Cancer Cell
Previews that SR9243 metabolically reprograms the rapidly growing cancer cells to ‘‘normal’’ metabolic cells that cannot sustain cancer cell growth, and this triggers apoptosis of the cancer cells. The authors extend our molecular understanding of the transcriptional network of LXRs by introducing an inverse agonist. In the unliganded form, LXRs are associated with transcriptional corepressors. Upon agonist activation, LXRs undergo a conformational change where the corepressors dissociate and transcriptional coactivators are recruited. SR9243 interacts with LXRs and strengthens the binding of LXRs to corepressors, and thereby this inverse agonist suppresses LXR-mediated transcription of target genes to below basal levels. Furthermore, SR9243 sensitizes chemotherapy treatment using cytotoxic drugs (50 -fluorouracil and cisplatin) in a combination treatment strategy. Convincingly, in vivo experiments using xenograft models confirmed the anti-tumor effect of SR9243 and reduced expression of glycolytic lipogenic enzymes without inducing weight loss. Multiple studies report on the anti-inflammatory feature of LXRs (Jakobsson et al., 2012), and studies have reported that tumors produce LXR agonists to
avoid the body’s tumor immune surveillance (Villablanca et al., 2010). Flaveny et al. (2015) show that SR9243 specifically induces expression of TNF-a in tumor cells and suggest that SR9243 could ‘‘unmask’’ tumors to be recognized by the immune system. Cytokines in the tumor microenvironment are acknowledged as important factors involved in the control of tumor growth. Interestingly, a recent study linked LXR-mediated survival rates and tumor free animals in lung cancer xenograft models to increased interferon-g production (Wang et al., 2014). While the anti-inflammatory role of LXR is well documented, the cross talk between the effect of LXR signaling in metabolism and the LXR-mediated modulation of the immune response dealing with tumors has only recently been investigated. While Flaveny et al. (2015) provide interesting evidence that targeting LXRs to suppress glycolysis and lipogenesis is a promising new strategy for cancer treatment, further studies investigating the impact and association of LXR signaling in metabolism, immunity/inflammation, and proliferation might unravel novel mechanisms to advance the battle against cancer. And the inverse agonist SR9243 could prove a valuable tool in this quest.
REFERENCES Bovenga, F., Sabba`, C., and Moschetta, A. (2015). Cell Metab. 21, 517–526. Flaveny, C.A., Griffett, K., El-Gendy, B.E.-D.M., Kazantzis, M., Sengupta, M., Amelio, A.L., Chatterjee, A., Walker, J., Solt, L.A., Kamenecka, T.M., and Burris, T.P. (2015). Cancer Cell 28, this issue, 42–56. Jakobsson, T., Treuter, E., Gustafsson, J.A., and Steffensen, K.R. (2012). Trends Pharmacol. Sci. 33, 394–404. Pelicano, H., Martin, D.S., Xu, R.H., and Huang, P. (2006). Oncogene 25, 4633–4646. Pencheva, N., Buss, C.G., Posada, J., Merghoub, T., and Tavazoie, S.F. (2014). Cell 156, 986–1001. Tu, Y., Thupari, J.N., Kim, E.K., Pinn, M.L., Moran, T.H., Ronnett, G.V., and Kuhajda, F.P. (2005). Endocrinology 146, 486–493. Viennois, E., Mouzat, K., Dufour, J., Morel, L., Lobaccaro, J.M., and Baron, S. (2012). Mol. Cell. Endocrinol. 351, 129–141. Villablanca, E.J., Raccosta, L., Zhou, D., Fontana, R., Maggioni, D., Negro, A., Sanvito, F., Ponzoni, M., Valentinis, B., Bregni, M., et al. (2010). Nat. Med. 16, 98–105. Wang, Q., Ma, X., Chen, Y., Zhang, L., Jiang, M., Li, X., Xiang, R., Miao, R., Hajjar, D.P., Duan, Y., and Han, J. (2014). Biochem. J. 459, 345–354. Warburg, O., Wind, F., and Negelein, E. (1927). J. Gen. Physiol. 8, 519–530.
Altering the Course of Small Cell Lung Cancer: Targeting Cancer Stem Cells via LSD1 Inhibition C. Allison Stewart1 and Lauren Averett Byers1,* 1Department of Thoracic and Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.ccell.2015.06.011
In this issue of Cancer Cell, Mohammad et al. describe LSD1, a histone demethylase, as a therapeutic target in SCLC with a unique epigenetic signature to predict drug sensitivity. Inhibition of LSD1 reduces cell proliferation and stem cell maintenance while promoting cell differentiation and reducing tumor growth in preclinical models. Small cell lung carcinoma (SCLC) is one of the most genetically complex cancers (Peifer et al., 2012). Beyond mutations, epigenetic changes also play a key role in promoting aggressive behavior of
SCLC. 31,000 patients are diagnosed with SCLC annually in the United States, a majority of whom have widely disseminated disease at presentation and will succumb to their cancer within a year
4 Cancer Cell 28, July 13, 2015 ª2015 Elsevier Inc.
despite current treatments. Unlike nonsmall cell lung carcinoma (NSCLC), where a growing number of druggable genetic alterations have transformed treatment (e.g., EGFR mutations and ALK, RET,
Cancer Cell
Previews and ROS1 fusions), in SCLC there are currently no targeted therapies with established efficacy and there are no validated biomarkers to guide treatment selection. As a result, a decades-old regimen of platinum-etoposide chemotherapy remains the standard of care. A major challenge in treating SCLC is the rapid emergence of drug resistance, which typically occurs within months of completing chemotherapy. Average survival after recurrence is only 4-6 months due to a lack of effective second-line treatment options. Previous studies in a variety of cancer types have demonstrated the ability of epigenetic therapy to modulate the expression of genes regulating chemoresistance and other critical oncogenic behaviors (Azad et al., 2013). Recently, by comparing methylation patterns in SCLC tumors versus normal lung, Poirier et al. (2015) demonstrated that methylation regulates key SCLC genes, including overexpression of BCL2 and silencing of RB1. Using human tumors, patient-derived xenografts (PDXs), and cell lines, they then identified distinct, reproducible methylation subgroups within SCLC that likely represent subsets with distinct therapeutic responses. Some of these epigenetic changes may be regulated by recurring mutations that include several chromatin modifiers and epigenetic readers (Peifer et al., 2012; Rudin et al., 2012). Clinically, FDA-approved indications for epigenetic therapies are limited to hematological malignancies. However, epigenetic machinery has emerged as an important target for additional diseases including lung cancer. In SCLC, preclinical activity of the histone deacetylase inhibitors vorinostat and belinostat in combination with cisplatin/etoposide (standard first-line treatment) or topotecan (the only FDA approved second-line therapy for SCLC) has led to clinical trials investigating these drugs in combination with chemotherapy. In this issue of Cancer Cell, Mohammad et al. (2015) describe the discovery and characterization of GSK2879552, a selective, highly potent small molecule inhibitor of lysine demethylase 1 (LSD1). LSD1 is a histone modifier that maintains the pleuripotency of embryonic stem cells through demethylation of histone H3 lysine 4 (H3K4) and subsequent repression of genes controlling cell differentia-
tion (Adamo et al., 2011). Prior studies have shown that LSD1 is overexpressed in many cancer types and that inhibition promotes differentiation and reduces cancer cell growth, migration, and invasion (Lv et al., 2012). Because of its central role in stem cell maintenance and cancer progression, the authors sought to identify potent inhibitors of LDS1. This led ultimately to the identification of three LSD1 inhibitory molecules, including GSK2879552 and GSK-LSD1. Further characterization demonstrated that GSK2879552 completely and irreversibly inactivates LSD1’s enzymatic activity and is highly specific for LSD1, despite LSD1 having a structure closely related to LSD2, MAO-A, and MAO-B. The authors then treated 165 cell lines representing multiple cancer types with the newly discovered inhibitors. Most were insensitive to GSK2879552; however, a significant subset of acute myeloid leukemia (AML) and SCLC cell lines were sensitive. The sensitivity of AML to LSD1 inhibition was not surprising based on previously published reports (Harris et al., 2012) and the established use of epigenetic therapies for AML. In contrast, activity in SCLC cell lines (30% of those tested) was a novel and unexpected observation—and one with the potential to address a significant unmet need. As such, the authors performed a detailed investigation into the effects of GSK2879552 in SCLC models. Consistent with the pro-differentiation effect of LSD1 inhibition, GSK2879552 was primarily cytostatic, rather than cytotoxic, in SCLC preclinical models, resulting in a delayed onset of growth inhibition in vitro. Similarly, in SCLC xenografts, tumors did not significantly regress, but rather growth was pronouncedly delayed in treated animals versus controls. Confident in the therapeutic activity of GSK2879552 in SCLC models, the investigators then demonstrated that LSD1 protein is highly expressed in patient tumors and that expression of genes involved in neuroendocrine differentiation (a hallmark of SCLC) changed following GSK2879552 treatment. Next, an integrated analysis of epigenetic changes caused by LSD1 inhibition found LSD1 and H3K4 methylation enrichment surrounding transcriptional start sites of genes involved in the regulation of cell
state. These findings implicate a role for LSD1 in maintaining SCLC stemness, with LSD1 inhibition promoting differentiation, similar to what has been observed in other cancer types. Because only a subset of SCLC models demonstrate sensitivity to LSD1 inhibition, the authors were interested in biomarkers that could potentially identify those SCLC patients likely to derive the greatest benefit from LSD1 targeted therapy. They failed to identify mRNA biomarkers but did identify a set of 45 methylation probes with differences between sensitive and resistant preclinical models. Critically, these 45 probes also separated SCLC human tumors and/or PDX models into two groups—supporting their potential to stratify patients based on the likelihood of response. Most intriguingly, the authors then demonstrated the ability of their methylation signature ‘‘score’’ to correctly predict the response of three PDX models to treatment with GSK2879552 (Figure 1A). Taken together, the findings in this study support GSK2879552 as an LSD1 inhibitor with potential activity against SCLC. Today, patients with SCLC continue to be treated with a ‘‘one-sizefits-all’’ approach using chemotherapy regimens that have not significantly changed in 30 years. However, a growing understanding of the molecular heterogeneity of this disease should allow us to exploit unique molecular features of an individual’s cancer to target specific therapeutic vulnerabilities. The preclinical findings described in this issue are of particular translational relevance given a current multicenter phase 1 study of GSK2879552 in patients with relapsed/ refractory SCLC (NCT02034123). Given the critical issue of drug resistance in SCLC and the potential contribution of stem-cell enrichment to this clinical problem, the introduction of a novel drug that promotes differentiation may be especially effective in treating or preventing SCLC relapse. SCLC cell lines contain large populations of stem cells (Sullivan et al., 2010), which are implicated in chemotherapy resistance and metastasis, both of which are major challenges in SCLC. In fact, CD133 levels, a marker of stem cells, were elevated in SCLC tumors following chemotherapy (Sarvi et al., 2014). By promoting differentiation, rather than stem cell maintenance,
Cancer Cell 28, July 13, 2015 ª2015 Elsevier Inc. 5
Cancer Cell
Previews
recurrence (Figure 1B). In conclusion, this is a promising novel therapeutic agent with unexpected activity in SCLC. In addition to introducing potentially active epigenetic therapy, this study provides the first epigenetic biomarker for SCLC and represents a step toward more tailored treatment for SCLC patients. ACKNOWLEDGMENTS L.A.B. is supported in part by the NCI Cancer Clinical Investigator Team Leadership Award (P30 CA016672), UT Lung Spore (5P50 CA070907), The Sidney Kimmel Foundation for Cancer Research, R. Lee Clark Fellow Award (supported by the Jeane F. Shelby Scholarship Fund), and the MDACC Physician Scientist Award.
REFERENCES Adamo, A., Sese´, B., Boue, S., Castan˜o, J., Paramonov, I., Barrero, M.J., and Izpisua Belmonte, J.C. (2011). Nat. Cell Biol. 13, 652–659. Azad, N., Zahnow, C.A., Rudin, C.M., and Baylin, S.B. (2013). Nat. Rev. Clin. Oncol. 10, 256–266. Harris, W.J., Huang, X., Lynch, J.T., Spencer, G.J., Hitchin, J.R., Li, Y., Ciceri, F., Blaser, J.G., Greystoke, B.F., Jordan, A.M., et al. (2012). Cancer Cell 21, 473–487.
Figure 1. Proposed DNA Hypomethylation Signature to Predict SCLC Sensitivity (A) A signature of 45 differentially methylated CpGs was associated with in vitro sensitivity to the LSD1 inhibitor GSK2879552. To test the performance of the methylation signature, patient-derived xenografts (PDXs) were scored to predict drug response. Two PDXs with positive methylation signature scores responded to GSK2879552, whereas a PDX with a negative score was resistant. (B) Clinical schema of proposed mechanism of GSK2879552 in a biomarker selected SCLC patient population. Following an initial treatment period with chemotherapy, treatment of stem-cell enriched residual SCLC tumor leads to further regression and disease control.
LSD1 inhibition may prolong sensitivity to chemotherapy. The work presented here represents an exciting step toward the possibility of personalized cancer therapy in SCLC. Nevertheless, important questions remain. First, further investigation into the mechanism of action of GSK2879552 in SCLC is warranted given that methylation markers—but not mRNA levels (which should change in response to alterations in methylation)—were predictive of drug response. This raises the possibility of additional mechanisms by which the
LSD1 inhibitor may be acting, such as decreasing the stability of E2F1 protein (Kontaki and Talianidis, 2010). SCLC is an E2F1 ‘‘addicted’’ tumor due to the loss of RB1, and this may contribute to its sensitivity to LSD1 inhibition. Second, the ongoing clinical trial will begin to address whether GSK2879552 has single agent activity in patients with relapse. However, this drug may be most effective in the maintenance setting after the bulky disease has been reduced by chemotherapy and a cancer stem cell population may be enriched and poised for disease
6 Cancer Cell 28, July 13, 2015 ª2015 Elsevier Inc.
Kontaki, H., and Talianidis, I. (2010). Mol. Cell 39, 152–160. Lv, T., Yuan, D., Miao, X., Lv, Y., Zhan, P., Shen, X., and Song, Y. (2012). PLoS ONE 7, e35065. Peifer, M., Ferna´ndez-Cuesta, L., Sos, M.L., George, J., Seidel, D., Kasper, L.H., Plenker, D., Leenders, F., Sun, R., Zander, T., et al. (2012). Nat. Genet. 44, 1104–1110. Poirier, J.T., Gardner, E.E., Connis, N., Moreira, A.L., de Stanchina, E., Hann, C.L., and Rudin, C.M. (2015). Oncogene. Published online March 9, 2015. http://dx.doi.org/10.1038/onc.2015.38. Rudin, C.M., Durinck, S., Stawiski, E.W., Poirier, J.T., Modrusan, Z., Shames, D.S., Bergbower, E.A., Guan, Y., Shin, J., Guillory, J., et al. (2012). Nat. Genet. 44, 1111–1116. Sarvi, S., Mackinnon, A.C., Avlonitis, N., Bradley, M., Rintoul, R.C., Rassl, D.M., Wang, W., Forbes, S.J., Gregory, C.D., and Sethi, T. (2014). Cancer Res. 74, 1554–1565. Sullivan, J.P., Spinola, M., Dodge, M., Raso, M.G., Behrens, C., Gao, B., Schuster, K., Shao, C., Larsen, J.E., Sullivan, L.A., et al. (2010). Cancer Res. 70, 9937–9948.
Previews that SR9243 metabolically reprograms the rapidly growing cancer cells to ‘‘normal’’ metabolic cells that cannot sustain cancer cell growth, and this triggers apoptosis of the cancer cells. The authors extend our molecular understanding of the transcriptional network of LXRs by introducing an inverse agonist. In the unliganded form, LXRs are associated with transcriptional corepressors. Upon agonist activation, LXRs undergo a conformational change where the corepressors dissociate and transcriptional coactivators are recruited. SR9243 interacts with LXRs and strengthens the binding of LXRs to corepressors, and thereby this inverse agonist suppresses LXR-mediated transcription of target genes to below basal levels. Furthermore, SR9243 sensitizes chemotherapy treatment using cytotoxic drugs (50 -fluorouracil and cisplatin) in a combination treatment strategy. Convincingly, in vivo experiments using xenograft models confirmed the anti-tumor effect of SR9243 and reduced expression of glycolytic lipogenic enzymes without inducing weight loss. Multiple studies report on the anti-inflammatory feature of LXRs (Jakobsson et al., 2012), and studies have reported that tumors produce LXR agonists to
avoid the body’s tumor immune surveillance (Villablanca et al., 2010). Flaveny et al. (2015) show that SR9243 specifically induces expression of TNF-a in tumor cells and suggest that SR9243 could ‘‘unmask’’ tumors to be recognized by the immune system. Cytokines in the tumor microenvironment are acknowledged as important factors involved in the control of tumor growth. Interestingly, a recent study linked LXR-mediated survival rates and tumor free animals in lung cancer xenograft models to increased interferon-g production (Wang et al., 2014). While the anti-inflammatory role of LXR is well documented, the cross talk between the effect of LXR signaling in metabolism and the LXR-mediated modulation of the immune response dealing with tumors has only recently been investigated. While Flaveny et al. (2015) provide interesting evidence that targeting LXRs to suppress glycolysis and lipogenesis is a promising new strategy for cancer treatment, further studies investigating the impact and association of LXR signaling in metabolism, immunity/inflammation, and proliferation might unravel novel mechanisms to advance the battle against cancer. And the inverse agonist SR9243 could prove a valuable tool in this quest.
REFERENCES Bovenga, F., Sabba`, C., and Moschetta, A. (2015). Cell Metab. 21, 517–526. Flaveny, C.A., Griffett, K., El-Gendy, B.E.-D.M., Kazantzis, M., Sengupta, M., Amelio, A.L., Chatterjee, A., Walker, J., Solt, L.A., Kamenecka, T.M., and Burris, T.P. (2015). Cancer Cell 28, this issue, 42–56. Jakobsson, T., Treuter, E., Gustafsson, J.A., and Steffensen, K.R. (2012). Trends Pharmacol. Sci. 33, 394–404. Pelicano, H., Martin, D.S., Xu, R.H., and Huang, P. (2006). Oncogene 25, 4633–4646. Pencheva, N., Buss, C.G., Posada, J., Merghoub, T., and Tavazoie, S.F. (2014). Cell 156, 986–1001. Tu, Y., Thupari, J.N., Kim, E.K., Pinn, M.L., Moran, T.H., Ronnett, G.V., and Kuhajda, F.P. (2005). Endocrinology 146, 486–493. Viennois, E., Mouzat, K., Dufour, J., Morel, L., Lobaccaro, J.M., and Baron, S. (2012). Mol. Cell. Endocrinol. 351, 129–141. Villablanca, E.J., Raccosta, L., Zhou, D., Fontana, R., Maggioni, D., Negro, A., Sanvito, F., Ponzoni, M., Valentinis, B., Bregni, M., et al. (2010). Nat. Med. 16, 98–105. Wang, Q., Ma, X., Chen, Y., Zhang, L., Jiang, M., Li, X., Xiang, R., Miao, R., Hajjar, D.P., Duan, Y., and Han, J. (2014). Biochem. J. 459, 345–354. Warburg, O., Wind, F., and Negelein, E. (1927). J. Gen. Physiol. 8, 519–530.
Altering the Course of Small Cell Lung Cancer: Targeting Cancer Stem Cells via LSD1 Inhibition C. Allison Stewart1 and Lauren Averett Byers1,* 1Department of Thoracic and Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.ccell.2015.06.011
In this issue of Cancer Cell, Mohammad et al. describe LSD1, a histone demethylase, as a therapeutic target in SCLC with a unique epigenetic signature to predict drug sensitivity. Inhibition of LSD1 reduces cell proliferation and stem cell maintenance while promoting cell differentiation and reducing tumor growth in preclinical models. Small cell lung carcinoma (SCLC) is one of the most genetically complex cancers (Peifer et al., 2012). Beyond mutations, epigenetic changes also play a key role in promoting aggressive behavior of
SCLC. 31,000 patients are diagnosed with SCLC annually in the United States, a majority of whom have widely disseminated disease at presentation and will succumb to their cancer within a year
4 Cancer Cell 28, July 13, 2015 ª2015 Elsevier Inc.
despite current treatments. Unlike nonsmall cell lung carcinoma (NSCLC), where a growing number of druggable genetic alterations have transformed treatment (e.g., EGFR mutations and ALK, RET,
Cancer Cell
Previews and ROS1 fusions), in SCLC there are currently no targeted therapies with established efficacy and there are no validated biomarkers to guide treatment selection. As a result, a decades-old regimen of platinum-etoposide chemotherapy remains the standard of care. A major challenge in treating SCLC is the rapid emergence of drug resistance, which typically occurs within months of completing chemotherapy. Average survival after recurrence is only 4-6 months due to a lack of effective second-line treatment options. Previous studies in a variety of cancer types have demonstrated the ability of epigenetic therapy to modulate the expression of genes regulating chemoresistance and other critical oncogenic behaviors (Azad et al., 2013). Recently, by comparing methylation patterns in SCLC tumors versus normal lung, Poirier et al. (2015) demonstrated that methylation regulates key SCLC genes, including overexpression of BCL2 and silencing of RB1. Using human tumors, patient-derived xenografts (PDXs), and cell lines, they then identified distinct, reproducible methylation subgroups within SCLC that likely represent subsets with distinct therapeutic responses. Some of these epigenetic changes may be regulated by recurring mutations that include several chromatin modifiers and epigenetic readers (Peifer et al., 2012; Rudin et al., 2012). Clinically, FDA-approved indications for epigenetic therapies are limited to hematological malignancies. However, epigenetic machinery has emerged as an important target for additional diseases including lung cancer. In SCLC, preclinical activity of the histone deacetylase inhibitors vorinostat and belinostat in combination with cisplatin/etoposide (standard first-line treatment) or topotecan (the only FDA approved second-line therapy for SCLC) has led to clinical trials investigating these drugs in combination with chemotherapy. In this issue of Cancer Cell, Mohammad et al. (2015) describe the discovery and characterization of GSK2879552, a selective, highly potent small molecule inhibitor of lysine demethylase 1 (LSD1). LSD1 is a histone modifier that maintains the pleuripotency of embryonic stem cells through demethylation of histone H3 lysine 4 (H3K4) and subsequent repression of genes controlling cell differentia-
tion (Adamo et al., 2011). Prior studies have shown that LSD1 is overexpressed in many cancer types and that inhibition promotes differentiation and reduces cancer cell growth, migration, and invasion (Lv et al., 2012). Because of its central role in stem cell maintenance and cancer progression, the authors sought to identify potent inhibitors of LDS1. This led ultimately to the identification of three LSD1 inhibitory molecules, including GSK2879552 and GSK-LSD1. Further characterization demonstrated that GSK2879552 completely and irreversibly inactivates LSD1’s enzymatic activity and is highly specific for LSD1, despite LSD1 having a structure closely related to LSD2, MAO-A, and MAO-B. The authors then treated 165 cell lines representing multiple cancer types with the newly discovered inhibitors. Most were insensitive to GSK2879552; however, a significant subset of acute myeloid leukemia (AML) and SCLC cell lines were sensitive. The sensitivity of AML to LSD1 inhibition was not surprising based on previously published reports (Harris et al., 2012) and the established use of epigenetic therapies for AML. In contrast, activity in SCLC cell lines (30% of those tested) was a novel and unexpected observation—and one with the potential to address a significant unmet need. As such, the authors performed a detailed investigation into the effects of GSK2879552 in SCLC models. Consistent with the pro-differentiation effect of LSD1 inhibition, GSK2879552 was primarily cytostatic, rather than cytotoxic, in SCLC preclinical models, resulting in a delayed onset of growth inhibition in vitro. Similarly, in SCLC xenografts, tumors did not significantly regress, but rather growth was pronouncedly delayed in treated animals versus controls. Confident in the therapeutic activity of GSK2879552 in SCLC models, the investigators then demonstrated that LSD1 protein is highly expressed in patient tumors and that expression of genes involved in neuroendocrine differentiation (a hallmark of SCLC) changed following GSK2879552 treatment. Next, an integrated analysis of epigenetic changes caused by LSD1 inhibition found LSD1 and H3K4 methylation enrichment surrounding transcriptional start sites of genes involved in the regulation of cell
state. These findings implicate a role for LSD1 in maintaining SCLC stemness, with LSD1 inhibition promoting differentiation, similar to what has been observed in other cancer types. Because only a subset of SCLC models demonstrate sensitivity to LSD1 inhibition, the authors were interested in biomarkers that could potentially identify those SCLC patients likely to derive the greatest benefit from LSD1 targeted therapy. They failed to identify mRNA biomarkers but did identify a set of 45 methylation probes with differences between sensitive and resistant preclinical models. Critically, these 45 probes also separated SCLC human tumors and/or PDX models into two groups—supporting their potential to stratify patients based on the likelihood of response. Most intriguingly, the authors then demonstrated the ability of their methylation signature ‘‘score’’ to correctly predict the response of three PDX models to treatment with GSK2879552 (Figure 1A). Taken together, the findings in this study support GSK2879552 as an LSD1 inhibitor with potential activity against SCLC. Today, patients with SCLC continue to be treated with a ‘‘one-sizefits-all’’ approach using chemotherapy regimens that have not significantly changed in 30 years. However, a growing understanding of the molecular heterogeneity of this disease should allow us to exploit unique molecular features of an individual’s cancer to target specific therapeutic vulnerabilities. The preclinical findings described in this issue are of particular translational relevance given a current multicenter phase 1 study of GSK2879552 in patients with relapsed/ refractory SCLC (NCT02034123). Given the critical issue of drug resistance in SCLC and the potential contribution of stem-cell enrichment to this clinical problem, the introduction of a novel drug that promotes differentiation may be especially effective in treating or preventing SCLC relapse. SCLC cell lines contain large populations of stem cells (Sullivan et al., 2010), which are implicated in chemotherapy resistance and metastasis, both of which are major challenges in SCLC. In fact, CD133 levels, a marker of stem cells, were elevated in SCLC tumors following chemotherapy (Sarvi et al., 2014). By promoting differentiation, rather than stem cell maintenance,
Cancer Cell 28, July 13, 2015 ª2015 Elsevier Inc. 5
Cancer Cell
Previews
recurrence (Figure 1B). In conclusion, this is a promising novel therapeutic agent with unexpected activity in SCLC. In addition to introducing potentially active epigenetic therapy, this study provides the first epigenetic biomarker for SCLC and represents a step toward more tailored treatment for SCLC patients. ACKNOWLEDGMENTS L.A.B. is supported in part by the NCI Cancer Clinical Investigator Team Leadership Award (P30 CA016672), UT Lung Spore (5P50 CA070907), The Sidney Kimmel Foundation for Cancer Research, R. Lee Clark Fellow Award (supported by the Jeane F. Shelby Scholarship Fund), and the MDACC Physician Scientist Award.
REFERENCES Adamo, A., Sese´, B., Boue, S., Castan˜o, J., Paramonov, I., Barrero, M.J., and Izpisua Belmonte, J.C. (2011). Nat. Cell Biol. 13, 652–659. Azad, N., Zahnow, C.A., Rudin, C.M., and Baylin, S.B. (2013). Nat. Rev. Clin. Oncol. 10, 256–266. Harris, W.J., Huang, X., Lynch, J.T., Spencer, G.J., Hitchin, J.R., Li, Y., Ciceri, F., Blaser, J.G., Greystoke, B.F., Jordan, A.M., et al. (2012). Cancer Cell 21, 473–487.
Figure 1. Proposed DNA Hypomethylation Signature to Predict SCLC Sensitivity (A) A signature of 45 differentially methylated CpGs was associated with in vitro sensitivity to the LSD1 inhibitor GSK2879552. To test the performance of the methylation signature, patient-derived xenografts (PDXs) were scored to predict drug response. Two PDXs with positive methylation signature scores responded to GSK2879552, whereas a PDX with a negative score was resistant. (B) Clinical schema of proposed mechanism of GSK2879552 in a biomarker selected SCLC patient population. Following an initial treatment period with chemotherapy, treatment of stem-cell enriched residual SCLC tumor leads to further regression and disease control.
LSD1 inhibition may prolong sensitivity to chemotherapy. The work presented here represents an exciting step toward the possibility of personalized cancer therapy in SCLC. Nevertheless, important questions remain. First, further investigation into the mechanism of action of GSK2879552 in SCLC is warranted given that methylation markers—but not mRNA levels (which should change in response to alterations in methylation)—were predictive of drug response. This raises the possibility of additional mechanisms by which the
LSD1 inhibitor may be acting, such as decreasing the stability of E2F1 protein (Kontaki and Talianidis, 2010). SCLC is an E2F1 ‘‘addicted’’ tumor due to the loss of RB1, and this may contribute to its sensitivity to LSD1 inhibition. Second, the ongoing clinical trial will begin to address whether GSK2879552 has single agent activity in patients with relapse. However, this drug may be most effective in the maintenance setting after the bulky disease has been reduced by chemotherapy and a cancer stem cell population may be enriched and poised for disease
6 Cancer Cell 28, July 13, 2015 ª2015 Elsevier Inc.
Kontaki, H., and Talianidis, I. (2010). Mol. Cell 39, 152–160. Lv, T., Yuan, D., Miao, X., Lv, Y., Zhan, P., Shen, X., and Song, Y. (2012). PLoS ONE 7, e35065. Peifer, M., Ferna´ndez-Cuesta, L., Sos, M.L., George, J., Seidel, D., Kasper, L.H., Plenker, D., Leenders, F., Sun, R., Zander, T., et al. (2012). Nat. Genet. 44, 1104–1110. Poirier, J.T., Gardner, E.E., Connis, N., Moreira, A.L., de Stanchina, E., Hann, C.L., and Rudin, C.M. (2015). Oncogene. Published online March 9, 2015. http://dx.doi.org/10.1038/onc.2015.38. Rudin, C.M., Durinck, S., Stawiski, E.W., Poirier, J.T., Modrusan, Z., Shames, D.S., Bergbower, E.A., Guan, Y., Shin, J., Guillory, J., et al. (2012). Nat. Genet. 44, 1111–1116. Sarvi, S., Mackinnon, A.C., Avlonitis, N., Bradley, M., Rintoul, R.C., Rassl, D.M., Wang, W., Forbes, S.J., Gregory, C.D., and Sethi, T. (2014). Cancer Res. 74, 1554–1565. Sullivan, J.P., Spinola, M., Dodge, M., Raso, M.G., Behrens, C., Gao, B., Schuster, K., Shao, C., Larsen, J.E., Sullivan, L.A., et al. (2010). Cancer Res. 70, 9937–9948.
