How Thalidomide Works Against Cancer A. Keith Stewart Science 343, 256 (2014); DOI: 10.1126/science.1249543
If you wish to distribute this article to others, you can order high-quality copies for your colleagues, clients, or customers by clicking here. Permission to republish or repurpose articles or portions of articles can be obtained by following the guidelines here. The following resources related to this article are available online at www.sciencemag.org (this information is current as of January 16, 2014 ): Updated information and services, including high-resolution figures, can be found in the online version of this article at: http://www.sciencemag.org/content/343/6168/256.full.html This article cites 15 articles, 6 of which can be accessed free: http://www.sciencemag.org/content/343/6168/256.full.html#ref-list-1
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2014 by the American Association for the Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS.
Downloaded from www.sciencemag.org on January 16, 2014
This copy is for your personal, non-commercial use only.
PERSPECTIVES order of magnitude improvement over the previous bound measured in YbF (3). An alternative approach to neutral beams is to use trapped molecular ions. For an ion held in a radio-frequency trap, a static electric field of sufficient strength to polarize the molecule will also push it out of the trap. The proposed solution to the problem was applying a strong rotating field (4). In the frame of that field, one gains the benefits of both holding trapped ions for a long time and polarization of the molecule (see the figure). Loh et al. use the rotating field method to limit the electron electric dipole moment to be less than 1.5 × 10−25 e⋅cm. This initial experiment is three orders of magnitude above the ThO result of Baron et al. The experiment of Loh et al. shows that precision measurements can be performed with molecular ions, and future experiments will be competitive with the neutral molecule and atom measurements. Of course, more exciting than limiting the electron electric dipole moment would be to measure it. Why does theoretical physics tell us to expect it, and what do we expect
the magnitude to be? These are both challenging questions to explain simply. An electric dipole moment requires an interaction that violates both parity and time symmetry. Everyday laws of physics are invariant if we relabel forward and backward in space and time. However, the laws that govern subatomic particles are not. They satisfy a combined symmetry of charge conjugation, parity, and time. The Standard Model of particle physics allows for a violation of time and parity symmetry, and from the known interactions we can estimate that the electron electric dipole moment will be smaller than 10−38 e⋅cm (5). Extensions to the Standard Model, for example, supersymmetric or left-right symmetric models, can produce electron electric dipole moments near the current limits of detection. As a result, tabletop experiments are beginning to limit which theoretical models are compatible with the observed world. Normally, when considering questions about particle physics, one thinks of large particle accelerator experiments. The excitement of the discovery of the Higgs boson at
the Large Hadron Collider (LHC) (6, 7) and the award of this year’s Nobel prize for its prediction are testaments to this method of inquiry. A challenge for the tabletop experiments is that at present the results at the LHC are consistent with the Standard Model. The lack of detection of other new particles also limits possible theoretical models of our world and, as a result, the value of the electron electric dipole moment. It is unclear at the moment whether investigation at high precision or investigation at high energy will be first to reveal additional physics beyond the Standard Model. References 1. H. Loh et al., Science 342, 1220 (2013). 2. J. Baron et al., Science 343, 269 (2014); 10.1126/ science.1248213. 3. J. J. Hudson et al., Nature 473, 493 (2011). 4. A. E. Leanhardt et al., J. Mol. Spectrosc. 270, 1 (2011). 5. E. D. Commins, in Advances in Atomic, Molecular, and Optical Physics, B. Bederson, H. Walther, Eds. (Academic Press, 1999), vol. 40, pp. 1–55. 6. ATLAS Collaboration, Phys. Lett. B 716, 1 (2012). 7. C. M. S. Collaboration, Phys. Lett. B 716, 30 (2012). Published online 19 December 2013 10.1126/science.1246820
MEDICINE
How Thalidomide Works Against Cancer
The surprising ability of thalidomide and its analogs to treat various hematologic malignancies is through the loss of two transcription factors.
A. Keith Stewart
T
he 55-year history of the drug thalidomide is Shakespearean in scope, awash in unintended consequences, tragedy, resilience, driven characters, and redemption. Indeed, the most notorious pharmaceutical of modern times comes replete with images of devastating birth defects still firmly embedded in the public consciousness. Less well known has been the resurgence in its use as a therapy to treat hematologic malignancy. On pages 305 and 301 of this issue, Lu et al. (1) and Krönke et al. (2), respectively, report that thalidomide and derivative compounds have a toxic effect on multiple myeloma by causing the degradation of two transcription factors, Ikaros and Aiolos. This loss halts myeloma growth while simultaneously altering immune cell function. In an archetypal example of drug repositioning, reports emerged 15 years ago that Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA. E-mail: [email protected]
256
thalidomide could be profoundly effective in patients with multiple myeloma (3), a tumor of antibody-producing plasma cells in the bone marrow. The malignancy is characterized by anemia, bone fractures, kidney failure, and recurrent infection. Subsequently, the thalidomide analogs lenalidomide and pomalidomide (collectively called immune modulating drugs or IMiDs) were shown to be even more potent in treating multiple myeloma, and today these small molecules form a highly effective backbone of therapy for this increasingly treatable cancer and for other hematologic malignancies (4). Many studies over the years have sought to explain the mechanism of teratogenicity of thalidomide. Thalidomide, lenalidomide, and pomalidomide were found to have wide-ranging and seemingly disparate cellular actions, including induction of oxidative stress and inhibition of angiogenesis, as well as multiple effects on the immune system—enhanced production of the cyto-
kine interleukin-2 (IL-2) (which spurs T cell production), inhibition of the cytokine tumor necrosis factor (TNF), and the stimulation of natural killer cells (5). The property of antiangiogenesis inspired the suggestion that thalidomide might be useful as a lastgasp attempt to control drug-resistant multiple myeloma. A remarkable success story in controlling this cancer with thalidomide soon followed (3). Unfortunately, it did not take long to show that although antiangiogenesis may be a consequence of thalidomide therapy, it was not the mechanism of action that explained its clinical effect. The seminal breakthrough emerged in 2010 when thalidomide was found to bind to the protein cereblon (6). Cereblon forms an E3 ubiquitin ligase complex with the proteins damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (Roc1). This complex tags specific proteins with ubiquitin, thereby targeting them for proteolysis. The drug-protein interaction
17 JANUARY 2014 VOL 343 SCIENCE www.sciencemag.org Published by AAAS
CREDIT: H. MACDONALD/SCIENCE
PERSPECTIVES disrupts the activity of the Another per plexing E3 ubiquitin ligase complex, clinical dilemma is that the which underpins the cytoaction of IMiD drugs seems toxic and immune-modulatto absolutely require effecing effects of IMiDs. Some tive proteasomal degradaof these effects were reverstion of Ikaros and Aiolos ible by overexpressing the —a finding that flies in the downstream proteins whose face of clinical experience, expression was reduced folwhich seems to support lowing IMiD treatment, that combining an immune such as the transcription facmodulator with a proteators interferon regulatory some inhibitor as a highly factor 4 (IRF4) and Myc effective strategy for treat( 7– 9). Although research ing multiple myeloma (4). into the clinical importance Evidently, the scientific of this observation is still saga of thalidomide and its fresh, it seems clear that analogs is a story still not low amounts of cereblon in fully told. multiple myeloma cells corIt is tempting to update relate with clinical drug the mythic tale of the resistance and poor survival Greek god Ikaros flying outcomes (10). too close to the Sun, only to Lu et al. and Krönke et have his waxed wings melt, al. demonstrate that the zinc to the genomic-era equivafinger–containing transcriplent as the namesake Ikaros tion factors Ikaros (IKZF1) transcription factor comes and Aiolos (IKZF3) are too close to its molecuselectively bound by cerelar sun—namely, cereblon blon. After direct binding, that is bound to an immune IMiDs activate cereblon’s modulatory drug, with E3 ligase activity, resultits inevitable degradation ing in the rapid ubiquiti- Immune modulators and myeloma. The small-molecule drugs thalidomide, lenalidomide, (see the figure). A final but nation and degradation of and pomalidomide bind to the protein cereblon (CRBN), which activates the enzymatic activity speculative conclusion of of the CRBN E3 ubiquitin ligase complex. The transcription factors Ikaros (IKZF1) and Aiolos Ikaros and Aiolos. Ikaros the studies by Lu et al. and (IKZF3) are modified with ubiquitin (Ub) molecules, targeting them for proteolysis. This alters and Aiolos are transcrip- the function of T cells and B cells, with a toxic outcome for multiple myeloma cells. Krönke et al. is that small tional regulators of B and molecules that enhance the T cell development ( 11, ubiquitination and degra12). Aiolos is required for normal plasma an effective anticancer target but also act as dation of specific target proteins may reprecell development in mice (13). The toxic a tumor suppressor underpinning the devel- sent a new class of therapeutics for manipueffects on multiple myeloma cells resulting opment of acute lymphoblastic leukemia, an lating proteins that were previously viewed from the loss of these two transcription fac- early B cell malignancy (14)? Presumably, as undruggable. tors are reversed by deletion of critical cere- different Ikaros isoforms function as reguReferences blon-binding regions of Ikaros prior to drug lators of gene expression in different cellu1. G. Lu et al., Science 343, 305 (2014); 10.1126/ treatment. Under normal conditions, Ikaros lar contexts. A logical progression might be science.1244917. suppresses expression of the gene encod- that deletion of Ikaros by the IMiDs, under 2. J. Krönke et al., Science 343, 301 (2014); 10.1126/ science.1244851. ing IL-2 in T cells but conversely stimulates the wrong circumstances, could simultane3. S. Singhal et al., N. Engl. J. Med. 341, 1565 (1999). expression of IRF4 (a transcription factor ously kill multiple myeloma cells but pro4. A. K. Stewart, P. G. Richardson, J. F. San-Miguel, Blood that responds to infection). Thus, a decrease mote pre–B cell leukemogenesis. Indeed, 114, 5436 (2009). in Ikaros explains the perplexing question of clinical experience demonstrates a slightly 5. Y. X. Zhu, K. M. Kortuem, A. K. Stewart, Leuk. Lymphoma 54, 683 (2013). how one drug can both activate the immune higher risk of leukemias and B cell malig6. T. Ito et al., Science 327, 1345 (2010). system (a boost in IL-2 production by T cells nancies in patients treated with immune 7. Y. X. Zhu et al., Blood 118, 4771 (2011). stimulates immune responses) and degrade modulatory drugs, albeit only after exposure 8. A. L. Shaffer et al., Nature 454, 226 (2008). 9. L. H. Zhang et al., Br. J. Haematol. 160, 487 (2013). B cell function (as the result of reduced to a second genotoxic DNA-damaging agent, IRF4 expression) simultaneously. such as Melphalan, a commonly used multi- 10. S. R. Schuster et al., Leuk. Res. 38, 23 (2014). 11. B. Morgan et al., EMBO J. 16, 2004 (1997). Analysis of the cereblon–Ikaros/Aiolos– ple myeloma treatment (15). There are other 12. K. Georgopoulos et al., Cell 79, 143 (1994). IRF4/Myc signaling pathway now opens clinical dilemmas that remain unexplained, 13. M. Cortés, K. Georgopoulos, J. Exp. Med. 199, 209 (2004). doors to developing of more precise and such as why only one-third of relapsed 14. C. G. Mullighan et al., Nature 453, 110 (2008). effective therapeutics and biomarkers for patients respond to a single-agent immune 15. H. Ludwig et al., Blood 119, 3003 (2012). drug response while raising some more issues modulatory drug and why patients lose cerefor biologists and clinicians. For example, blon or find alternative pathways to become 10.1126/science.1249543 how can Ikaros depletion simultaneously be resistant to these drugs. www.sciencemag.org SCIENCE VOL 343 17 JANUARY 2014 Published by AAAS
257
If you wish to distribute this article to others, you can order high-quality copies for your colleagues, clients, or customers by clicking here. Permission to republish or repurpose articles or portions of articles can be obtained by following the guidelines here. The following resources related to this article are available online at www.sciencemag.org (this information is current as of January 16, 2014 ): Updated information and services, including high-resolution figures, can be found in the online version of this article at: http://www.sciencemag.org/content/343/6168/256.full.html This article cites 15 articles, 6 of which can be accessed free: http://www.sciencemag.org/content/343/6168/256.full.html#ref-list-1
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2014 by the American Association for the Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS.
Downloaded from www.sciencemag.org on January 16, 2014
This copy is for your personal, non-commercial use only.
PERSPECTIVES order of magnitude improvement over the previous bound measured in YbF (3). An alternative approach to neutral beams is to use trapped molecular ions. For an ion held in a radio-frequency trap, a static electric field of sufficient strength to polarize the molecule will also push it out of the trap. The proposed solution to the problem was applying a strong rotating field (4). In the frame of that field, one gains the benefits of both holding trapped ions for a long time and polarization of the molecule (see the figure). Loh et al. use the rotating field method to limit the electron electric dipole moment to be less than 1.5 × 10−25 e⋅cm. This initial experiment is three orders of magnitude above the ThO result of Baron et al. The experiment of Loh et al. shows that precision measurements can be performed with molecular ions, and future experiments will be competitive with the neutral molecule and atom measurements. Of course, more exciting than limiting the electron electric dipole moment would be to measure it. Why does theoretical physics tell us to expect it, and what do we expect
the magnitude to be? These are both challenging questions to explain simply. An electric dipole moment requires an interaction that violates both parity and time symmetry. Everyday laws of physics are invariant if we relabel forward and backward in space and time. However, the laws that govern subatomic particles are not. They satisfy a combined symmetry of charge conjugation, parity, and time. The Standard Model of particle physics allows for a violation of time and parity symmetry, and from the known interactions we can estimate that the electron electric dipole moment will be smaller than 10−38 e⋅cm (5). Extensions to the Standard Model, for example, supersymmetric or left-right symmetric models, can produce electron electric dipole moments near the current limits of detection. As a result, tabletop experiments are beginning to limit which theoretical models are compatible with the observed world. Normally, when considering questions about particle physics, one thinks of large particle accelerator experiments. The excitement of the discovery of the Higgs boson at
the Large Hadron Collider (LHC) (6, 7) and the award of this year’s Nobel prize for its prediction are testaments to this method of inquiry. A challenge for the tabletop experiments is that at present the results at the LHC are consistent with the Standard Model. The lack of detection of other new particles also limits possible theoretical models of our world and, as a result, the value of the electron electric dipole moment. It is unclear at the moment whether investigation at high precision or investigation at high energy will be first to reveal additional physics beyond the Standard Model. References 1. H. Loh et al., Science 342, 1220 (2013). 2. J. Baron et al., Science 343, 269 (2014); 10.1126/ science.1248213. 3. J. J. Hudson et al., Nature 473, 493 (2011). 4. A. E. Leanhardt et al., J. Mol. Spectrosc. 270, 1 (2011). 5. E. D. Commins, in Advances in Atomic, Molecular, and Optical Physics, B. Bederson, H. Walther, Eds. (Academic Press, 1999), vol. 40, pp. 1–55. 6. ATLAS Collaboration, Phys. Lett. B 716, 1 (2012). 7. C. M. S. Collaboration, Phys. Lett. B 716, 30 (2012). Published online 19 December 2013 10.1126/science.1246820
MEDICINE
How Thalidomide Works Against Cancer
The surprising ability of thalidomide and its analogs to treat various hematologic malignancies is through the loss of two transcription factors.
A. Keith Stewart
T
he 55-year history of the drug thalidomide is Shakespearean in scope, awash in unintended consequences, tragedy, resilience, driven characters, and redemption. Indeed, the most notorious pharmaceutical of modern times comes replete with images of devastating birth defects still firmly embedded in the public consciousness. Less well known has been the resurgence in its use as a therapy to treat hematologic malignancy. On pages 305 and 301 of this issue, Lu et al. (1) and Krönke et al. (2), respectively, report that thalidomide and derivative compounds have a toxic effect on multiple myeloma by causing the degradation of two transcription factors, Ikaros and Aiolos. This loss halts myeloma growth while simultaneously altering immune cell function. In an archetypal example of drug repositioning, reports emerged 15 years ago that Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA. E-mail: [email protected]
256
thalidomide could be profoundly effective in patients with multiple myeloma (3), a tumor of antibody-producing plasma cells in the bone marrow. The malignancy is characterized by anemia, bone fractures, kidney failure, and recurrent infection. Subsequently, the thalidomide analogs lenalidomide and pomalidomide (collectively called immune modulating drugs or IMiDs) were shown to be even more potent in treating multiple myeloma, and today these small molecules form a highly effective backbone of therapy for this increasingly treatable cancer and for other hematologic malignancies (4). Many studies over the years have sought to explain the mechanism of teratogenicity of thalidomide. Thalidomide, lenalidomide, and pomalidomide were found to have wide-ranging and seemingly disparate cellular actions, including induction of oxidative stress and inhibition of angiogenesis, as well as multiple effects on the immune system—enhanced production of the cyto-
kine interleukin-2 (IL-2) (which spurs T cell production), inhibition of the cytokine tumor necrosis factor (TNF), and the stimulation of natural killer cells (5). The property of antiangiogenesis inspired the suggestion that thalidomide might be useful as a lastgasp attempt to control drug-resistant multiple myeloma. A remarkable success story in controlling this cancer with thalidomide soon followed (3). Unfortunately, it did not take long to show that although antiangiogenesis may be a consequence of thalidomide therapy, it was not the mechanism of action that explained its clinical effect. The seminal breakthrough emerged in 2010 when thalidomide was found to bind to the protein cereblon (6). Cereblon forms an E3 ubiquitin ligase complex with the proteins damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (Roc1). This complex tags specific proteins with ubiquitin, thereby targeting them for proteolysis. The drug-protein interaction
17 JANUARY 2014 VOL 343 SCIENCE www.sciencemag.org Published by AAAS
CREDIT: H. MACDONALD/SCIENCE
PERSPECTIVES disrupts the activity of the Another per plexing E3 ubiquitin ligase complex, clinical dilemma is that the which underpins the cytoaction of IMiD drugs seems toxic and immune-modulatto absolutely require effecing effects of IMiDs. Some tive proteasomal degradaof these effects were reverstion of Ikaros and Aiolos ible by overexpressing the —a finding that flies in the downstream proteins whose face of clinical experience, expression was reduced folwhich seems to support lowing IMiD treatment, that combining an immune such as the transcription facmodulator with a proteators interferon regulatory some inhibitor as a highly factor 4 (IRF4) and Myc effective strategy for treat( 7– 9). Although research ing multiple myeloma (4). into the clinical importance Evidently, the scientific of this observation is still saga of thalidomide and its fresh, it seems clear that analogs is a story still not low amounts of cereblon in fully told. multiple myeloma cells corIt is tempting to update relate with clinical drug the mythic tale of the resistance and poor survival Greek god Ikaros flying outcomes (10). too close to the Sun, only to Lu et al. and Krönke et have his waxed wings melt, al. demonstrate that the zinc to the genomic-era equivafinger–containing transcriplent as the namesake Ikaros tion factors Ikaros (IKZF1) transcription factor comes and Aiolos (IKZF3) are too close to its molecuselectively bound by cerelar sun—namely, cereblon blon. After direct binding, that is bound to an immune IMiDs activate cereblon’s modulatory drug, with E3 ligase activity, resultits inevitable degradation ing in the rapid ubiquiti- Immune modulators and myeloma. The small-molecule drugs thalidomide, lenalidomide, (see the figure). A final but nation and degradation of and pomalidomide bind to the protein cereblon (CRBN), which activates the enzymatic activity speculative conclusion of of the CRBN E3 ubiquitin ligase complex. The transcription factors Ikaros (IKZF1) and Aiolos Ikaros and Aiolos. Ikaros the studies by Lu et al. and (IKZF3) are modified with ubiquitin (Ub) molecules, targeting them for proteolysis. This alters and Aiolos are transcrip- the function of T cells and B cells, with a toxic outcome for multiple myeloma cells. Krönke et al. is that small tional regulators of B and molecules that enhance the T cell development ( 11, ubiquitination and degra12). Aiolos is required for normal plasma an effective anticancer target but also act as dation of specific target proteins may reprecell development in mice (13). The toxic a tumor suppressor underpinning the devel- sent a new class of therapeutics for manipueffects on multiple myeloma cells resulting opment of acute lymphoblastic leukemia, an lating proteins that were previously viewed from the loss of these two transcription fac- early B cell malignancy (14)? Presumably, as undruggable. tors are reversed by deletion of critical cere- different Ikaros isoforms function as reguReferences blon-binding regions of Ikaros prior to drug lators of gene expression in different cellu1. G. Lu et al., Science 343, 305 (2014); 10.1126/ treatment. Under normal conditions, Ikaros lar contexts. A logical progression might be science.1244917. suppresses expression of the gene encod- that deletion of Ikaros by the IMiDs, under 2. J. Krönke et al., Science 343, 301 (2014); 10.1126/ science.1244851. ing IL-2 in T cells but conversely stimulates the wrong circumstances, could simultane3. S. Singhal et al., N. Engl. J. Med. 341, 1565 (1999). expression of IRF4 (a transcription factor ously kill multiple myeloma cells but pro4. A. K. Stewart, P. G. Richardson, J. F. San-Miguel, Blood that responds to infection). Thus, a decrease mote pre–B cell leukemogenesis. Indeed, 114, 5436 (2009). in Ikaros explains the perplexing question of clinical experience demonstrates a slightly 5. Y. X. Zhu, K. M. Kortuem, A. K. Stewart, Leuk. Lymphoma 54, 683 (2013). how one drug can both activate the immune higher risk of leukemias and B cell malig6. T. Ito et al., Science 327, 1345 (2010). system (a boost in IL-2 production by T cells nancies in patients treated with immune 7. Y. X. Zhu et al., Blood 118, 4771 (2011). stimulates immune responses) and degrade modulatory drugs, albeit only after exposure 8. A. L. Shaffer et al., Nature 454, 226 (2008). 9. L. H. Zhang et al., Br. J. Haematol. 160, 487 (2013). B cell function (as the result of reduced to a second genotoxic DNA-damaging agent, IRF4 expression) simultaneously. such as Melphalan, a commonly used multi- 10. S. R. Schuster et al., Leuk. Res. 38, 23 (2014). 11. B. Morgan et al., EMBO J. 16, 2004 (1997). Analysis of the cereblon–Ikaros/Aiolos– ple myeloma treatment (15). There are other 12. K. Georgopoulos et al., Cell 79, 143 (1994). IRF4/Myc signaling pathway now opens clinical dilemmas that remain unexplained, 13. M. Cortés, K. Georgopoulos, J. Exp. Med. 199, 209 (2004). doors to developing of more precise and such as why only one-third of relapsed 14. C. G. Mullighan et al., Nature 453, 110 (2008). effective therapeutics and biomarkers for patients respond to a single-agent immune 15. H. Ludwig et al., Blood 119, 3003 (2012). drug response while raising some more issues modulatory drug and why patients lose cerefor biologists and clinicians. For example, blon or find alternative pathways to become 10.1126/science.1249543 how can Ikaros depletion simultaneously be resistant to these drugs. www.sciencemag.org SCIENCE VOL 343 17 JANUARY 2014 Published by AAAS
257
