then migrate into tissues where they differentiate into resident tissue macrophages and help to protect these sites from infection and injury. Monocytes that migrate into cancerous tissues, on the other hand, differentiate into tumor-associated macrophages (TAMs), which are capable of promoting tumor growth and metastasis. Evidence suggests that, in addition to their role in innate immunity, macrophages also play an important role in the regulation of angiogenesis in both normal and diseased tissues, including malignant tumors73–75. When associated with tumors, macrophages demonstrate functional “polarization” towards one of two phenotypically different subsets of macrophages: TH1 (also M1) macrophages or TH2 (also M2) macrophages76,77. The M2 macrophage promotes tumor growth and development through stimulation of angiogenesis as well as matrix dissolution76. Therapeutic blockade of TAMs by preventing their recruitment is of clinical interest. Monocyte chemoattractant protein-1 (MCP-1, CCL2) is an important chemokine that is known to regulate monocyte/macrophage trafficking 2. Pre-clinical and clinical aspects
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and has been reported to be present in several solid tumor beds78–81. The blockade of TAMs induced by CCL2 using the anti-CCL2 antibody CNTO888, or carlumab, did not show anti-tumor activity as a single agent in metastatic castration-resistant prostate cancer82 but is under clinical investigation against other solid tumors83. The lack of efficacy was demonstrated to be due to an inability of the antibody to block free CCL2 in patients. Treatment resulted in an increase in free CCL2 as the host responded to the presence of the antibody blocking production. The CCR2specific monoclonal antibody MLN1202 is also under investigation for this purpose (NCT01015560). Other therapeutic targets against TAMs include the direct killing of TAMs (by bisphosphonates), repolarization of M2 macrophages (by pantoprazole, NCT01163903), and the inhibition of their pro-tumor function84.
TARGETING HEMATOPOIETIC PROGENITOR CELLS Hematopoietic progenitor cells (HPCs) are a critical part of the bone microenvironment. While it may be impractical to target interactions between HPCs and cancer cells at this time, it is clear that cancer cells metastasizing to bone marrow hijack several properties exhibited by HPCs that traffic through the circulation and bone marrow2,6. These mechanisms offer therapeutic targets which are currently under pre-clinical investigation. Prostate cancer, breast cancer, and multiple myeloma cells mimic hematopoietic stem/progenitor cells by upregulating the expression of CXC chemokine receptor 4 (CXCR4), which is the receptor for stromal-derived factor-1 (SDF-1, also known as CXCL12)9. This results in chemoattraction to the SDF-1/CXCL12 secreted by osteoblasts9. Disruption of the SDF-1/CXCR4 axis is the target of multiple agents. Filgrastim is a G-CSF analog clinically used to increase the number of HSCs in the blood for transplantation by degrading SDF-1 in the marrow via neutrophil elastase85. AMD3100 is an agent which directly prohibits SDF-1 from binding CXCR486. Filgrastim and AMD3100 are experimentally shown to mobilize metastatic cancer cells from the bone marrow niche in pre-clinical prostate86 and breast87 cancer models. This could be utilized in a therapeutic strategy to mobilize cancer cells “hidden” in the bone marrow out into the circulation where they could be targeted.
BONE AND DRUG RESISTANCE The bone marrow microenvironment is a stressful, yet ideal location for metastatic tumor cells as several of its components lead to drug resistance. Soluble factors and adhesion to extracellular matrix proteins facilitate the survival and proliferation of resident cells and can provide a sanctuary for tumor cell survival88. As a result, this microenvironment can provide for therapeutic resistance. Several soluble factors in the bone marrow microenvironment encourage tumor cell survival, potentially in the face of therapeutic activity, via soluble factor-mediated drug resistance. Bone marrow stromal cells produce IL-6, which upregulates the transcription of Bcl-XL in tumor cells and thus promotes cell survival88. IL-6-mediated drug resistance also occurs via STAT1, STAT3, and gp13088. Cancer cell adhesion to the bone marrow ECM proteins is another source of therapeutic resistance in multiple myeloma. Fibronectin and hyaluronan are two major components of the bone marrow ECM and have been shown to significantly contribute to drug resistance in multiple myeloma89. Fibronectin adhesion leads to drug resistance by antagonizing Fas-mediated apoptosis, causing cell cycle arrest in the G1 phase, and preventing drug-induced DNA damage89. Hyaluronin, on the other hand, forms a gel-like network that keeps autocrine and paracrine survival factors accessible to cancer cells and may serve to physically shield drugs from target cells89.
CONCLUSION Metastatic cancer in the skeleton is the result of complex interplay between the cancer cells themselves and the bone microenvironment, resulting in a heterogeneous disease that induces a combination of osteolytic and osteoblastic lesions. The pathogenesis of bone metastases includes interactions between the cancer cells and osteoclasts, osteoblasts, endothelial cells, stromal cells, hematopoietic progenitor cells, cells of the immune system, and the bone matrix. A paradigm shift from the early treatment strategy primarily targeting tumor cells directly, i.e. traditional chemotherapy, to new therapies that exploit the interactions and contributions of various microenvironmental cells and elements to the development of metastatic lesions is being explored and exploited to improve the lives of cancer patients living with skeletal metastases. However, there is a need for continued therapeutic development based III. BONE METASTASES
REFERENCES
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on this multi-targeted therapy against the bone microenvironment. Furthermore, while strides in therapy have come from developing therapies targeting single components of the networks supporting cancer growth, the co-targeting of the various tumor-supportive elements presents a new paradigm in cancer treatment. By interrupting multiple cooperating pathways at the tumor cellular, primary and metastatic microenvironmental, and systemic levels, “scaled network disruption”90,91 will be an important therapeutic paradigm.
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PROVENGE (Sipuleucel-T) in prostate cancer: the first FDA-approved therapeutic cancer vaccine. Clin Cancer Res Jun. 2011;17(11):3520–6. 59. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010;363(5):411–22. 60. So-Rosillo R, Small EJ. Sipuleucel-T (APC8015) for prostate cancer. Exp Rev Anticancer Ther 2006;6(9):1163–7. 61. Park JW, Melisko ME, Esserman LJ, et al. Treatment with autologous antigen-presenting cells activated with the HER-2-based antigen Lapuleucel-T: results of a phase I study in immunologic and clinical activity in HER-2 overexpressing breast cancer. J Clin Oncol Aug. 2007;25(24):3680–7. 62. de Gruijl TD, van den Eertwegh AJM, Pinedo HM, et al. Whole-cell cancer vaccination: from autologous to allogeneic tumor- and dendritic cell-based vaccines. Cancer Immunol Immunother Oct. 2008;57(10):1569–77. 63. Kantoff PW, Schuetz TJ, Blumenstein BA, et al. Overall survival analysis of a phase II randomized controlled trial of a poxviral-based PSAtargeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol Mar. 2010;28(7):1099–105. 64. Dayyani F, Gallick GE, Logothetis CJ, et al. Novel therapies for metastatic castrate-resistant prostate cancer. J Natl Cancer Inst Nov. 2011;103(22):1665–75. 65. Reck M, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-diseasesmall-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Ann Oncol Jan. 2013;24(1):75–83. 66. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncology May 2012;13(5):459–65. 67. Sun J, Schiffman J, Raghunath A, et al. Concurrent decrease in IL-10 with development of immune-related adverse events in a patient treated with anti-CTLA-4 therapy. Cancer Immun Jan. 2008;8:9–15. 68. Fulton A, Miller F, Weise A, et al. Prospects of controlling breast cancer metastasis by immune intervention. Breast Disease 2007;26:115–27. 69. Melero I, Grimaldi AM, Perez-Gracia JL, et al. Clinical development of immunostimulatory monoclonal antibodies and opportunities for combination. Clin Cancer Res Mar. 2013;19(5):997–1008.
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2. Pre-clinical and clinical aspects
54 A multi-targeted approach to treating bone metastases Daniel F Camacho1, Kenneth J Pienta2 1
Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA 2 Brady Urological Institute, Baltimore, MD, USA
INTRODUCTION Bone metastases are a major cause of morbidity and ultimately mortality for thousands of patients suffering from cancer worldwide each year. It is conservatively estimated that 280,000 U.S. adults had bone metastases at the end of 20081. In the vast majority of cases, cancer continues to be an incurable disease once it has spread from its primary site to osseous sites2. The traditional paradigm for treating metastatic cancer focuses on designing therapies to kill replicating tumor cells, but it has now been demonstrated that targeting the bone microenvironment can improve therapeutic benefit. Cancer cells exist within a complex environment requiring the cooperation, or at a minimum, the undermining, of normal functions of multiple normal cell types. Deeper understanding of the role of the tumor microenvironment has led to a paradigm shift in the treatment of bone metastases and continuing evolution of treatment requires a further understanding of the vicious cycle in which tumor cells interact with normal host cells of the bone microenvironment.
A MODEL FOR SUCCESSFUL CANCER METASTASIS TO BONE The spread of tumor cells to the bone follows the paradigm established by Stephen Paget in 1889 of seed and soil: the tumor cell (seed) invades the marrow space (fertile soil) to successfully form metastatic lesions3–5. We have extended this paradigm and have described metastasis in terms of successful migration from a point of origin to a distant site utilizing ecological principles (Figure 54.1). Cancer cells must successfully leave the primary tumor environment (emigration), travel to a new site (migration), land and establish themselves (immigration), and, finally, flourish in their new environment (naturalization)6. Each of these steps requires the acquisition of properties or traits that are usually tightly regulated in non-cancerous cells to maintain host homeostasis. Early in the life of a tumor, cells grow at an uncontrollable rate7. As the cancer grows, it must be supplied by new blood vessels or cells start to die from a lack of nutrient supply8. Hence, hypoxia creates a “famine” environment for the tumor, analogous to the potato famine in Ireland which started emigration to new countries6. Emigration, however, is only the first step in successful migration. Tumor cells, like migrants, must survive a journey to a distant destination and must find a hospitable place to land, establish themselves, and flourish. To accomplish successful metastasis to the bone marrow, cancer cells hijack several properties exhibited by normal cells that use the circulation and bone marrow as their natural environment. Hypoxia, as occurs in a tumor cell mass, leads to the upregulation of HIF-1a. Increased expression of this factor activates several cellular programs that mimic those expressed by hematopoietic progenitor cells (HPCs). This includes increased expression of CXC chemokine receptor 4 (CXCR4), the receptor for stromal derived factor-1 (SDF-1, CXCL12). Multiple tumor types, including breast, prostate, and multiple myeloma exhibit osteotropism through mimicry of HPCs which use this receptor to migrate to the bone marrow through chemoattraction to the CXCL12 secreted by osteoblasts9–11. Moreover, CXCL12 signaling through CXCR4 triggers an immigrant phenotype by triggering the adhesion of these cells to bone marrow endothelial cells Bone Cancer. DOI: 10.1016/B978-0-12-416721-6.00054-6 Copyright © 2015 Elsevier Inc. All rights reserved
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FIGURE 54.1 Metastasis mimics the behavior of invasive species in ecosystems. The generalized steps necessary for a species to invade a new ecologic niche are directly analogous to the steps of cancer metastasis (modified from Chen and Pienta91). The transport, establishment, and spread of invasive species can be compared to the intravasation of cancer cells into the blood stream (emigration), where they are transported to a target organ (migration) where they extrasavate (immigration). The cancer cells then enter a dormant period (lag period for invasive species) before growing, and displacing the host cells (native species). This results in damage to the local organ and eventually the host patient.
and osteoblasts through activation of CD164 and avb2 integrin12–14. The high frequency of prostate cancer cell metastasis to bone, which occurs in virtually all patients, may be explained by the fact that these prostate cancer cells also bind to annexin-2, an adhesive-localization molecule used by HPCs15–17. Once established in the bone, metastatic cells flourish (naturalize) by utilizing a supporting framework of multiple host cells (Figure 54.2). An understanding of the biologic underpinnings of these interactions has allowed the development of several therapeutic strategies that target more than simply the cancer cells. Importantly, these strategies target supportive host cells as well as the complex interactions between the cancer cells and the host environment in addition to the crosstalk between the different host cells co-opted to support tumor growth (Figure 54.2 and Table 54.1).
TARGETING OSTEOCLAST FUNCTION Osteoclasts are active in bone remodeling and offer targets for interruption of the bone destruction associated with metastases. These cells are known to be activated by a variety of growth factors, many of which are secreted by cancer cells (e.g. PTHrP, IL-6, IL-8, IL-11, TNF, and M-CSF)18. The activation of osteoclasts leads to the catalysis of the bone matrix and subsequent release of multiple growth factors and cytokines which are capable of stimulating metastatic growth in the bone, thereby establishing the vicious cycle of further cancer growth and further bone destruction19,20. Bisphosphonates are pyrophosphate analogs which bind exposed bone matrix and block bone resorption by inducing osteoclast apoptosis. Furthermore, nitrogen-containing bisphosphonates halt osteoclast function and activation by inhibiting farnesyl diphosphate synthase in the biosynthetic mevalonate pathway21,22. Poisoning of osteoclast function has been used in multiple tumor types, including prostate, breast, lung, and multiple myeloma to decrease the morbidity of skeletal metastases23–25. For example, zoledronic acid has been shown to decrease skeletal-related events such as fractures in many groups of cancer patients, including those with androgen-independent prostate cancer, lung cancer, renal cancer, and multiple myeloma26. The receptor activator of nuclear factor-kB ligand (RANKL), its receptor (RANK), and its natural decoy receptor osteoprotegerin (OPG) are the final effector molecules of osteoclastic bone resorption27. Interruption of this axis allows for the inhibition of osteoclast function. RANKL inhibition leads to osteoclast apoptosis. The fully human monoclonal antibody denosumab is directed against RANKL and is approved for the treatment of osteoporosis or for delaying skeletal-related events in patients with bone metastases secondary to breast or prostate cancer28. The Src pathway is also known to regulate normal osteoclast function29. Several agents offer promise in inhibiting this pathway for therapeutic benefit in the context of metastatic cancer. Dasatinib is a tyrosine kinase inhibitor that is approved for the treatment of chronic myelogenous leukemia and Philadelphia-chromosome positive acute lymphoblastic leukemia30. Dasatinib has been shown to inhibit the proliferation, survival, and activity of osteoclasts by blocking signaling through c-fms in vivo31. The use of this agent for treating cancer metastases is currently under clinical evaluation. III. BONE METASTASES
Targeting Osteoclast Function
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FIGURE 54.2 Tumor cell–bone microenvironment interactions. The relationship between the tumor cell and the surrounding tissue is complex. Bone extracellular matrix, stromal cells, osteoblasts, osteoclasts, hematopoietic progenitor cells, endothelial cells, and cells of the immune system coordinate a sophisticated series of interactions with cancer cells to promote tumor cell survival and proliferation. The ability of targeted therapies to interrupt the vicious tumor-supportive environment is critical to treatment. See text for a description of agents.
TABLE 54.1 Treating bone metastases: agents and their presumed targets within cells of the bone microenvironment Cell type
Target
Example agents (Ref)
Osteoclast
Pyrophosphate (bone matrix)
Bisphosphonates26, samarium38, strontium39, Alpharadin44
RANKL
Denosumab28
SRC
Dasatinib30
Osteoblast
Proteosome
Bortezomib32–37
Endothelial cell
VEGF
Bevacizumab47,48, VEGF-TRAP, lenalidomide45, thalidomide46
VEGFR
Sunitinib, vatalanib, sorafenib, cabozantinib52
avb3/5 integrin
Cilengitide53, Abegrin57, CNTO9554,55
Hematopoietic progenitor cell
Stromal-derived factor-1
Filgrastim85, AMD310086
Immunologic activation
Macrophages
Carlumab82,83, MLN1202, bisphosphonates84, pantoprazole84
T cells (CTLA-4, PD-1)
Ipilimumab64–67, nivolumab69
Complement (CD55)
105AD771
Dendritic cells
Sipuleucel-T58–60, Lapuleucel-T61, GVAX62, PROSTVAC63,64
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TARGETING OSTEOBLAST FUNCTION Osteoblasts play a key role in the bone metastatic microenvironment. Several growth factors (e.g. insulin-like growth factor 1, insulin-like growth factor 2, and TGF-b) produced by osteoblasts act as chemoattractants for cancer cells, as well as promote tumor growth and proliferation32. Other factors produced by osteoblasts (TNF-a, IL-1b) reduce cancer cell growth32. A strategy of clinical importance is to turn on osteoblast function to ameliorate the inappropriate osteolytic activity as seen in diseases such as multiple myeloma33. In bone metastasis where there is a predominantly lytic component, osteoblast activity is inappropriately repressed34–36. The proteasome inhibitor bortezomib has been demonstrated to activate osteoblast activity and is an effective therapy in both multiple myeloma and mantle cell lymphoma37, suggesting that this agent may be a useful addition in treating lytic lesions induced by other cancers33–36.
TARGETING BONE MATRIX Another approach for creating an inhospitable microenvironment for tumor cells in the bone involves the use of systemic radioisotopes38,39. Radioisotopes are effective therapeutic agents for the management and palliation of bone-specific disease due to the high levels of radioisotope retention by bone metastases; retention of these substances is high in damaged bone, less in normal bone tissue, and is not seen outside of bone. The most common radioisotopes used are strontium-89 and samarium-153, which are both beta-emitting isotopes38,39. The mechanism of radiotherapy-induced palliation is associated with the combination of the radioisotope with the calcium component of hydroxyapatite in damaged bone. Radioisotopes have been successfully utilized to palliate pain in patients with bone metastases40,41. Adding systemic radioisotopes to chemotherapy regimens for patients with advanced prostate cancer appeared to increase response rates and survival42,43. Recently, the alpha-emitting radioisotope radium-223 has been investigated in the advanced prostate cancer setting44. Alpha-emitting radioisotopes deliver more energy through a shorter tissue range in comparison to beta-emitting radioisotopes, and so offer the advantage of less toxicity to normal marrow44. In the phase III ALSYMPCA trial, which focused on symptomatic, bone-metastatic mCRPC patients, Radium-223 (Alpharadin®) was shown to be the first bone-targeted radiopharmaceutical to demonstrate a survival benefit and it was recently approved by the FDA to treat prostate cancer bone metastases44.
TARGETING ENDOTHELIAL CELL FUNCTION Cancer metastases, even those in the bone marrow microenvironment, require blood vessels for growth8. Multiple strategies are being pursued to block blood vessel proliferation, including the blockade of the interaction of VEGF with its receptors. This can be done by decreasing VEGF production, through antibodies to VEGF (i.e. bevacizumab), antibodies to the VEGF receptors to themselves, or by inhibiting the tyrosine kinase activity of the receptors. The secretion of VEGF by tumor cells as well as many of the supporting cells of the microenvironment can be inhibited by agents such as thalidomide and lenalidomide45,46. These agents have demonstrated significant activity in multiple myeloma. The efficacy of directly blocking the growth factor with the anti-VEGF antibody bevacizumab in prostate cancer did not appear to be effective, but this may be due to the addition of the drug to late in the disease course47,48. Several small molecule inhibitors of tyrosine kinase activity have demonstrated activity in clinical trials in multiple cancers that metastasize to bone49–51. Cabozantinib is a c-MET and VEGFR2 inhibitor currently under investigation for advanced prostate cancer52. Another strategy targets integrin binding to block the sprouting of new blood vessels into the tumor microenvironment53–57. Tumor-related blood vessels sprout into the extracellular matrix through a process that is mediated by the integrins avb3 and avb5 which bind to a variety of ECM molecules including vitronectin54. Integrins avb3 and avb5 bind molecules containing the amino acid sequence Arg-Gly-Asp (RGD), allowing endothelial cells to attach to the extracellular matrix54. EMD121974 (Cilengitide), a cyclized pentapeptide containing the amino acid sequence RGD, is in clinical trials for patients with advanced prostate cancer53. Two different antibodies that block the avb3 and avb5 integrins, Abegrin and CNTO95, are also under clinical development for patients with bone metastases54–57. III. BONE METASTASES
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ENHANCING IMMUNE RESPONSE Inhibition of cancer growth by host immune response enhancement is being pursued with a variety of therapies, each targeting different immune components or processes. Current immune targets include antigen presenting cells, immune regulatory mechanisms, and the complement system. Sipuleucel-T (APC8015, Provenge®) was approved by the FDA in 2010 as an option for patients with metastatic castrate-resistant prostate cancer58. Provenge® therapy involves the exposure of autologous antigen presenting cells to PA2024 with subsequent reintroduction to the patient59. PA2024 is a fusion protein consisting of prostatic acid phosphatase (PAP), an antigen expressed specifically in prostate tissue and in 95% of prostate cancers, in addition to GM-CSF, which promotes presentation of the protein to APCs60. Sensitization of immune cells to PAP is thought to result. Similarly, Lapuleucel-T (APC8024, Neuvenge®) is an autologous active cellular immunotherapy, currently in clinical trials, that activates APCs with a HER-2 based antigen to treat breast cancer patients61. Other therapies aim to stimulate antigen presenting cells. GVAX is an immunotherapy that is comprised of two irradiated prostate cancer cell lines that have been genetically modified to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF), which encourages the development of APCs62. GVAX cancer vaccines are currently in phase III clinical trials for treatment of prostate cancer and in various stages of clinical study in leukemia, myeloma, melanoma, as well as breast and colorectal cancers. A non-cellular vaccine, PROSTVAC, is a pox-based virus against PSA which also contains three costimulatory molecules important for APC stimulation: B-lymphocyte activation antigen B7-1 (B7.1), intercellular adhesion molecule 1 (ICAM-1), and lymphocyte function-associated antigen 3 (LFA-3)63,64. PROSTVAC is currently in phase III trials. Another important approach is the induced dysregulation of immune regulatory mechanisms which impede antitumoral response, two of which include the CTLA-4 and the PD-1 pathways. Blockade of the T-cell inhibitory receptor CTL-associated antigen-4 (CTLA-4) using the monoclonal antibody ipilimumab provides one method for boosting and extending T-cell response and is under active clinical investigation to elicit anti-tumor immunity. Ipilimumab, approved for use in melanoma, is currently in phase III clinical trials for metastatic prostate cancer (NCT00861614 and NCT01057810)64 and in other cancers65–67. Blockade of Treg cells is actively being pursued68. PD-1 (CD279) signaling in T cells is responsible for tolerance and exhaustion of T cells69. Anti-PD-1 antibodies are in various phases of clinical investigation with the goal of inhibiting immune activation against tumor cells. Nivolumab (BMS-936558) is one such antibody which binds PD-1 and blocks is interaction with its two receptors69. Nivolumab has yielded favorable outcomes in the treatment of melanoma, renal cell cancer, and non-small cell lung cancer in phase I and II trials, and other anti-PD-1 drugs are expected to follow suit in the near future69. An alternative approach within the concept of targeting the immune system is to target the complement system. CD55 is a membrane-bound complement regulatory protein overexpressed in a variety of cancers which protects cells against complement-mediated lysis70. Currently, an anti-idiotypic monoclonal antibody, 105AD7, is in clinical trials as a cancer vaccine that mimics the tumor-associated antigen CD55 and has demonstrated the applicability of vaccine-targeted approaches in cancer treatment71. These strategies could be used in conjunction with chemotherapy as well as primary cell therapy early in the disease course.
TARGETING TUMOR ASSOCIATED MACROPHAGES Many malignant tumors are infiltrated with cancer-promoting tumor-associated macrophages72. Macriphages are an essential component of the innate immune system and are derived from myeloid progenitor cells in the bone marrow compartment. These progenitor cells develop into pro-monocytes and are released into the circulation where they differentiate into monocytes. Monocytes then migrate into tissues where they differentiate into resident tissue macrophages and help to protect these sites from infection and injury. Monocytes that migrate into cancerous tissues, on the other hand, differentiate into tumor-associated macrophages (TAMs), which are capable of promoting tumor growth and metastasis. Evidence suggests that, in addition to their role in innate immunity, macrophages also play an important role in the regulation of angiogenesis in both normal and diseased tissues, including malignant tumors73–75. When associated with tumors, macrophages demonstrate functional “polarization” towards one of two phenotypically different subsets of macrophages: TH1 (also M1) macrophages or TH2 (also M2) macrophages76,77. The M2 macrophage promotes tumor growth and development through stimulation of angiogenesis as well as matrix dissolution76. Therapeutic blockade of TAMs by preventing their recruitment is of clinical interest. Monocyte chemoattractant protein-1 (MCP-1, CCL2) is an important chemokine that is known to regulate monocyte/macrophage trafficking 2. Pre-clinical and clinical aspects
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and has been reported to be present in several solid tumor beds78–81. The blockade of TAMs induced by CCL2 using the anti-CCL2 antibody CNTO888, or carlumab, did not show anti-tumor activity as a single agent in metastatic castration-resistant prostate cancer82 but is under clinical investigation against other solid tumors83. The lack of efficacy was demonstrated to be due to an inability of the antibody to block free CCL2 in patients. Treatment resulted in an increase in free CCL2 as the host responded to the presence of the antibody blocking production. The CCR2specific monoclonal antibody MLN1202 is also under investigation for this purpose (NCT01015560). Other therapeutic targets against TAMs include the direct killing of TAMs (by bisphosphonates), repolarization of M2 macrophages (by pantoprazole, NCT01163903), and the inhibition of their pro-tumor function84.
TARGETING HEMATOPOIETIC PROGENITOR CELLS Hematopoietic progenitor cells (HPCs) are a critical part of the bone microenvironment. While it may be impractical to target interactions between HPCs and cancer cells at this time, it is clear that cancer cells metastasizing to bone marrow hijack several properties exhibited by HPCs that traffic through the circulation and bone marrow2,6. These mechanisms offer therapeutic targets which are currently under pre-clinical investigation. Prostate cancer, breast cancer, and multiple myeloma cells mimic hematopoietic stem/progenitor cells by upregulating the expression of CXC chemokine receptor 4 (CXCR4), which is the receptor for stromal-derived factor-1 (SDF-1, also known as CXCL12)9. This results in chemoattraction to the SDF-1/CXCL12 secreted by osteoblasts9. Disruption of the SDF-1/CXCR4 axis is the target of multiple agents. Filgrastim is a G-CSF analog clinically used to increase the number of HSCs in the blood for transplantation by degrading SDF-1 in the marrow via neutrophil elastase85. AMD3100 is an agent which directly prohibits SDF-1 from binding CXCR486. Filgrastim and AMD3100 are experimentally shown to mobilize metastatic cancer cells from the bone marrow niche in pre-clinical prostate86 and breast87 cancer models. This could be utilized in a therapeutic strategy to mobilize cancer cells “hidden” in the bone marrow out into the circulation where they could be targeted.
BONE AND DRUG RESISTANCE The bone marrow microenvironment is a stressful, yet ideal location for metastatic tumor cells as several of its components lead to drug resistance. Soluble factors and adhesion to extracellular matrix proteins facilitate the survival and proliferation of resident cells and can provide a sanctuary for tumor cell survival88. As a result, this microenvironment can provide for therapeutic resistance. Several soluble factors in the bone marrow microenvironment encourage tumor cell survival, potentially in the face of therapeutic activity, via soluble factor-mediated drug resistance. Bone marrow stromal cells produce IL-6, which upregulates the transcription of Bcl-XL in tumor cells and thus promotes cell survival88. IL-6-mediated drug resistance also occurs via STAT1, STAT3, and gp13088. Cancer cell adhesion to the bone marrow ECM proteins is another source of therapeutic resistance in multiple myeloma. Fibronectin and hyaluronan are two major components of the bone marrow ECM and have been shown to significantly contribute to drug resistance in multiple myeloma89. Fibronectin adhesion leads to drug resistance by antagonizing Fas-mediated apoptosis, causing cell cycle arrest in the G1 phase, and preventing drug-induced DNA damage89. Hyaluronin, on the other hand, forms a gel-like network that keeps autocrine and paracrine survival factors accessible to cancer cells and may serve to physically shield drugs from target cells89.
CONCLUSION Metastatic cancer in the skeleton is the result of complex interplay between the cancer cells themselves and the bone microenvironment, resulting in a heterogeneous disease that induces a combination of osteolytic and osteoblastic lesions. The pathogenesis of bone metastases includes interactions between the cancer cells and osteoclasts, osteoblasts, endothelial cells, stromal cells, hematopoietic progenitor cells, cells of the immune system, and the bone matrix. A paradigm shift from the early treatment strategy primarily targeting tumor cells directly, i.e. traditional chemotherapy, to new therapies that exploit the interactions and contributions of various microenvironmental cells and elements to the development of metastatic lesions is being explored and exploited to improve the lives of cancer patients living with skeletal metastases. However, there is a need for continued therapeutic development based III. BONE METASTASES
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on this multi-targeted therapy against the bone microenvironment. Furthermore, while strides in therapy have come from developing therapies targeting single components of the networks supporting cancer growth, the co-targeting of the various tumor-supportive elements presents a new paradigm in cancer treatment. By interrupting multiple cooperating pathways at the tumor cellular, primary and metastatic microenvironmental, and systemic levels, “scaled network disruption”90,91 will be an important therapeutic paradigm.
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