- Email: [email protected]
Unlocking New Therapeutic Targets and Resistance Mechanisms in Mantle Cell Lymphoma
Cancer Cell
Previews Unlocking New Therapeutic Targets and Resistance Mechanisms in Mantle Cell Lymphoma Dolors Colomer1 and Elı´as Campo1,* 1Hospital Clinic, Institut d’Investigacions Biome ` diques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona 08036, Spain *Correspondence: [email protected] http://dx.doi.org/10.1016/j.ccr.2013.12.011
Mantle cell lymphoma is an aggressive tumor for which new drugs targeting underlying molecular mechanisms are opening promising avenues. A recent study has elucidated the basis for targeting B cell receptor signaling in these lymphomas and identified somatic mutations in NF-kB regulatory genes that confer resistance to this therapy. Mantle cell lymphoma (MCL) is an aggressive lymphoid neoplasia derived from mature B cells and is considered incurable with current therapies. The primary oncogenic driver is the t(11;14)(q13;q32) translocation, which causes cyclin D1 overexpression. This event is usually followed by additional chromosomal alterations that target genes regulating DNA damage response, cell cycle, and cell survival pathways (Jares et al., 2012). The clinical and biological features of MCL now seem more heterogeneous than initially recognized. Recent studies have identified a subset of tumors with an indolent behavior that tends to present with leukemic instead of extensive nodal disease. The tumor cells have simple karyotypes, frequent hypermutated IGHV, and a gene expression signature that does not include SOX11, a transcription factor that promotes oncogenic growth of conventional MCL (Jares et al., 2012; Vegliante et al., 2013). These indolent tumors may acquire additional oncogenic alterations and eventually progress to a more aggressive form. Although the outcome for MCL patients has improved globally in past years through the use of new combined immunochemotherapy and intensive regimens such as stem cell transplantation, many patients will relapse and eventually die of the disease. Increased understanding of the molecular mechanisms driving MCL has facilitated the development of new therapies that offer promising avenues (Pe´rez-Gala´n et al., 2011). The relevance of B cell receptor (BCR) signaling to the pathogenesis of several lymphomas has propelled investigation of a series of drugs that interfere with these pathways
(Young and Staudt, 2013). Initial clinical studies with some of these agents, particularly ibrutinib, a covalent inhibitor of the Bruton tyrosine kinase (BTK), have yielded substantial responses in different lymphoid neoplasms, including diffuse large B cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), and MCL (Young and Staudt 2013; Wang et al., 2013). However, the encouraging results obtained for MCL were somewhat surprising, because, contrary to DLBCL or CLL, evidence supporting a pathogenic role for BCR stimulation in MCL were limited. Suggestive findings from recent studies in MCL have identified a restricted immunoglobulin gene repertoire and often stereotyped configurations of the BCR, supporting the role of antigen selection in a subset of these tumors. In addition, different kinases in BCR signaling, including SYK, LYN, and BTK, may be amplified or phosphorylated in primary MCL, supporting the activation of this pathway in certain tumors (reviewed in Pe´rez-Gala´n et al., 2011 and Jares et al., 2012). A recent study by Wang et al. (2013) showed complete or partial responses to ibrutinib in up to 68% of patients who had failed to respond to other therapies. This response was higher than expected based on known BCR alterations in MCL. Beyond the positive clinical impact, this study highlighted our limited understanding of the molecular bases for both the high response rate and the resistance to BTK inhibition in these tumors. In a recent study in Nature Medicine, Rahal et al. (2013) found answers to some of the open questions surrounding clinical experience with ibrutinib in MCL. Using a large-scale pharmacological
profiling strategy across more than 100 hematological cell line models, the authors identified 4 MCL lines that were highly sensitive to the BCR signaling inhibitors ibrutinib and sotrastaurin and 6 lines that were resistant to the treatments. Intriguingly, both subsets of sensitive and resistant cell lines were dependent on IKKb-NF-kB signaling, confirming previously reported constitutive NF-kB activation in MCL (Pham et al., 2003). However, the sensitive, but not the resistant, cells were addicted to signaling through the CARD11-BCL10MALT1 (CBM) complex downstream of BTK and PKC, which sustained activation of the classical NF-kB pathway (Figure 1). To understand the possible mechanisms underlying NF-kB activation in resistant cells, the authors performed RNA sequencing and found inactivating mutations of TRAF2 and TRAF3 in two of the resistant cell lines. TRAF2 and TRAF3 are negative regulators of the alternative NF-kB signaling pathway interacting with cIAP1 and cIAP2 (gene products of BIRC2 and BIRC3, respectively) to downregulate NIK (encoded by MAP3K14), a central kinase in this pathway that promotes processing of the NF-kB precursor p100 into the active p52 isoform (Figure 1). Loss of TRAF2 and TRAF3 were essential for survival of the cells suggesting that NIK could be a new target in MCL that specifically bear these genetic alterations. Interestingly, three of the other resistant MCL lines in which the authors did not find similar mutations are known to be infected by Epstein-Barr virus (EBV), an activator of the alternative NF-kB pathway. Intriguingly, there was one resistant cell line without clear evidence of alternative
Cancer Cell 25, January 13, 2014 ª2014 Elsevier Inc. 7
Cancer Cell
Previews
Figure 1. Somatic Mutation and Activation of the NF-kB Pathway in MCL Activation of the classical and alternative NF-kB pathway in MCL may occur by chronic active BCR signaling and other mechanisms. Genomic sequencing studies have identified mutations in several elements of this regulatory pathway (denoted by red asterisks). Chronic active BCR (A) or Toll-like receptor (TLR) (B) signaling activate classical NF-kB pathway. MCL that is dependent on BCR activation (A) may be blocked by BCR signaling inhibitors. Somatic mutations in the inhibitors of the alternative pathways (C) cIAP1 and cIAP2 (gene products of BIRC2 and BIRC3, respectively) and TRAF2/3 activate the alternative NF-kB pathway and confer resistance to inhibitors of the BCR signaling pathway. Somatic mutations in other elements of these pathways (CARD11, IKKb, encoded by IKBKB, TLR2, and NIK, encoded by MAP3K14) have been also found in MCL by whole exome or genome sequencing .
NF-kB pathway activation as it was negative for EBV and TRAF2/3 mutations, suggesting that other mechanisms may create resistance to BCR inhibitors in MCL. Rahal et al. (2013) analyzed the presence of mutations in genes encoding members of the alternative NF-kB pathways TRAF2, TRAF3, BIRC2, BIRC3, and MAP3K14 across 165 primary MCLs and found TRAF2 and BIRC3 mutations in 6% and 10% of the cases, respectively. These observations are concordant with the findings in our recent whole genome and exome sequencing study of MCL in which we found BIRC3 mutations in 6% of cases (Bea` et al., 2013). BIRC3 is located at 11q22.2, a region frequently deleted in MCL. In our study, virtually all BIRC3 mutations were associated with 11q deletions, including a case without
ATM mutations, suggesting that, in addition to the dominant negative effect of these mutations suggested by Rahal et al. (2013), the deletion of the normal BIRC3 allele may confer an additional advantage to the cells. Although we did not observed TRAF2/3 mutations, we found mutations in other genes of the classical and alternative NF-kB pathway, including recurrent activating mutations in TLR2 as well as mutations in CARD11, MAP3K14 (NIK), and IKBKB (IKKb) (Figure 1). Although the functional implications of some of these mutations need to be confirmed, together, the studies suggest that genetic alterations in the NF-kB pathway in MCL may be more common than initially thought. The observations of Rahal et al. (2013), if confirmed in primary tumor cells, may have important clinical implications. The
8 Cancer Cell 25, January 13, 2014 ª2014 Elsevier Inc.
detection of RelB cleavage, as a downstream effect of PKC-CBM activity, and low levels of p52 identified cells sensitive to BCR inhibitors. In contrast, tumors with high p52 levels and genetic lesions in the alternative NFkB pathway predicted resistance to these agents. Therefore, these alterations may be useful biomarkers for selecting targeted therapies in MCL. The involvement of the alternative NF-kB pathway in resistance to BCR inhibitors may also be of interest for other lymphoid neoplasms. Mutations in genes of the alternative (BIRC3, TRAF3, and MAP3K14) and classical (TNFAIP3 and IKBKB) NF-kB pathways have been described in 36% of splenic marginal zone lymphomas (Rossi et al., 2011) and 24% of advanced or chemoresistant CLL (Rossi et al., 2012). The functional relationship between these mutations
Cancer Cell
Previews and the response to new therapies in lymphomas deserves further exploration. Additional mechanisms, such as mutations in BTK or in other targets of the new drugs, may also emerge and confer resistance in MCL. The preclinical results presented by Rahal et al. (2013) provide critical insights into understanding the mechanisms of response to new drugs and suggest innovative therapeutic strategies for tumors refractory to BCR signaling inhibitors. The study also highlights the increasing clinical interest of sequencing tumors to guide the selection of new therapies in lymphoid neoplasms.
is supported by Red Tema´tica de Investigacio´n Cooperativa en Ca´ncer (RD12/0036) and Plan Nacional (SAF10/21165, SAF12/38432); E.C. is an Institucio´ Catalana de Recerca i Estudis Avanc¸ats-Academia (ICREA) investigator.
lished online December 22, 2013. http://dx.doi. org/10.1038/nm.3435. Rossi, D., Deaglio, S., Dominguez-Sola, D., Rasi, S., Vaisitti, T., Agostinelli, C., Spina, V., Bruscaggin, A., Monti, S., Cerri, M., et al. (2011). Blood 118, 4930–4934.
REFERENCES Bea`, S., Valde´s-Mas, R., Navarro, A., Salaverria, I., Martı´n-Garcia, D., Jares, P., Gine´, E., Pinyol, M., Royo, C., Nadeu, F., et al. (2013). Proc. Natl. Acad. Sci U S A. 110, 18250–18255. Jares, P., Colomer, D., and Campo, E. (2012). J. Clin. Invest. 122, 3416–3423. Pe´rez-Gala´n, P., Dreyling, M., and Wiestner, A. (2011). Blood 117, 26–38.
ACKNOWLEDGMENTS
Pham, L.V., Tamayo, A.T., Yoshimura, L.C., Lo, P., and Ford, R.J. (2003). J. Immunol. 171, 88–95.
We thank Dr. Xose A. Puente and Silvia Bea` for their helpful comments. The work of the authors
Rahal, R., Frick, M., Romero, R., Korn, J.M., Kridel, R., Chan, F.Ch., Meissner, B., Bhang, H., Ruddy, D., Kauffmann, A., et al. (2013). Nat. Med. Pub-
Rossi, D., Fangazio, M., Rasi, S., Vaisitti, T., Monti, S., Cresta, S., Chiaretti, S., Del Giudice, I., Fabbri, G., Bruscaggin, A., et al. (2012). Blood 119, 2854– 2862. Vegliante, M.C., Palomero, J., Pe´rez-Gala´n, P., Roue´, G., Castellano, G., Navarro, A., Clot, G., Moros, A., Sua´rez-Cisneros, H., Bea`, S., et al. (2013). Blood 121, 2175–2185. Wang, M.L., Rule, S., Martin, P., Goy, A., Auer, R., Kahl, B.S., Jurczak, W., Advani, R.H., Romaguera, J.E., Williams, M.E., et al. (2013). N. Engl. J. Med. 369, 507–516. Young, R.M., and Staudt, L.M. (2013). Nat. Rev. Drug Discov. 12, 229–243.
From Anecdote to Targeted Therapy: The Curious Case of Thalidomide in Multiple Myeloma Jonathan D. Licht,1,* Jake Shortt,2,3 and Ricky Johnstone2,3 1Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA 2Gene Regulation Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC 3002, Australia 3Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3052, Australia *Correspondence: [email protected] http://dx.doi.org/10.1016/j.ccr.2013.12.019
Thalidomide and related drugs are key drugs for the treatment of multiple myeloma (MM). These agents bind to cereblon, a component of a ubiquitin ligase complex, altering the specificity of the complex to induce the ubiquitylation and degradation of Ikaros (IKZF1) and Aiolos (IKZF3), transcription factors essential for MM growth. The story of the use of thalidomide and related compounds in the treatment of multiple myeloma (MM) represents a remarkable case of bedside to bench research. Thalidomide may have first been discovered during World War II as a potential antidote to nerve gas and was developed as a sedative used for morning sickness in the 1950s. This culminated in a great medical tragedy because of the extraordinary teratogenic effects on limb development. The drug was abandoned but was later explored for the treatment of leprosy ulcers, HIV/ AIDS, and autoimmune diseases. These
anti-inflammatory effects were linked to inhibition of tumor necrosis factor secretion, providing an early indication that thalidomide functioned as an immune modulatory drug (IMiD). Dr. Judah Folkman and colleagues subsequently found that thalidomide inhibited tumor associated angiogenesis. Folkman’s advice to a patient to try thalidomide in MM (http://www.nytimes.com/1999/11/18/us/ thalidomide-found-to-slow-a-bone-cancer. html) led to a seminal study showing a 32% response rate of MM patients to a single agent thalidomide treatment, including complete responses in several
patients refractory to all prior therapies (Singhal et al., 1999). Thalidomide in combination with dexamethasone as an initial therapy yields response rates of >60%, while lenalidomide, a chemically similar IMiD with fewer constitutional side effects, plus dexamethasone yields responses in 80% of patients. The use of these IMiDs along with the proteasome inhibitor bortezomib has extended the median survival of MM patients to greater than 7 years. This remarkable progress occurred in the absence of clear molecular and biological mechanisms of action of thalidomide,
Cancer Cell 25, January 13, 2014 ª2014 Elsevier Inc. 9
Previews Unlocking New Therapeutic Targets and Resistance Mechanisms in Mantle Cell Lymphoma Dolors Colomer1 and Elı´as Campo1,* 1Hospital Clinic, Institut d’Investigacions Biome ` diques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona 08036, Spain *Correspondence: [email protected] http://dx.doi.org/10.1016/j.ccr.2013.12.011
Mantle cell lymphoma is an aggressive tumor for which new drugs targeting underlying molecular mechanisms are opening promising avenues. A recent study has elucidated the basis for targeting B cell receptor signaling in these lymphomas and identified somatic mutations in NF-kB regulatory genes that confer resistance to this therapy. Mantle cell lymphoma (MCL) is an aggressive lymphoid neoplasia derived from mature B cells and is considered incurable with current therapies. The primary oncogenic driver is the t(11;14)(q13;q32) translocation, which causes cyclin D1 overexpression. This event is usually followed by additional chromosomal alterations that target genes regulating DNA damage response, cell cycle, and cell survival pathways (Jares et al., 2012). The clinical and biological features of MCL now seem more heterogeneous than initially recognized. Recent studies have identified a subset of tumors with an indolent behavior that tends to present with leukemic instead of extensive nodal disease. The tumor cells have simple karyotypes, frequent hypermutated IGHV, and a gene expression signature that does not include SOX11, a transcription factor that promotes oncogenic growth of conventional MCL (Jares et al., 2012; Vegliante et al., 2013). These indolent tumors may acquire additional oncogenic alterations and eventually progress to a more aggressive form. Although the outcome for MCL patients has improved globally in past years through the use of new combined immunochemotherapy and intensive regimens such as stem cell transplantation, many patients will relapse and eventually die of the disease. Increased understanding of the molecular mechanisms driving MCL has facilitated the development of new therapies that offer promising avenues (Pe´rez-Gala´n et al., 2011). The relevance of B cell receptor (BCR) signaling to the pathogenesis of several lymphomas has propelled investigation of a series of drugs that interfere with these pathways
(Young and Staudt, 2013). Initial clinical studies with some of these agents, particularly ibrutinib, a covalent inhibitor of the Bruton tyrosine kinase (BTK), have yielded substantial responses in different lymphoid neoplasms, including diffuse large B cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), and MCL (Young and Staudt 2013; Wang et al., 2013). However, the encouraging results obtained for MCL were somewhat surprising, because, contrary to DLBCL or CLL, evidence supporting a pathogenic role for BCR stimulation in MCL were limited. Suggestive findings from recent studies in MCL have identified a restricted immunoglobulin gene repertoire and often stereotyped configurations of the BCR, supporting the role of antigen selection in a subset of these tumors. In addition, different kinases in BCR signaling, including SYK, LYN, and BTK, may be amplified or phosphorylated in primary MCL, supporting the activation of this pathway in certain tumors (reviewed in Pe´rez-Gala´n et al., 2011 and Jares et al., 2012). A recent study by Wang et al. (2013) showed complete or partial responses to ibrutinib in up to 68% of patients who had failed to respond to other therapies. This response was higher than expected based on known BCR alterations in MCL. Beyond the positive clinical impact, this study highlighted our limited understanding of the molecular bases for both the high response rate and the resistance to BTK inhibition in these tumors. In a recent study in Nature Medicine, Rahal et al. (2013) found answers to some of the open questions surrounding clinical experience with ibrutinib in MCL. Using a large-scale pharmacological
profiling strategy across more than 100 hematological cell line models, the authors identified 4 MCL lines that were highly sensitive to the BCR signaling inhibitors ibrutinib and sotrastaurin and 6 lines that were resistant to the treatments. Intriguingly, both subsets of sensitive and resistant cell lines were dependent on IKKb-NF-kB signaling, confirming previously reported constitutive NF-kB activation in MCL (Pham et al., 2003). However, the sensitive, but not the resistant, cells were addicted to signaling through the CARD11-BCL10MALT1 (CBM) complex downstream of BTK and PKC, which sustained activation of the classical NF-kB pathway (Figure 1). To understand the possible mechanisms underlying NF-kB activation in resistant cells, the authors performed RNA sequencing and found inactivating mutations of TRAF2 and TRAF3 in two of the resistant cell lines. TRAF2 and TRAF3 are negative regulators of the alternative NF-kB signaling pathway interacting with cIAP1 and cIAP2 (gene products of BIRC2 and BIRC3, respectively) to downregulate NIK (encoded by MAP3K14), a central kinase in this pathway that promotes processing of the NF-kB precursor p100 into the active p52 isoform (Figure 1). Loss of TRAF2 and TRAF3 were essential for survival of the cells suggesting that NIK could be a new target in MCL that specifically bear these genetic alterations. Interestingly, three of the other resistant MCL lines in which the authors did not find similar mutations are known to be infected by Epstein-Barr virus (EBV), an activator of the alternative NF-kB pathway. Intriguingly, there was one resistant cell line without clear evidence of alternative
Cancer Cell 25, January 13, 2014 ª2014 Elsevier Inc. 7
Cancer Cell
Previews
Figure 1. Somatic Mutation and Activation of the NF-kB Pathway in MCL Activation of the classical and alternative NF-kB pathway in MCL may occur by chronic active BCR signaling and other mechanisms. Genomic sequencing studies have identified mutations in several elements of this regulatory pathway (denoted by red asterisks). Chronic active BCR (A) or Toll-like receptor (TLR) (B) signaling activate classical NF-kB pathway. MCL that is dependent on BCR activation (A) may be blocked by BCR signaling inhibitors. Somatic mutations in the inhibitors of the alternative pathways (C) cIAP1 and cIAP2 (gene products of BIRC2 and BIRC3, respectively) and TRAF2/3 activate the alternative NF-kB pathway and confer resistance to inhibitors of the BCR signaling pathway. Somatic mutations in other elements of these pathways (CARD11, IKKb, encoded by IKBKB, TLR2, and NIK, encoded by MAP3K14) have been also found in MCL by whole exome or genome sequencing .
NF-kB pathway activation as it was negative for EBV and TRAF2/3 mutations, suggesting that other mechanisms may create resistance to BCR inhibitors in MCL. Rahal et al. (2013) analyzed the presence of mutations in genes encoding members of the alternative NF-kB pathways TRAF2, TRAF3, BIRC2, BIRC3, and MAP3K14 across 165 primary MCLs and found TRAF2 and BIRC3 mutations in 6% and 10% of the cases, respectively. These observations are concordant with the findings in our recent whole genome and exome sequencing study of MCL in which we found BIRC3 mutations in 6% of cases (Bea` et al., 2013). BIRC3 is located at 11q22.2, a region frequently deleted in MCL. In our study, virtually all BIRC3 mutations were associated with 11q deletions, including a case without
ATM mutations, suggesting that, in addition to the dominant negative effect of these mutations suggested by Rahal et al. (2013), the deletion of the normal BIRC3 allele may confer an additional advantage to the cells. Although we did not observed TRAF2/3 mutations, we found mutations in other genes of the classical and alternative NF-kB pathway, including recurrent activating mutations in TLR2 as well as mutations in CARD11, MAP3K14 (NIK), and IKBKB (IKKb) (Figure 1). Although the functional implications of some of these mutations need to be confirmed, together, the studies suggest that genetic alterations in the NF-kB pathway in MCL may be more common than initially thought. The observations of Rahal et al. (2013), if confirmed in primary tumor cells, may have important clinical implications. The
8 Cancer Cell 25, January 13, 2014 ª2014 Elsevier Inc.
detection of RelB cleavage, as a downstream effect of PKC-CBM activity, and low levels of p52 identified cells sensitive to BCR inhibitors. In contrast, tumors with high p52 levels and genetic lesions in the alternative NFkB pathway predicted resistance to these agents. Therefore, these alterations may be useful biomarkers for selecting targeted therapies in MCL. The involvement of the alternative NF-kB pathway in resistance to BCR inhibitors may also be of interest for other lymphoid neoplasms. Mutations in genes of the alternative (BIRC3, TRAF3, and MAP3K14) and classical (TNFAIP3 and IKBKB) NF-kB pathways have been described in 36% of splenic marginal zone lymphomas (Rossi et al., 2011) and 24% of advanced or chemoresistant CLL (Rossi et al., 2012). The functional relationship between these mutations
Cancer Cell
Previews and the response to new therapies in lymphomas deserves further exploration. Additional mechanisms, such as mutations in BTK or in other targets of the new drugs, may also emerge and confer resistance in MCL. The preclinical results presented by Rahal et al. (2013) provide critical insights into understanding the mechanisms of response to new drugs and suggest innovative therapeutic strategies for tumors refractory to BCR signaling inhibitors. The study also highlights the increasing clinical interest of sequencing tumors to guide the selection of new therapies in lymphoid neoplasms.
is supported by Red Tema´tica de Investigacio´n Cooperativa en Ca´ncer (RD12/0036) and Plan Nacional (SAF10/21165, SAF12/38432); E.C. is an Institucio´ Catalana de Recerca i Estudis Avanc¸ats-Academia (ICREA) investigator.
lished online December 22, 2013. http://dx.doi. org/10.1038/nm.3435. Rossi, D., Deaglio, S., Dominguez-Sola, D., Rasi, S., Vaisitti, T., Agostinelli, C., Spina, V., Bruscaggin, A., Monti, S., Cerri, M., et al. (2011). Blood 118, 4930–4934.
REFERENCES Bea`, S., Valde´s-Mas, R., Navarro, A., Salaverria, I., Martı´n-Garcia, D., Jares, P., Gine´, E., Pinyol, M., Royo, C., Nadeu, F., et al. (2013). Proc. Natl. Acad. Sci U S A. 110, 18250–18255. Jares, P., Colomer, D., and Campo, E. (2012). J. Clin. Invest. 122, 3416–3423. Pe´rez-Gala´n, P., Dreyling, M., and Wiestner, A. (2011). Blood 117, 26–38.
ACKNOWLEDGMENTS
Pham, L.V., Tamayo, A.T., Yoshimura, L.C., Lo, P., and Ford, R.J. (2003). J. Immunol. 171, 88–95.
We thank Dr. Xose A. Puente and Silvia Bea` for their helpful comments. The work of the authors
Rahal, R., Frick, M., Romero, R., Korn, J.M., Kridel, R., Chan, F.Ch., Meissner, B., Bhang, H., Ruddy, D., Kauffmann, A., et al. (2013). Nat. Med. Pub-
Rossi, D., Fangazio, M., Rasi, S., Vaisitti, T., Monti, S., Cresta, S., Chiaretti, S., Del Giudice, I., Fabbri, G., Bruscaggin, A., et al. (2012). Blood 119, 2854– 2862. Vegliante, M.C., Palomero, J., Pe´rez-Gala´n, P., Roue´, G., Castellano, G., Navarro, A., Clot, G., Moros, A., Sua´rez-Cisneros, H., Bea`, S., et al. (2013). Blood 121, 2175–2185. Wang, M.L., Rule, S., Martin, P., Goy, A., Auer, R., Kahl, B.S., Jurczak, W., Advani, R.H., Romaguera, J.E., Williams, M.E., et al. (2013). N. Engl. J. Med. 369, 507–516. Young, R.M., and Staudt, L.M. (2013). Nat. Rev. Drug Discov. 12, 229–243.
From Anecdote to Targeted Therapy: The Curious Case of Thalidomide in Multiple Myeloma Jonathan D. Licht,1,* Jake Shortt,2,3 and Ricky Johnstone2,3 1Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA 2Gene Regulation Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC 3002, Australia 3Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3052, Australia *Correspondence: [email protected] http://dx.doi.org/10.1016/j.ccr.2013.12.019
Thalidomide and related drugs are key drugs for the treatment of multiple myeloma (MM). These agents bind to cereblon, a component of a ubiquitin ligase complex, altering the specificity of the complex to induce the ubiquitylation and degradation of Ikaros (IKZF1) and Aiolos (IKZF3), transcription factors essential for MM growth. The story of the use of thalidomide and related compounds in the treatment of multiple myeloma (MM) represents a remarkable case of bedside to bench research. Thalidomide may have first been discovered during World War II as a potential antidote to nerve gas and was developed as a sedative used for morning sickness in the 1950s. This culminated in a great medical tragedy because of the extraordinary teratogenic effects on limb development. The drug was abandoned but was later explored for the treatment of leprosy ulcers, HIV/ AIDS, and autoimmune diseases. These
anti-inflammatory effects were linked to inhibition of tumor necrosis factor secretion, providing an early indication that thalidomide functioned as an immune modulatory drug (IMiD). Dr. Judah Folkman and colleagues subsequently found that thalidomide inhibited tumor associated angiogenesis. Folkman’s advice to a patient to try thalidomide in MM (http://www.nytimes.com/1999/11/18/us/ thalidomide-found-to-slow-a-bone-cancer. html) led to a seminal study showing a 32% response rate of MM patients to a single agent thalidomide treatment, including complete responses in several
patients refractory to all prior therapies (Singhal et al., 1999). Thalidomide in combination with dexamethasone as an initial therapy yields response rates of >60%, while lenalidomide, a chemically similar IMiD with fewer constitutional side effects, plus dexamethasone yields responses in 80% of patients. The use of these IMiDs along with the proteasome inhibitor bortezomib has extended the median survival of MM patients to greater than 7 years. This remarkable progress occurred in the absence of clear molecular and biological mechanisms of action of thalidomide,
Cancer Cell 25, January 13, 2014 ª2014 Elsevier Inc. 9