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C.M. Rudin
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MS02 - Stem Cells and Epigenetics in Lung Cancer (ID 19)
- Event: WCLC 2013
- Type: Mini Symposia
- Track: Biology
- Presentations: 1
- Moderators:G. Sozzi, J. Minna
- Coordinates: 10/28/2013, 14:00 - 15:30, Bayside 103, Level 1
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MS02.4 - Targeting Epigenetic Changes in Lung Cancer (ID 465)
15:05 - 15:25 | Author(s): C.M. Rudin
- Abstract
- Presentation
Abstract
The process of carcinogenesis is driven by clonally maintained genetic and epigenetic events that lead to aberrant cell proliferation, inhibit cell death, promote cell dissemination, and affect other key pathways. Research in the past decade has led to new insights into the epigenetic mechanisms controlling gene expression, and into the multiple ways in which these mechanisms are specifically disrupted in cancer. Epigenetic control of gene expression is dependent on modifications of the DNA itself, primarily methylation at CpG dinucleotides, and also by a host of site-specific protein modifications of histones, histone modifiers, and transcriptional machinery. Progress in understanding the multiple layers of epigenetic control is leading to the development and clinical testing of anti-cancer agents specifically targeting these aberrant pathways. DNA methylation and histone acetylation are two well established epigenetic control mechanisms that are known to be aberrantly regulated in essentially all cancers, including lung cancer. We conducted an exploratory phase I/II trial combining an inhibitor of DNA methyltransferase, azacitidine, and an inhibitor of histone deacetylase, entinostat, in patients with recurrent metastatic non-small cell lung cancer. DNA methylation of gene promoters, and loss of histone acetylation, are coordinately regulated processes that can lead to selective silencing of gene expression: this mechanism has been implicated in silencing key tumor suppressor genes in cancer. Treatment with the combination of azacitidine and entinostat led to rare but impressive objective responses, including a complete response in a patient with extensively pretreated disease. In addition, a surprising fraction of patients experienced objective responses to the immediate subsequent therapy, including standard cytotoxic agents and investigational agents targeting the PD-1/PD-L1 immune checkpoint pathway. Preclinical data offer some potential explanations for this observation: many relevant immunoregulatory pathways in both tumor cells and immune effectors are markedly affected by azacitidine. We are now following up on the priming hypotheses suggested by these data, in randomized phase II studies assessing whether limited duration epigenetic therapy can enhance subsequent chemotherapy or immunotherapy efficacy in patients with advanced non-small cell lung cancer. This study represents an initial foray into combinatorial epigenetic strategy in lung cancer: many other strategies are now possible and are being pursued. “Second generation” agents targeting DNA methyltransferase, including an oral formulation of azacitidine and a prodrug, SG-110, are in early phase clinical development. So too are newer histone deacetylase inhibitors differing in specificity, selectivity, route of administration, and pharmacokinetics. Among the exciting new horizons in epigenetic therapy are new agents targeting more recently defined modifiers of epigenetic control, including many of the readers, writers, and erasers of histone modification. The recent remarkable expansion in knowledge about epigenetic regulatory pathways, and how they become dysregulated in cancer, is opening new therapeutic opportunities in lung cancer and other diseases.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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PL02 - Will Personalised Therapies Ever “Cure” Metastatic NSCLC? (ID 73)
- Event: WCLC 2013
- Type: Plenary Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:D. Gandara, D. Carney
- Coordinates: 10/28/2013, 08:15 - 09:45, Plenary Hall, Ground Level
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PL02.2 - Dark Matter: Defining Oncogenic Drivers in the Epigenome (ID 634)
08:40 - 09:00 | Author(s): C.M. Rudin
- Abstract
Abstract
The single most important advance in the approach to lung cancer treatment in the past decade has been the iterative identification and targeting of subsets of lung cancer defined by distinct oncogenic driver mutations. This has changed the way we think about these diseases, and is accelerating the development of driver-targeted therapies that are improving multiple measures of clinical outcome, most dramatically documented by waterfall plots of tumor response, for patients with advanced lung cancer. Despite the clinically meaningful benefits provided by selective inhibition of mutated oncogenic drivers, however, none of these treatments have changed the fundamental incurability of metastatic lung cancer. Hence the impetus for this series of talks: we have markedly improved the short-term prognosis for select subsets of our patients, but the survival curves even for these subsets go to ground. This observation, entirely consistent with the clinical experience of targeted inhibitor development in other malignancies, has prompted focused research in a number of directions, including inhibiting secondary mutations and escape pathways implicated in acquired resistance, priming the immune system to effectively respond to advanced cancer, and defining and targeting non-mutational (epigenetic) mechanisms contributing to oncogenesis and disease persistence. Epigenetics refers to the somatically heritable differences in gene expression not attributable to intrinsic alterations in the primary sequence of DNA. In general, the cells that comprise an individual have identical genomes, but have many entirely different epigenomes that dictate tissue specificity and cellular function. The past decade has seen remarkable expansion of our understanding of how epigenetic control influences the patterns of gene expression, how these controls can be manipulated, and how such manipulation can influence cell fate. These emerging insights have clear translational implications for therapeutic targeting epigenetic abnormalities in cancer. Cancers of all types demonstrate extensive and biologically significant changes in the epigenetic code; these changes collectively can be termed the “cancer epigenome.” Clonally heritable alterations in the cancer epigenome include important oncogenic drivers, entirely analogous to somatic mutations in the cancer genome. One nice example demonstrating the complementary nature of genetic and epigenetic alterations in cancer has emerged from The Cancer Genome Atlas sequencing efforts in lung cancer, revealing key tumor suppressors affected by mutational inactivation or epigenetic silencing in non-overlapping sets of cases. There is a key difference between genetic and epigenetic changes in cancer-causing genes. Mutation is in general irreversible, while epigenetic changes are not: these could be reversed with appropriately directed therapy. This plasticity may represent both an opportunity and a limitation for epigenetic therapy approaches. The existence of intermediate states of gene silencing or activation can further complicate identification of epigenetically dysregulated “driver” and “passenger” genes in cancer. I will review our recent progress in epigenetic profiling of small cell lung cancer. The development of epigenetically targeted anti-cancer drugs has lagged behind the recent explosive expansion of mutant kinase inhibitors. In part, this may be because many key components of epigenetic dysregulation in cancer are only now being described. Currently available epigenetically targeted drugs include the DNA methyltransferase inhibitors azacitidine and decitabine and the histone deacetylase inhibitors romidepsin and vorinostat; a much larger portfolio of both of these classes of drugs, particularly the HDAC inhibitors, are now in development. These classes of drugs both induce broad changes in gene expression. Our experience in combining azacitidine with the HDAC inhibitor entinostat in patients with advanced lung cancer will be discussed in another presentation at this meeting. An additional development with translational implications for drug development that has emerged from recent genomic sequencing efforts is the recognition that virtually all tumors harbor mutations in critical regulators of the epigenome. Novel agents targeting other epigenetic factors, including multiple chromatin modifiers, are now in development. Bromodomain inhibitors targeting the BET family proteins may be of particular interest in blocking activation of MYC target genes, of central relevance in small cell lung cancer. If cancer-specific epigenetic alterations were just an alternative to mutation in heritably affecting specific oncogenic drivers, one might not expect epigenetically directed therapy to lead to durable responses. However, several preclinical observations that suggest that effective epigenetic therapy could have very different, and potentially complementary, effects. One set of observations, first noted by the Settleman laboratory, suggests a strategy to convert excellent responses to targeted therapy to durable responses. These investigators define drug-tolerant “persisters” among driver-oncogene dependent tumor cells treated with supratherapeutic doses of tyrosine kinase inhibitors – these persisters are clonogenic but are dependent on a particular histone demethylase (KDM5A) and can be eliminated by exposure to any of multiple HDAC inhibitors. A second set of observations, from the Baylin laboratory and others, demonstrates that low dose exposure to demethylating agents alone, below the level of substantial cytotoxicity, can alter the long-term clonogenic and tumorigenic potential of cancer cells. A final set of observations concerns the extensive array of cancer-relevant pathways and processes that can be concomitantly affected by epigenetically targeted therapy; of particular note are multiple immunologically relevant pathways in both tumor cells and immunologic effectors. Induced re-expression of silenced tumor antigens together with stimulation of immune response pathways may enhance tumor susceptibility to immunotherapy. These recent observations define clinically testable hypotheses using currently available investigational agents that could affect the long-term survival of patients with lung cancer.
