Virtual Library
Start Your Search
D. Gandara
Moderator of
-
+
PL02 - Will Personalised Therapies Ever “Cure” Metastatic NSCLC? (ID 73)
- Event: WCLC 2013
- Type: Plenary Session
- Track: Medical Oncology
- Presentations: 5
- Moderators:D. Gandara, D. Carney
- Coordinates: 10/28/2013, 08:15 - 09:45, Plenary Hall, Ground Level
-
+
PL02.0 - Chair Intro (ID 632)
08:15 - 08:20 | Author(s): D. Gandara
- Abstract
Abstract not provided
-
+
PL02.1 - Identifying Druggable Targets Through Whole Genome Sequencing: TCGA (ID 633)
08:20 - 08:40 | Author(s): M. Meyerson
- Abstract
Abstract not provided
-
+
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. -
+
PL02.3 - Tumour Heterogeneity as an Obstacle to Cure (ID 635)
09:00 - 09:20 | Author(s): C. Swanton
- Abstract
Abstract
Despite advances in cancer genomics, most advanced solid tumors remain incurable and drug resistance is almost inevitable. Two important lessons have emerged, which may provide an explanation for difficulties that have been encountered in improving cancer survival outcomes. First, each tumor contains an individual assortment of multiple genomic aberrations, few of which are shared between patients with the same histopathological tumor subtype. Second, evidence suggests that these anomalies appear to vary within individual tumors, both spatially and temporally during the disease course, indicating substantial intratumor heterogeneity. Branched evolutionary growth and intratumor heterogeneity results in coexisting cancer cell subclones with variegated genotypes and phenotypes that may be regionally separated within the same tumor and alter in dominance over time. Variegated phenotypes, resulting from intratumoral genetic heterogeneity and the emergence of new subclones at relapse, are likely to have important implications for developing novel targeted therapies and for preventing the emergence of drug resistance. Intratumor heterogeneity and sampling bias, resulting from single biopsy-driven biomarker discovery and validation approaches, may also contribute to the recently reported failures in implementation of robust biomarkers in the clinical setting. In this talk, the two fundamental principles of Darwinian Evolution, diversity and selection, will be discussed in relation to achieving better cancer survival outcomes. -
+
PL02.4 - What is Cure and How Can We Achieve This With Targeted Therapies? (ID 636)
09:20 - 09:40 | Author(s): T. Mok
- Abstract
Abstract not provided
Author of
-
+
MO18 - NSCLC - Targeted Therapies IV (ID 116)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:L. Horn, J. Wolf
- Coordinates: 10/29/2013, 16:15 - 17:45, Bayside Auditorium B, Level 1
-
+
MO18.08 - Phase II/III Biomarker-Driven Master Protocol for Second Line Therapy of Squamous Cell Lung Cancer (SCCA). (ID 1958)
16:55 - 17:00 | Author(s): D. Gandara
- Abstract
- Presentation
Background
There are few new effective therapeutic options for patients with advanced, lung SCCA; overall survival for metastatic disease being less than one year. The Cancer Genome Atlas (TCGA) project and similar studies have detected a significant number of somatic gene mutations/amplifications in patients with this disease, some of which are targetable by investigational agents. However, the frequency of these changes is low (5-20%) in these patients, making recruitment and treatment very challenging in the traditional single-agent trial setting. Our approach is to use a common platform (Next Generation DNA Sequencing) to enable a single “umbrella screening protocol” to efficiently find patients with varied, uncommon molecular changes.Methods
Figure 1 This is a prospective, multi-substudy randomized Phase II/III Master Registration Protocol in which patients with advanced stage Lung SCCA (2[nd] line therapy)are randomized to biomarker-driven targeted therapy (TT) or standard of care (SOC) as shown in the schema after undergoing genomic screening. Genomic screening of a large patient resource provided by sites participating in the NCI North American Intergroup will identify molecular targets/biomarkers with an analytically validated diagnostic assay and a new drug match, leading to appropriate drug treatment-arm assignment. Archival FFPE tumor and/or core needle biopsies will be screened by a broad analytically validated next generation sequencing (NGS) platform centrally to establish eligibility within 10-14 days. This platform will be supplemented by individual immune-histochemical (IHC) protein assays performed in a CLIA setting as necessitated by the specific experimental agent used. Patients will be screened with homogeneous eligibility criteria. The overall trial objective is to establish a mechanism to genomically screen large but homogeneous cancer populations and subsequently assign and accrue simultaneously to multiple substudies comparing new TT to SOC therapy based on the identified therapeutic biomarker-drug combination. Each sub-study will function autonomously and will open and close independently of the other sub-studies. Drug combinations in the experimental arm will be allowed in appropriate settings and where appropriate the control arm may consist of FDA approved targeted therapy such as erlotinib. Each sub-study is independently powered for OS with an interim analysis for PFS to determine the “go-no go” decision to proceed from Phase II into Phase III. Each agent, along with the paired biomarker, that is successful at the interim analysis based on PFS will advance to a Phase III randomized registration trial (on behalf of the Master Protocol Steering Committee).Results
NAConclusion
NAOnly 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.
-
+
MO20 - Preclinical Therapeutic Models II (ID 93)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Biology
- Presentations: 1
- Moderators:P. Waring, M. Kohonen-Corish
- Coordinates: 10/30/2013, 10:30 - 12:00, Bayside Gallery B, Level 1
-
+
MO20.04 - Divergent activity of afatinib (AFAT) and cetuximab (CET) in patient-derived xenograft (PDX) models of acquired erlotinib resistance. (ID 1458)
10:45 - 10:50 | Author(s): D. Gandara
- Abstract
- Presentation
Background
The combination of AFAT and CET has demonstrated remarkable clinical activity in patients with acquired resistance to erlotinib. Preclinical modeling in genetically engineered mice and cell lines predicted activity in cases where erlotinib resistance was mediated by the EGFR T790M gatekeeper mutation. However, in the clinic, patients lacking T790M-positive tumors showed equivalent benefit from this combination, suggesting alternative mechanisms of synergy. We explored the individual and combined molecular and growth inhibitory activity of these agents in PDX models derived from NSCLC patient tumors with distinct mechanisms of acquired resistance to erlotinib. These models were developed by the UC Davis - Jackson Laboratories Consortium, which has xenotransplanted over 170 NSCLC models using the nod/scid/IL2Rgamma chain-null (NSG) mouse.Methods
EGFR-mutant PDX models LG0703 (T790M-negative) and LG1049 (T790M-positive) were established from tumor biopsies from patients who progressed following durable responses to erlotinib. Both patients were subsequently treated with AFAT+CET, with the LG0703 donor patient exhibiting a prolonged response and the LG1049 donor patient exhibiting a transient response followed by rapid progression. Excised tumors from passage 1 PDXs were fragmented and implanted into treatment cohorts. When tumors reached 300mm[3], mice were randomized to erlotinib (50 mg/kg qd po), AFAT (20 mg/kg qd po), CET (10 mg/kg twice weekly iv), AFAT-CET, or vehicle control (n per arm = 12) for 3 weeks followed by a 75-day monitoring period. In a parallel cohort, tumor pharmacodynamic changes in signal transduction mediators and RTKs were assessed after 6 and 24h treatment exposures using kinase arrays (R&D systems) and immunoblotting.Results
In LG0703, AFAT, CET and AFAT-CET resulted in complete tumor response (CR) during the 21-day treatment period. After cessation of treatment, mice treated with CET or AFAT-CET remained in complete remission; whereas AFAT-treated mice progressed within 2 weeks. Clinical activity in this model was associated with complete blockade of EGFR and Her2 phosphorylation. Substantial down-regulation of AKT1, AKT2, ERK1, p38a, RSK1 and p70S6K phosphorylation was evident within 6h of treatment. In contrast, the T790M-postive LG1049 model demonstrated only modest clinical benefit from AFAT, with no single-agent CET activity, and no CET-mediated synergy with AFAT. No treatments were able to ablate EGFR phosphorylation or downstream signal transduction, and compensatory induction of EGFR, HER2, ERK1 and p38 were noted after 24h of drug exposure.Conclusion
In these PDX models derived from patients with EGFR-activating mutant cancer with acquired resistance to erlotinib, treatment with AFAT+CET recapitulated the clinical experience of the donor patients receiving this combination. In the LG0703 model, both the AFAT-CET combination as well as single-agent CET resulted in complete tumor regression associated with total ablation of EGFR phosphorylation and subsequent blockade of multiple signal transduction pathways. In the LG1049 model, AFAT prompted limited but statistically significant tumor delay, with no additional benefit from CET. These experiments demonstrate the considerable potential of this PDX resource to assess therapeutic strategies in models representing individual patients. Supported by BJALCF.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.
-
+
MS13 - Statistics of Personalised Medicine (ID 30)
- Event: WCLC 2013
- Type: Mini Symposia
- Track: Statistics
- Presentations: 1
- Moderators:M. Redman, J. Crowley
- Coordinates: 10/29/2013, 14:00 - 15:30, Parkside 110 A+B, Level 1
-
+
MS13.4 - The Future of RCTs in the Molecular Era? (ID 519)
15:05 - 15:25 | Author(s): D. Gandara
- Abstract
- Presentation
Abstract not provided
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.
-
+
O01 - Prognostic and Predictive Biomarkers I (ID 94)
- Event: WCLC 2013
- Type: Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:T. Mitsudomi, V. Gregorc
- Coordinates: 10/28/2013, 10:30 - 12:00, Parkside Auditorium, Level 1
-
+
O01.08 - DISCUSSANT (ID 3910)
11:45 - 12:00 | Author(s): D. Gandara
- Abstract
- Presentation
Abstract not provided
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.
-
+
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
-
+
PL02.0 - Chair Intro (ID 632)
08:15 - 08:20 | Author(s): D. Gandara
- Abstract
Abstract not provided
