Virtual Library
Start Your Search
Kenneth Obyrne
Moderator of
-
+
ES 09 - Recent Progress in the Management of Small Cell Lung Cancer (ID 518)
- Event: WCLC 2017
- Type: Educational Session
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 5
- Moderators:David S Ettinger, Kenneth Obyrne
- Coordinates: 10/18/2017, 14:30 - 16:15, Room 501
-
+
ES 09.01 - Genomics and Translational Research (ID 7619)
14:30 - 14:50 | Presenting Author(s): Charles M Rudin
- 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.
-
+
ES 09.02 - Cytotoxic Chemotherapy (ID 7620)
14:50 - 15:10 | Presenting Author(s): Yoichi Nakanishi
- Abstract
- Presentation
Abstract:
Untreated small-cell lung cancer (SCLC) is highly sensitive to both chemotherapy and radiotherapy, although its growth is very rapid. Clinically, SCLC is classified into limited-diseases (LD) and extensive-disease (ED). Although there is no distinct criteria, LD is generally accepted to be a disease which is confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph nodes without malignant effusion, i.e., a disease that curative radiotherapy is applicable. Nearly 30% of SCLC is LD at initial diagnosis. LD-SCLC is potentially curable disease, and standard treatment is chemo-radiotherapy, especially concurrent use of chemotherapy and radiotherapy is chosen if performance status of patient is 2 or less and organ function is good. Cisplatin plus etoposide is usually administered together with radiotherapy, since the combination chemotherapy is one of the most effective regimens and also risk of radiation pneumonia is low when the combination is chosen. Median survival time of LD-SCLC is 16 to 24 months and 5-year survival is nearly 15%. On the other hand, median survival time of ED-SCLC is 6-12 months, and long-term disease-free survival is rare. Chemotherapy alone is chosen to ED-SCLC. Globally, combination of cisplatin/carboplatin plus etoposide is recognized as a standard chemotherapy. In Japanese guideline, a combination with cisplatin plus irinotecan is the first choice if tolerable. One of the reasons why standard therapy is different between western and eastern countries is based on distribution of uridine diphosphate glucuronosyltransferase (UGT) 1A1 gene polymorphisms. Although drug therapy with cytotoxic agents to SCLC used be the only successful treatment modality for metastatic lung cancer in the past century, its development now appears to slow down. To maximize the effect of cytotoxic agents, combination with immune checkpoint inhibitors or novel targeted drugs would be critical.
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.
-
+
ES 09.03 - Immunotherapy (ID 7621)
15:10 - 15:30 | Presenting Author(s): Caicun Zhou | Author(s): M. Qiao
- Abstract
- Presentation
Abstract:
Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor which accounts for 10-15% of all lung cancers[1]. It is extremely lethal with rapid recurrence and dismal prognosis. Although it is sensitive to chemotherapy with 50%-80% overall response rate (ORR), it inevitably recurs within 6 months, especially those in extensive-stage (ES) SCLC[2, 3]. However, treatment options are limited for those who relapse after first-line chemotherapy and standard options have few improvements in SCLC for several decades. How to tackle the chemo-resistant SCLC patients with rapid recurrence after first-line chemotherapy? How to prolong the effective duration of standard chemotherapy? How to improve the prognosis after the second line treatment? These tough concerns need to be addressed. Immunotherapy, especially the inhibitors targeting immune checkpoints such as cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), programmed death-1(PD-1) and programmed death ligand-1(PD-L1), achieved great success and durable anti-tumor response across multiple tumor types[4, 5]. In terms of SCLC, the high frequency of somatic mutations[6], along with the approximately 10% incidence rate of para-neoplastic and neoplastic triggered autoimmune disease, for instance, Lambert-Eaton myasthenia[7], prompts that the SCLC is a immunogenic type of cancer and possibly, responds to immunotherapy. Therefore, several clinical trials come up then. At present, in the context of high ORR of the first-line chemotherapy treatment, the purpose of the clinical studies based on the immune checkpoint inhibitors (ICI) in the treatment of SCLC can be divided into two categories: 1) integrating ICI into standard chemotherapy as first-line regimen or maintenance therapy 2) single ICI ( nivolumab/ipilimumab/atezolizumab)/ combined with chemotherapy/combined with multiple immune checkpoint inhibitors as compelling options as second or subsequent line regmen. In summary, these regimens could be subdivided into: 1) Ipilimumab plus chemotherapy 2) PD-1/PD-L1 inhibitors alone or together with chemotherapy 3) combination of CTLA-4 blockade and PD-1/PD-L1 inhibitors with or without chemotherapy. Since the outcome from a phase III trial regarding ipilimumab plus chemotherapy was dismal[8], the paradigm has been shifted from single CTLA-4 blockade plus chemotherapy to PD-1 inhibitor, and indeed, PD-1 inhibitor alone or combined with CTLA-4 blockade seem more promising in the treatment of SCLC. In 2017 ASCO, a phase II study evaluating the role of maintenance pembrolizumab in newly diagnosed SCLC patients demonstrated that this regimen didn’t improve the PFS (median PFS: 1.4 months). However, an exploratory analysis from this study suggested that patients with expression of PD-L1 in tumor stromal interface had better outcome( longer PFS: 5.5 months VS 1.3 months and OS: 10.1 VS 7.2 months)[9]. Multiple trials are ongoing to define the roles of this drug in SCLC patients, for instance, pembrolizumab plus chemotherapy in first-line settings (Keynote011), in second or subsequent settings. Additionally, a phase III study is ongoing to determine the effectiveness of nivolumab monotherapy compared to chemotherapy in relapsed SCLC (Checkmate 331). As for atezolizumab, a phase I/III study is underway to evaluate the efficacy of combination of atezolizumab and carboplatin/etoposide as first-line treatment of ES-SCLC (IMPOWER 133). In terms of combination of PD-1 inhibitors and CTLA-4 blockade, Checkmate 032, the first trial evaluating the combination of nivolumab and ipilimumab in the treatment of patients with SCLC who had progressed after one or more treatment regimens was reported in ASCO recently. Both nivolumab monotherapy and nivolumab plus ipilimumab showed promising anti-tumor activity with durable responses and manageable safety profiles[10]. These data prompted nivolumab alone or nivolumab-ipilimumab combination regimen to be incorporated into NCCN guidelines for SCLC as second line treatment recommendation. Moreover, in 2017 ASCO, the updated data from Checkmate032 was reported. With longer follow up in non-randomized cohort, the response remains encouraging. 2-year OS could be achieved 14% and 26%, respectively in monotherapy and combination therapy[11]. In this setting, a phase III trial, termed Checkmate451 assessing the role of nivolumab monotherapy, nivolumab-ipilimumab combination and placebo as maintenance therapy in ES-SCLC and a phase II trial, STIMULI, in LS-SCLC were initiated. Plus, a phase II trial regarding the tremelimumab and durvalumab with or without radiation in relapsed SCLC patients is ongoing and more data are warranted . However, many questions remain. The immune microenvironment in SCLC is distinct from other tumor types for SCLC cells express low levels PD-L1, though with high mutation burdens. In Checkmate032, there is no observation on clear association between tumor PD-L1 expression and clinical benefit. However, as mentioned above, patients with positive PD-L1 expression in the stromal interface had better PFS and OS observed in a phase II trial[9]. The prediction value of PD-L1 expression is supposed to be shifted from tumor cells to surrounding immune cells in SCLC. Thus, it is important to define a specific biomarker to predict the response to immunotherapy and explore the distinct tumor microenvironment in SCLC. Moreover, potential toxicity is not supposed to be underestimated, especially the immune-related adverse effects. Immune related side effects will happen in the course of the treatment. Close monitoring is essential and oncologists are suggested to balance the risks and benefits of immunotherapy in the clinical practice. References 1. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359:1367-1380. 2. Rossi A, Di Maio M, Chiodini P, et al. Carboplatin- or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: the COCIS meta-analysis of individual patient data. J Clin Oncol. 2012;30:1692-1698. 3. Lehman JM, Gwin ME, Massion PP. Immunotherapy and Targeted Therapy for Small Cell Lung Cancer: There Is Hope. Curr Oncol Rep. 2017;19:49. 4. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016;375:1823-1833. 5. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320-330. 6. Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415-421. 7. Gozzard P, Woodhall M, Chapman C, et al. Paraneoplastic neurologic disorders in small cell lung carcinoma: A prospective study. Neurology. 2015;85:235-239. 8. Reck M, Luft A, Szczesna A, et al. Phase III Randomized Trial of Ipilimumab Plus Etoposide and Platinum Versus Placebo Plus Etoposide and Platinum in Extensive-Stage Small-Cell Lung Cancer. J Clin Oncol. 2016;10.1200/JCO.2016.67.6601. 9. Gadgeel SM, Ventimiglia J, Kalemkerian GP, et al. Phase II study of maintenance pembrolizumab (pembro) in extensive stage small cell lung cancer (ES-SCLC) patients (pts). Journal of Clinical Oncology. 2017;35:8504-8504. 10. Antonia SJ, Lopez-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016;17:883-895. 11. Hellmann MD, Ott PA, Zugazagoitia J, et al. Nivolumab (nivo) ± ipilimumab (ipi) in advanced small-cell lung cancer (SCLC): First report of a randomized expansion cohort from CheckMate 032. Journal of Clinical Oncology. 2017;35:8503-8503.
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.
-
+
ES 09.05 - Management of Paraneoplastic Syndromes in SCLC (ID 7623)
15:30 - 15:50 | Presenting Author(s): Lucio Crinò
- Abstract
- Presentation
Abstract:
Small cell lung cancer (S.C.L.C.) represents approximately 15% of lung cancers and offers a unique profile of clinical and biological features) S.C.C.L. is a fast growing tumor with are estimated doubling time of 10 days, high propensity to metastatic diffusion since the early beginning of the disease, high sensitivity to chemoradiotherapy but early and common development of pleiotropic drug resistance. Unfortunately in the past 30 years very few advances have been realized in the treatment of S.C.L.C. which in most of the patients is a fatal disease with a median survival of 16-18 months in limited thoracic and 11 months in extensive disease. S.C.L.C. is the most common cancer associated with paraneoplastic syndromes because of it’s propensity to release endocrine peptides, ectopic hormones and neoantigens that can develop the para neoplastic syndromes.Paraneoplastic syndromes constitutes different and heterogeneous clinical conditions associated with cancer development, affecting various tissues at remote locations from theprimary tumour , with an unpredictable clinical behavior. In SCLC, a large number of paraneoplastic syndromes have been reported, involving different organ functions and complicating the clinical course of the disease, including endocrine, neurological and miscellaneous less frequent manifestations. The most common paraneoplastic syndromes in SCLC, can be divided in ectopic hormone-associated syndromes, and immunomediated neurologic syndromes. According to the S.C.L.C. produced hormones we can recognized among the ectopic hormone-associated syndromes, the Hyponatremia (10%) of S.C.L.C., the ectropic Cushing syndrome (5%) Hypertension reninrelated (1%), galactorrhea (1%) and hyperamylasemia (1%). S.C.L.C. has the unique feature to be often heralded or accompanied by a number of immune-mediated neurologic syndromes, the Lambert-Eaton myastemic syndrome 1%, the limbic encephalopaty and the encephalomyelitis, the sensory polyneuropathy, the cerebellar degeneration the opsoclonus myoclonus, all accounting for less than 1%. In most of the cases the neurological symptoms develop before the onset of clinical overt S.C.L.C manifestation and the stage seems not to be related to the presence of paraneoplastic neurological syndrome, whose evolution usually mirrors the behavior and the clinical manifestation. In most of the cases the starting of systemic chemoterapy can induce a dramatic improvement of neurological symptoms in advance to clinical response, and viceversa the worsening of the neurological condition can indicate progressive disease and resistance to the treatment.The study and the improved understanding of pathophisiolgy mechanisms of paraneoplasic syndromes in SCLC can contribute to elucidate the natural history of a fascinating and still largely unknown disease which was erroneously predicted to be a potential curable disease in the eighty years. From that time the treatment strategies and the therapeutic results have been only marginally improved and the undersanding and resolution of paraneoplastic syndromes can contribute substantially to the cure improvement of SCLC.
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.
-
+
ES 09.06 - NCI’s Small Cell Lung Cancer Consortium: New Answers to Old Questions (ID 10941)
15:50 - 16:10 | Presenting Author(s): Peter Ujhazy
- Abstract
- Presentation
Abstract:
The worldwide toll in mortality due to small cell lung cancer (SCLC) is still unacceptable. Based on an analysis conducted by the National Cancer Institute US (NCI) in 2014, there are five priorities in SCLC that need to be addressed by scientists and clinicians: 1. Development of better research tools for the study of SCLC; 2. Conduct of comprehensive genomic profiling of SCLC; 3. Creation of new diagnostic and prevention approaches for SCLC; 4. Therapeutic development efforts; and 5. Study of mechanisms underlying both high rate of initial response and rapid emergence of drug and radiation resistance. These priorities are being currently addressed by the newly established NCIs SCLC Consortium, an effort to coordinate and network investigators focusing on pre-clinical studies of the disease. The SCLC Consortium currently includes a coordinating resource center, members with their individual projects, and associate members funded through other grant mechanisms. The Principal Investigator of the Coordinating Center is Dr. Charles Rudin from the Sloan Kettering Institute for Cancer Research in New York, NY and he is joined by Drs. John Minna (University of Texas South Western), Tyler Jacks (Broad Institute), You Shyr (Vanderbilt University), and Afshin Dowlati (Case Western Reserve University). The Coordinating Center provides administrative, meeting, and communication support, a bioinformatics database, centralized tissue banking and virtual biospecimen database, centralized biostatistics, cell line and animal model repository. The four Research Projects in the Consortium were selected by a standard peer review process and they focus on: 1) the use of extracellular vesicles for early detection of SCLC; 2) preclinical development of a DLL3-targeted theranostic for SCLC; 3) targeting the transcriptional and epigenetic landscape in chemo-refractory SCLC; and 4) novel therapeutic approaches for enhancing anti-tumor immunity in SCLC. The first project, led by Drs. Serge Nana-Sinkam from Virginia Commonwealth University and James Lee from Ohio State University attempts to carry out an analysis of nucleic acids found in exosomes using molecular beacons contained on biochips to detect specific mRNA and miRNA sequences. The hypothesis is that unique nucleic acid differences in exosomes exist that can differentiate among normal smokers and SCLC patients. The goal is to obtain a biochip that can be used as a biomarker for early stage SCLC that can be applied broadly to blood samples. The second project is conducted by Dr. John Thomas Poirer (Sloan Kettering Institute for Cancer Research) and it builds on the earlier clinical success of the antibody-drug conjugate against a ligand of the Notch pathway, DLL3, selectively expressed on the surface of SCLC cells. The new project will develop a radioimmunotherapy reagent targeted against DLL3, expressed in 70-80% of SCLC. If even moderately successful, this work may provide therapeutic options to some patients who currently have none. The third project designed by Drs. Kwok Kin Wong from New York University and Nathanael Schiander Gray from Dana-Farber Harvard Cancer Institute aims to define transcriptional and epigenetic factors that contribute to chemotherapy-resistance in both tumor cells and the surrounding microenvironment and assess the efficacy of transcriptional CDK inhibitors alone or in combination with novel investigational therapies, utilizing in vivo SCLC models. This is a compelling, well-rationalized, project that pursues an important new direction for both understanding the fundamental biology of SCLC tumor cells and exploiting that information for therapeutic development. The latest addition to the Consortium is project 4 by John Heymach, Lauren Byers (both from the University of Texas MD Anderson Cancer Center), and Julien Sage from Stanford University. The investigators seek to identify improved treatment strategies in SCLC using immunotherapeutic agents targeting the PD1 pathway. The overarching goals of this project are to exploit the intersection of DNA damage repair and immunotherapy in SCLC for new targets and therapies, and to enhance the benefit of existing therapeutic options or ongoing clinical studies. Besides the main Research Projects, the Consortium serves as a hub for Associate Members with additional SCLC projects funded through NCI grants. The topics of these projects include new determinants of acquired resistance, Notch signaling in SCLC, molecular and cellular mechanisms of metastasis, therapeutic strategies for targeting PARP1, kinase dependent chemotherapy resistance mechanisms, and investigating CREBBP as a tumor suppressor. The NCI accepts applications for membership in the SCLC Consortium through two program announcements PAR-16-049 and PAR-16-051. International teams are encouraged to apply.
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.
Author of
-
+
MA 03 - Chemotherapy (ID 651)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Jin-Hyoung Kang, W. Su
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 502
-
+
MA 03.11 - Targeting CDCA3 Enhances Sensitivity to Platinum-Based Chemotherapy in Non-Small Cell Lung Cancer (ID 9607)
12:10 - 12:15 | Author(s): Kenneth Obyrne
- Abstract
- Presentation
Background:
Lung cancer is the leading cause of cancer-related mortality worldwide with a 5 year survival rate of 15%. Non-small cell lung cancer (NSCLC) is the most commonly diagnosed form of lung cancer. Cisplatin-based regimens are currently the most effective chemotherapy for NSCLC, however, chemoresistance poses a major therapeutic problem. New and reliable strategies are required to avoid drug resistance in NSCLC. Cell division cycle associated 3 (CDCA3) is a key regulator of the cell cycle. CDCA3 modulates this process by enabling cell entry into mitosis through degradation of the mitosis-inhibitory factor WEE1. Herein, we describe CDCA3 as a novel prognostic target to delay or prevent cisplatin resistance in NSCLC.
Method:
CDCA3 expression was investigated using bioinformatic analysis, tissue microarray immunohistochemistry and western blot analysis of matched NSCLC tumour and normal tissue. CDCA3 function in NSCLC was determined using several in vitro assays by siRNA depleting CDCA3 in a panel of three immortalized bronchial epithelial cell lines (HBEC) and seven NSCLC cell lines. To determine strategies to suppress CDCA3 activity the phosphorylation status of CDCA3 was assessed using mass spectrometry analysis. Kinases that phosphorylate CDCA3 were identified using a siRNA screen and high content immunofluorescence and microscopy approaches.
Result:
We have previously shown that CDCA3 transcripts and protein levels are elevated in resected NSCLC patient tissue, high mRNA levels being associated with poor survival. CDCA3 depletion markedly impairs proliferation in seven NSCLC cell lines by inducing a G2 cell cycle arrest. Silencing of CDCA3 also greatly sensitises NSCLC cell lines to cisplatin. Consistently, NSCLC patients with elevated CDCA3 levels and treated with cisplatin have a poorer outcome than patients with reduced CDCA3 levels. To aid patient response to cisplatin, we have been looking at strategies to suppress CDCA3 expression in tumour cells. Accordingly, in response to cisplatin, CDCA3 is phosphorylated (S[222]) via casein kinase 2 (CK2) which prevents CDCA3 degradation in NSCLC cells. Moreover, the CK2 inhibitor CX-4945 reduces CDCA3 levels in cisplatin treated cells. CX-4945 increased cisplatin-induced cell death in control cells. The efficacy was further enhanced in CDCA3 depleted NSCLC cells.
Conclusion:
Our data highlight CDCA3 as a novel factor in the pathogenesis of NSCLC. We propose that preventing cisplatin-induced CDCA3 phosphorylation by targeting CK2 is a worthwhile and novel strategy in treating NSCLC and may ultimately benefit patient outcome by preventing cisplatin resistance.
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.
-
+
MA 12 - Circumventing EGFR Resistance (ID 665)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Wan Ling Tan, Nobuyuki Yamamoto
- Coordinates: 10/17/2017, 11:00 - 12:30, F205 + F206 (Annex Hall)
-
+
MA 12.12 - Discussant - MA 12.09, MA 12.10, MA 12.11 (ID 10816)
12:15 - 12:30 | Presenting Author(s): Kenneth Obyrne
- 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.
-
+
P1.02 - Biology/Pathology (ID 614)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 3
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
-
+
P1.02-010 - Novel Role of hSSB2 in the Base Excision Repair Pathway (BER) (ID 9579)
09:30 - 09:30 | Author(s): Kenneth Obyrne
- Abstract
Background:
The base excision repair (BER) pathway is responsible for removing damaged or incorrectly incorporated uracil bases in the genome. Mismatched bases that persist in the genome and remain unrepaired may result in either lethal mutations or cytotoxic DNA double strand breaks. Previous studies have determined that hSSB1 is critical for the detection, signaling and repair of cytotoxic double strand DNA breaks and oxidized DNA lesions within the genome. The role of hSSB2 is, however, less clear. In this study, we have identified that the single stranded DNA binding proteins, hSSB1 and 2, are involved in the detection and removal of uracils within the genome and function as part of the BER pathway.
Method:
We identified a novel role for hSSB1 and hSSB2 in BER. EMSA and incision biochemical assays were used to determine the ability of hSSB1/2 to bind uracil containing mismatches. Incision assays were used to determine the effect hSSB2 and hSSB1 have on UNG2 activity. Two cytotoxic drugs (5-fluorouracil and pemetrexed), which induce uracil misincorporation in the genome, were used to determine the cell sensitivity in control and hSSB1/2-depleted cells using a live and dead cell assay. Immunoprecipitation, immunofluorescence and Protein-Protein interactions were carried out to determine whether hSSB2 and hSSB1 interacts with key regulatory proteins of the BER pathway.
Result:
This study demonstrates that hSSB1 and hSSB2 proteins can recognize and bind to double stranded DNA substrates containing a uracil mismatch. Interestingly, we have identified that hSSB1 and hSSB2 have a differential preference for uracil mismatches, with hSSB1 preferentially binding UA and hSSB2 UG mismatches. Furthermore, hSSB2 induces the incision activity of UNG2 by approximately two fold for a U:G mismatch but not a U:A mismatch. A549 lung adenocarcinoma cells depleted of both hSSB1 and hSSB2 are hypersensitive to 5-fluorouracil and pemetrexed. Loss of either hSSB1 or hSSB2 alone by siRNA results in a compensatory upregulation of hSSB2 or hSSB1 respectively, suggesting over-lapping functionality and substrate specificity.
Conclusion:
This study highlights the importance of hSSB2 and hSSB1 in the removal of uracil from the genome. Currently, pemetrexed and fluorouracil based agents are in use for treating lung cancer. This study raises the possibility that hSSB2 and hSSB1 may be biological indicators of response to fluorouracil and pemetrexed. Further, it may be possible to develop future hSSB2/hSSB1 inhibitors that could enhance the activity of these agents in the treatment of lung cancer.
-
+
P1.02-071a - Targeting Human Single Stranded DNA Binding Protein (hSSB) 1, a Novel Prognostic Factor, in Non-Small Cell Lung Cancer (ID 9210)
09:30 - 09:30 | Presenting Author(s): Kenneth Obyrne
- Abstract
Background:
Lung cancer is the leading cause of cancer death worldwide. The hallmark of all malignant disease is genomic instability leading to tissue invasion, metastasis and resistance to chemotherapy, notably cisplatin. hSSB1 is a guardian of the genome with a key role in the detection and repair of DNA double-strand breaks, replication fork arrest and oxidative stress damage. Recently we have shown that hSSB1 is directly phosphorylated by DNA-PK at serine residue 134 in response to replication stress to promote cellular survival. We hypothesized that hSSB1 may play a role in the pathogenesis of non-small cell lung cancer (NSCLC) and in the mechanism of resistance to cisplatin based chemotherapy observed for (NSCLC). Therefore we evaluated the role of hSSB1 as a prognostic factor and as a potential new target for therapy.
Method:
We analyzed the prognostic significance of hSSB1 mRNA expression from public on line databases and through assessment of protein expression in an NSCLC tissue macro-array (TMA) using immunohistochemistry. hSSB1 mRNA levels were analyzed in matched normal:tumour adenocarcinoma and squamous cell tumour samples, and in a platinum sensitive vs resistant cells. We also explored the impact of hSSB1 expression on NSCLC cell lines sensitivity to cisplatin (measured by cell proliferation) by over-expressing a Flag tagged hSSB1 or depleting hSSB1 with specific small interfering (si)RNA.
Result:
hSSB1 expression was associated with poor prognosis for lung cancer, high levels of mRNA and protein expression correlating with a worse overall survival. hSSB1 mRNA levels were prognostic in adenocarcinomas only. hSSB1 mRNA was also significantly increased in both adenocarcinoma and squamous cell carcinoma compared to matched normal tissue. Furthermore, we observed that hSSB1 was upregulated in H460 cisplatin resistant cells as compared to the parental line. Knockdown of hSSB1 in H460 cells was associated with a significant increase in sensitivity to cisplatin.
Conclusion:
Our results establish hSSB1 as a prognostic factor in non-small cell lung cancer. Moreover, targeting hSSB1 may prove an effective method of reversing platinum resistance. Evaluation of the potential role of DNA-PK inhibition in inhibiting hSSB1 activation and reversing cisplatin and radiotherapy resistance in tumours with high levels of hSSB1 expression is currently ongoing.
-
+
P1.02-071b - SASH1 Is a Prognostic Indicator and Future Target in NSCLC (ID 9591)
09:30 - 09:30 | Presenting Author(s): Kenneth Obyrne
- Abstract
Background:
Lung cancer is the most commonly diagnosed cancer in the world and the fifth most common in Australia, where it is responsible for almost one in five cancer deaths. SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor functioning to control of apoptosis and cellular proliferation. Previously SASH1 has been shown to be down-regulated in approximately 90% of lung cancers, however little is known about the role of SASH1 in the pathogenesis of the disease. Cytotoxic platinum based chemotherapy two-drug regimens remain a cornerstone NSCLC patient care, however, resistance to these agents is almost inevitable. The re-sensitisation of these cancer cells to chemotherapeutics is a key to improving patient survival. We hypothesised that modulation of SASH1 expression may alter cisplatin sensitivity.
Method:
A panel of lung cancer cell lines depleted of SASH1 (siRNA) or overexpressing SASH1 were analysed for protein levels via immunoblotting, cell proliferation, and survival/death assays. Treatment of lung cancer cells with the SASH1 protein stabilising compound chloropyramine (0-50 μM) and/or cisplatin (0-10 μM) was performed followed by immunoblotting for SASH1, cell proliferation, and survival/death assays. SASH1 IHC staining of adenocarcinoma and Squamous cell carcinomas was correlated with patient survival.
Result:
We demonstrated that SASH1 depletion results in a significant increase in cellular proliferation of NSCLC cancer cells. The depletion of SASH1 within lung cancer cell lines was associated with a significant increase in cisplatin resistance. Transfection of SASH1 into NSCLC cell lines induced cell death. The treatment of cells with the SASH1 protein stabilising compound chloropyramine increased SASH1 levels, reduced proliferation and induced apoptosis. Furthermore, chloropyramine increased cisplatin sensitivity. The relationship between SASH1 protein expression with overall survival was accessed in a NSCLC TMA panel. This showed that high SASH1 protein levels were associated with a poor prognosis in adenocarcinomas but were non-prognostic in squamous cell disease. Interestingly high SASH1 mRNA levels were associated with a favourable prognosis in adenocarcinoma but were not prognostic in squamous cell cancer. In a panel of cancer cell lines we observed no correlation between mRNA and protein levels that may explain this discrepancy.
Conclusion:
Agents that upregulate SASH1, or SASH1 gene therapy, are potential novel approaches to the management of NSCLC. Further preclinical and clinical studies of chloropyramine in combination with chemotherapy are justified in NSCLC.
-
+
P1.03 - Chemotherapy/Targeted Therapy (ID 689)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 4
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
-
+
P1.03-039 - Therapeutic Inhibition of the Cancer Stem Cell Marker, ALDH1, a Promising Mechanism by Which Cisplatin Sensitivity Can Be Restored in NSCLC (ID 9909)
09:30 - 09:30 | Author(s): Kenneth Obyrne
- Abstract
Background:
Cisplatin remains the cornerstone of current chemotherapeutic combination startegies in the treatment of NSCLC. Despite initial cisplatin sensitivity tumours develop resistance, which in turn undermines the efficacy of cisplatin as a therapuetic agent. Numerous mechanisms, signalling pathways and theories have been suggested and elucidated in terms of cisplatin resistance and in the development of it, however, to date the clinical issue of resistance has not been overcome. A current avenue of interest is the cancer stem cell (CSC) hypothesis, in which the survival and expansion of highly resistant CSCs during chemotherapeutic treatment are thought to be a contributing factor of resistance and recurrence. Specific inhibition of key CSC markers in combination with chemotherapy may undermine the inherent resistance of the CSC population and sensitise these cells to the cytotoxic effects of therapy. One such CSC marker observed across numerous tumours is aldehyde dehydrogenase 1 (ALDH1), our hypothesis suggests that inhibition of the ALDH1-positive CSC population within cisplatin resistant NSCLC will resensitise the cellls to the cytotoxic effects of cisplatin.
Method:
Using an isogenic panel of matched parent (PT) and cisplatin resistant (CisR) NSCLC cell lines ALDH1 was identified as a CSC marker present within the CisR sublines of each NSCLC histology and characterised as CSCs. ALDH1 was inhibited using two pharmacological ALDH1 inhibitors, diethlylaminobenzaldehyde (DEAB) and disulfiram (commercially known as Antabuse used in the treatment of alcoholism). ALDH1 inhibition was confirmed by flow cytometry. PT and CisR cell lines were treated with inhibitor alone and in combination with cisplatin and assessed in terms of proliferation, clonogenic survival and apoptosis relative to cisplatin-only treatment.
Result:
Both DEAB and the FDA-approved disulfiram significantly decreased the presence of the ALDH1-positive CSC subpopulation across all CisR cell lines. DEAB and disulfiram in combination with cisplatin induced a significant decrease in proliferation and clonogenic survival as well as significant increases in cisplatin-induced apoptosis across CisR sublines when compared to cisplatin alone.
Conclusion:
DEAB and disulfiram significantly reduced the presence of the highly resistant ALDH1-positive CSC subpopulation. This pharmacological CSC depletion in conjunction with cisplatin was associated with the resensitisation of cisplatin resistant cells to the cytotoxic effects of cisplatin, thus restoring cytotoxic efficacy. The resensitisation effect of the disulfiram-based combination strategy, as well as its FDA-approval and extentsive safety profile highlights this strategy as one of great promise. In summary, these data suggest a role for ALDH1 inhibition in the resensitisation and possible circumvention of cisplatin resistance.
-
+
P1.03-041 - Exploitation of the Cancer Stem Cell Marker ALDH1 Within the Vitamin a/Retinoic Acid Axis Promotes Re-Sensitisation of Cisplatin Resistant NSCLC (ID 9938)
09:30 - 09:30 | Author(s): Kenneth Obyrne
- Abstract
Background:
Despite significant advances in personalised medicine in recent decades, cisplatin remains the mainstay chemotherapy in the treatment of NSCLC. The major clinical challenge facing NSCLC today is the development of pan-resistance to platinum agents. Novel drug design, preclinical and clinical trials working toward the approval of new drugs is a lengthy and costly process and in the interim of the drug indentifcation and commercialisation research has turned its focus to two avenues of interest; overcoming cisplatin resistance and the repurposing of approved therapeutics with new indications. Cancer stem cells (CSCs) have been hypothesised to be the initiating cells of therapeutic resistance and tumour recurrence. An ALDH1-positive cell subset has been identified as a key CSC subpopulation present within cisplatin resistant NSCLC sublines. ALDH1 is involved in the metabolism of retinol (vitamin A) and the catalytic conversion of retinal to retinoic acid, where retinoic acid induces cell differentiation. All-trans retinoic acid (ATRA) is a well-established chemotherapeutic agent in the treatment of acute promyelocytic leukaemia; it induces the terminal differentiation of immature cells. We hypothesise that treatment of the cisplatin resistant NSCLC sublines with retinol or ATRA will deplete the ALDH1-positive population and subsequently increase or restore cisplatin sensitivity.
Method:
Flow cytometry on a panel of matched parent (PT) and cisplatin resistant (CisR) NSCLC cell lines revealed the greater presence of ALDH1-positive CSC subpopulations within the CisR sublines of each NSCLC histology relative to PT lines. Cells were treated with retinol (substrate of the retinoic acid pathway) or ATRA (product of the retinoic acid pathway) and the presence of the ALDH1-positive CSC subset reanalysed by flow cytometry. Following treatment of the PT and CisR cells with retinol or ATRA alone and in combination with cisplatin the functional parameters of proliferation, clonogenic survival and apoptosis were reassessed relative to cisplatin alone.
Result:
Treatment of the CisR sublines with retinol (1μM) or ATRA (5μM) significantly reduced the presence of the ALDH1-positive CSC subset across CisR sublines. Both retinol and ATRA when used in combination with cisplatin significantly reduced the proliferative and survival capacity of each CisR subline while significantly increasing apoptotic cell death compared to cisplatin alone.
Conclusion:
Exploitation of the vitamin A/retinoic acid pathway in combination with cisplatin re-sensitised resistant cells to the cytotoxic effects of cisplatin. These data suggest vitamin A supplementation or the addition of FDA-approved ATRA to the cisplatin-based chemotherapeutic regimen may be of clinical benefit in overcoming tumour recurrence and cisplatin resistance.
-
+
P1.03-042 - BBI608, a Small Molecule Stemness Inhibitor, Circumvents Cisplatin Resistance in NSCLC (ID 9947)
09:30 - 09:30 | Author(s): Kenneth Obyrne
- Abstract
Background:
The cancer stem cell (CSC) hypothesis is now a well-established and widely investigated field within oncology. It hypothesises that there is a robustly resistant stem-like population of cells that survive and thrive initial chemotherapeutic treatment. These surviving CSCs contribute to the recapitulation of a heterogeneous tumour via a combination of asymmetric and symmetric cell division, subsequently resulting in relapse and therapeutic resistance. BBI608 is a small molecule inhibitor of cancer stemness; it targets STAT3, leading to the inhibition of critical genes required for the maintenance of cancer stemness. Following initial in vitro and in vivo preclinical promise of BBI608 reported in the literature, phase II and III clinical trials are underway and are at various stages of recruitment, progress and completion to investigate BBI608 across a number of advanced malignancies and in combination with numerous chemotherapeutic agents.
Method:
Aldefluor (Stemcell Technologies) staining and flow cytometry analysis of a panel of matched parent (PT) and cisplatin resistant (CisR) NSCLC cell lines identified the ALDH1-positive (ALDH1+ve) subpopulation of cells as an omnipresent CSC subset across cisplatin resistant NSCLC sublines. PT and CisR cell lines were treated with BBI608 (1μM) and the presence of the ALDH1+ve CSC population was reassessed by flow cytometry and expression of stemness factors (Nanog, Oct-4, Sox-2, Klf4 and cMyc) were examined by reverse transcriptase PCR. The functional parameters of proliferation, clonogenic survival and apoptosis were investigated with increasing concentrations of cisplatin in the presence and absence of 1μM BBI608.
Result:
The NSCLC CisR sublines showed a significantly greater ALDH1+ve CSC population relative to their PT counterparts. Treatment of the CisR sublines with 1μM BBI608 significantly depleted the ALDH1+ve CSC population and decreased gene expression of stemness markers. BBI608 significantly decreased the proliferative capacity and clonogenic survival of the CisR sublines when in combination with cisplatin relative to cisplatin alone. Cisplatin in combination with BBI608 significantly increased cisplatin-induced apoptosis in the CisR sublines indicating restoration of cisplatin sensitivity.
Conclusion:
To date, BBI608 has not been investigated in terms of a cisplatin resistant ALDH1+ve CSC population in lung cancer. BBI608, via the inhibition of STAT3, pharmacologically depleted the CSC subpopulation and stemness expression while simultaneously restoring cisplatin sensitivity. There are currently a number of clinical trials in various stages of completion to further investigate BBI608. These data suggest a promising role for BBI608 in the treatment of non-responsive or recurrent NSCLC.
-
+
P1.03-048 - miR-34a and the Micromanagement of Cancer Stemness and Resistance in NSCLC. Does It Hold Therapeutic Benefit? (ID 9968)
09:30 - 09:30 | Author(s): Kenneth Obyrne
- Abstract
Background:
The capacity of microRNAs to post-transcriptionally regulate a myriad of genes has extended their remit into the realm of stemness and furthermore cancer stemness regulation. Disruption of Dicer-1, a crucial component of microRNA biogenesis, has been shown to completely deplete the stem cell pool in early development, indicating a potential role for microRNAs in the maintenance of stem cells. Such logic has led microRNAs to be investigated in the context of cancer stem cells (CSCs). Studies have revealed that microRNAs play a role in CSC self-renewal, differentiation, drug resistance and metastasis. With this, our hypothesis suggests that microRNAs associated with cisplatin resistance and CSC maintenance may be a key target by which the CSC root of cisplatin resistance could be overcome.
Method:
MicroRNA expression within a panel of age-matched parent (PT) and cisplatin resistant (CisR) NSCLC sublines was profiled using the 7[th] generation miRCURY LNA arrays (Exiqon) and validated by qPCR. Cell lines were stained for the presence of the CSC marker, aldehyde dehydrogenase 1 (ALDH1) and FACS was used to isolate the ALDH1-positive CSC population from the ALDH1-negative bulk cell population. Expression of the panel of cisplatin resistance-associated microRNAs was investigated within the ALDH1-positive CSC population relative to their negative counterparts by qPCR. Significantly altered miRNAs were inhibited in the CisR subline using antagomirs (Exiqon) and the presence of the ALDH1-positive subset reassessed by flow cytometry and expression of stemness genes (Nanog, Oct-4, Sox-2, Klf4, cMyc) determined. The presence of the cisplatin-associated miRNAs was investigated in FFPE murine tumours within a xenograft model of CSCs, in which 1x10[3] ALDH1-positive and negative subsets were injected into NOD/SCID mice.
Result:
Upon validation, a 5-miR signature was identified across NSCLC histologies to be associated with cisplatin resistance. When this panel was further investigated within the ALDH1-positive CSC subpopulation, it was observed that there was a significant up-regulation of miR-34a-5p relative to corresponding ALDH1-negative populations. Interestingly, the ALDH1-positive subpopulations showed significantly greater miR-34a-5p expression when compared to the CisR sublines from which they were isolated. This up-regulation was also observed within the FFPE xenograft tumours. However, inhibition of miR-34a-5p with antagomiRs did not significantly alter the presence of the ALDH1-positive CSC population, or the expression of stemness-associated genes.
Conclusion:
These data suggest that miR-34a-5p while significantly up-regulated in cisplatin resistance and CSCs may not play a functional role in CSC maintenance and further investigation is required to fully elucidate the role of miR-34a-5p in cancer stemness.
-
+
P1.07 - Immunology and Immunotherapy (ID 693)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
-
+
P1.07-044c - Neurological Complications Following Treatment with Anti-PD1 Immune Checkpoint Inhibitors (ID 9213)
09:30 - 09:30 | Presenting Author(s): Kenneth Obyrne
- Abstract
Background:
With increasing use of single agent and combination immune checkpoint inhibitors in non-small cell lung cancer (NSCLC), a wide spectrum of immune related adverse effects (irAEs) are posing new challenges for treating physicians.
Method:
We report 3 patients with NSCLC, developing neurological autoimmune toxicities on treatment with Nivolumab.
Result:
Patient 1 was a 66 years old man diagnosed in 2013 with a T1N0M1 adenocarcinoma and a solitary cerebral metastasis treated with resection of both lesions and post-operative whole brain radiotherapy. In 2015 he developed metastatic disease and was treated in the KEYNOTE-024 trial. Randomised to chemotherapy he developed progressive disease after 18 weeks and crossed over to Pembrolizumab. Following his second cycle the patient developed acute encephalopathy, confirmed on EEG, peripheral sensory neuropathy and related gait disturbance. He responded to high dose methylprednisone with a complete resolution of symptoms. Patient 2 was a 61 year old man treated with 2[nd] line Nivolumab. After four cycles he developed right ptosis, blurred vision, dysarthria, dysphonia, dysphagia, myositis and grade 2 hepatitis. Electromyogram showed fatiguing with repetitive stimulation. A diagnosis of Nivolumab induced myasthenia gravis like syndrome was made. This responded to intravenous immunoglobulin, pyridostigmine and methylprednisolone with complete resolution of symptoms. Patient 3, a 61 year old female diagnosed with resected T2N2 lung adenocarcinoma in 2010 developed metastatic disease treated in 2015 with 1[st] and 2[nd] line chemotherapy. On progression she received Nivolumab. Autoimmune thyroiditis and hypothyroidism developed after 2 cycles followed by dysarthria and dysphonia. Initially diagnosed as a CVA on MR imaging, her symptoms worsened over two weeks with the onset of dysphagia, bilateral facial weakness and tongue atrophy. She was diagnosed with myasthenia gravis like syndrome, treated with pyridostigmine and immunoglobulin and subsequently plasmaphoresis and glucocorticoids with a moderate improvement in speech, facial movements and dysphagia. EMG and nerve conduction studies suggested a likely neuromuscular junction disorder. In all cases laboratory investigations, including auto-antibody screens, and imaging were of no value in establishing the diagnosis. All three patients have had near complete tumour responses on follow-up imaging despite discontinuation of therapy.
Conclusion:
Although relatively rare, these cases demonstrate the variety of presentations possible with neurological irAEs. Early recognition and treatment with immunosuppressive agents is essential to avoiding long term sequelae. The remarkable responses and survival seen in these cases indicate the need for further research to define the optimal treatment duration with checkpoint inhibitors in NSCLC.
-
+
P1.09 - Mesothelioma (ID 695)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Mesothelioma
- Presentations: 2
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
-
+
P1.09-006 - JMJ and BRD Domain Family Members in Malignant Pleural Mesothelioma: Potential Therapeutic Targets or Not? (ID 9919)
09:30 - 09:30 | Author(s): Kenneth Obyrne
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is an aggressive rare cancer affecting the pleura and is predominantly associated with prior exposure to asbestos. Treatment options are limited, and most patients die within 24 months of diagnosis. There is an urgent unmet need to identify new therapeutic options for the treatment of MPM. Asbestos fibres contain transition metals such as iron, and may cause an alteration of iron homeostasis in the tissue. In addition, asbestos fibres have also been shown to have high affinity for histones, and therefore may result in high accumulation of iron around chromatin. Lysine Demethylases (KDMs) containing a JmjC domain require both Fe2+ and 2-oxoglutarate as co-factors to regulate gene expression. Bromodomain containing proteins a family of chromatin reader proteins, have potential therapeutic efficacy against various malignancies. Long non-coding RNAs (lncRNAs) have also been shown to play a role as oncogenic molecules in different cancers. Several such lncRNAs have now been shown to locate to the same chromosomal region as various KDMs. We therefore examined the expression of various JmjC and Brd members (along with any associated lncRNAs) in MPM and assessed some for their clinical potential using existing small molecule inhibitors.
Method:
A panel of MPM cell lines and a cohort of snap-frozen patient samples isolated at surgery comprising benign, epithelial, biphasic, and sarcomatoid histologies were screened for expression of various BRD and JmjC members and associated lncRNAs by RT-PCR. IHC for KDM4A was performed on a cohort of FFPE specimens. The effects of treatments with small molecule inhibitors targeting these proteins on both cellular health and gene expression were assessed.
Result:
The expression of the various KDMs was detectable across our panel of cell lines. In primary tumours the expression of many of these genes were significantly elevated in malignant MPM compared to benign pleura (p<0.05), and significant differences were also observed when samples were analysed across different histological subtypes. Treatment of mesothelioma cell lines with various small molecule inhibitors caused significant effects on cellular health and on the expression of a panel of genes.
Conclusion:
The expression of various KDMs, BRD genes and associated lncRNAs are significantly altered in MPM. Small molecule inhibitors directed against these show potential therapeutic efficacy with significant anti-proliferative effects. We continue to assess the effects of these compounds on gene expression and cellular health to confirm their potential utility as novel therapies for the treatment of MPM.
-
+
P1.09-007 - Targeting MET/TAM Receptors in Mesothelioma: Are Multi-TKIs Superior to Specific TKI? (ID 9959)
09:30 - 09:30 | Author(s): Kenneth Obyrne
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer associated with exposure to asbestos, and most patients die within 24 months of diagnosis. There is an urgent need to identify new therapies for treating MPM patients. Targeting “addicted” receptor tyrosine kinase (RTK) signalling networks has become a critical therapy option in cancer therapy. RTK hetero-dimerization may however, be a key element in the development of resistance to such therapy. As such Tyrosine kinase inhibitors (TKIs) with the ability to target multiple receptors may have superior efficacy to those targeting individual receptors. We and others have identified c-MET, MST1R (also known as RON), Axl and Tyro3 as RTKs frequently overexpressed and activated in MPM, making these attractive candidate targets. Several agents have been developed which target these. LCRF0004 specifically targets MST1R, whereas BMS-777607, RXDX-106 or Merestinib (LY2801653) are orally bioavailable small molecule inhibitors which inhibit c-MET, MST1R, Axl and Tyro3 at nM concentrations. These drugs may therefore have clinical utility in the treatment/management of MPM.
Method:
Expression of RON/MET/TAM and associated ligands were assessed in a cohort of patient samples and MPM cell lines comprising benign, epithelial, biphasic, and sarcomatoid histologies. In vitro and in vivo experiments were undertaken to determine the efficacy of single and multi RTK targeting agents (LCRF0004, RXDX-106, BMS-777607). The effects of LCRF0004 and BMS-777607 were subsequently examined in an in vivo SQ xenograft tumour model.
Result:
mRNA expression of the RON/MET/TAM family and associated ligands (MSP, GAS6) was detected in a large panel of normal pleural and MPM cell lines. In a cohort of patient samples, mRNA levels of c-MET, Axl, Tyro3 and various isoforms of MST1R (flRON, sfRON, t-ΔRON) and MSP but not Gas6 or MERTK were increased in tumours compared with benign pleural samples (p<0.05). No MET Exon 14 skipping mutations were detected. RTK targeting agents displayed in vitro efficacy in terms of reduced proliferation. In vivo, the multi-target TKI (BMS-777607) demonstrated superior anti-tumour activity compared with LCRF0004 (MST1R specific compound). IHC analysis of the xenograft tumours showed high cytoplasmic expression of Vimentin, Cytokeratin and Calretinin, with significant necrosis in many.
Conclusion:
Our data suggests that a multi-TKI, targeting the RON/MET/TAM signalling network, is superior to selective RTK inhibition as an interventional strategy in MPM.
-
+
P2.02 - Biology/Pathology (ID 616)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 3
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
-
+
P2.02-048 - Survival Correlation Between TP53 Gene and PD-L1 Tumour Expression in Resected Non-Small Cell Lung Carcinoma (ID 10272)
09:30 - 09:30 | Author(s): Kenneth Obyrne
- Abstract
Background:
Tumour suppressor gene TP53 mutation is common in human cancers, especially playing an important role in lung cancer tumourgenesis. Some clinical studies have shown that TP53 alterations in non-small cell lung carcinoma (NSCLC) carry a worse prognosis and may relatively more resistant to chemotherapy and radiation. We conducted this study to evaluate the impact of TP53 assessed by limited targeted profiling, correlating with PD-L1 tumour expression and clinicopathological variables in resected NSCLC.
Method:
NSCLC patients who underwent curative resection between 1998 and 2006 at our institution were included. PD-L1 status was assessed using Ventana SP142 antibody on archival FFPE surgical tumour specimens, arrayed on tissue microarrays (TMAs) with triplicate 0.6 mm cores. PD-L1 was scored as positive if membranous staining was present in >1% of tumour cells aggregated across the replicate cores to address heterogeneity. In collaboration with the Lung Cancer Genomics Ireland Study, a targeted panel of 49 genes was assessed by Sequenom MassArray including TP53 and genes in MAPK and PI3K pathways. Clinicopathological data was obtained from hospital electronic database.
Result:
Seventy-two patients were included, of which 40 (58.0%) were males, with a median age of 66.0 years (range: 51.0 – 82.6). 54.2%, n=39 with adenocarcinoma histological subtypes, 45.8%, n=33 were ex-smoker and 42.9%, n=30 had Stage IB disease. Most patients had T2 stage (71.4%, n=50), N0 nodal disease (55.2%, n=37) and grade 2 differentiation (65.7%, n=46). Presence of TP53 mutation was identified in 22 patients (30.5%). Five patients had co-presence of TP53 mutation and PD-L1 positivity. There was no correlation between PD-L1 positivity with TP53 status, KRAS, PTPN11, PHLPP2, PIK3CA, MET and PIK3R1. The median disease-free survival in TP53 mutation with PD-L1 positivity was not reached. In univariate/unadjusted analysis, co-presence of TP53 mutation and PD-L1 positivity appear to have superior disease-free survival over TP53 wild-type and PD-L1 negativity, HR 0.17 (95%CI 0.01-0.78, p=0.018). A trend was seen with overall survival but not statistically significant (TP53 mutant, PD-L1 positive vs TP53 wild-type, PD-L1 negative: NR vs 23.1 months, HR 0.34 (95% CI: 0.0.5-1.11, p=0.079). Independent PD-L1 positivity appears to be associated with better prognosis: DFS HR 0.36 (95% CI 0.11-0.90, p=0.0272) and OS HR 0.47 (95% CI 0.19-0.98, p=0.0427).
Conclusion:
In our cohort, co-presence of TP53 mutation and PD-L1 expression was not associated with poorer survival among resected NSCLC patients. Independently, PD-L1 expression was associated with better survival, a finding which warrants further investigations as potential biomarker.
-
+
P2.02-064 - A Novel 5-miR Signature Shows Potential as a Diagnostic Tool and as a Predictive Biomarker of Cisplatin Response in NSCLC (ID 9957)
09:30 - 09:30 | Author(s): Kenneth Obyrne
- Abstract
Background:
MicroRNAs are a class of small non-coding RNAs that range in size from 19-25 nucleotides. They have been shown to regulate a number of processes within tumour biology, including metastasis, invasion and angiogenesis. More recently, miRNAs have been linked to chemoresistance in solid tumours, including lung cancer. Their role in cisplatin resistance has yet to be determined.
Method:
MicroRNA expression within a panel of age-matched parent (PT) and cisplatin resistant (CisR) NSCLC cell lines was profiled using the 7[th] generation miRCURY LNA arrays (Exiqon) and subsequently validated by qPCR. Significantly altered miRNAs within the CisR sublines were manipulated using antagomirs (Exiqon) and Pre-miRs (Ambion) and functional studies were carried out in the presence and absence of cisplatin. To examine the translational relevance of these miRNAs, their expression was examined in a cohort of chemo-naïve patient-matched normal and lung tumour tissue and serum from NSCLC patients of different histologies. A xenograft model of cisplatin resistance was carried out in which 1x10[3] H460 PT or CisR cells were injected into 5-7week old NOD/SCID mice. Tumour volume was measured over time and harvested once the tumour mass measured 500mm[3] and formalin-fixed and paraffin embedded (FFPE). Expression of the 5-miR signature was analysed within FFPE murine tumours and compared between PT and CisR tumours.
Result:
Profiling and subsequent validation revealed a 5-miR signature associated with our model of cisplatin resistance (miR-30a-3p, miR-30b-5p, miR-30c-5p, miR-34a-5p, miR-4286). Inhibition of the miR-30 family and miR-34a-5p reduced clonogenic survival of CisR cells when treated cisplatin. Expression of the miRNA signature was significantly altered in both adenocarcinoma (AD) and squamous cell carcinoma (SCC) relative to matched normal lung tissue and between SCC and AD tissue. miR-4286 was significantly up-regulated in SCC sera compared to normal control and AD sera. Similarly to the cell line expression of the miRNAs, the miR-30 family members and miR-34a-5p were up-regulated in the CisR xenograft FFPE tissue relative to PT.
Conclusion:
A novel miRNA signature associated with cisplatin resistance was identified in vitro, genetic manipulation of which altered clonogenic response to cisplatin. The 5-miR signature showed both diagnostic and prognostic biomarker potential across a number of diagnostically relevant biological media.
-
+
P2.02-069 - Targeting Neuropilin-1 in NSCLC (ID 10205)
09:30 - 09:30 | Author(s): Kenneth Obyrne
- Abstract
Background:
Neuropilin-1 (NP1) is expressed by a wide variety of human tumour cell lines and diverse human neoplasms, and is implicated in mediating the effects of VEGF on the proliferation, survival and migration of cancer cells. It is extensively expressed in tumour vasculature, where NP1 over-expression is associated with tumour progression and poor clinical outcome. In this study, we examined the effects of targeting NP1 in NSCLC both in vitro and in vivo.
Method:
A panel of NSCLC cell lines (H460, H647, A549 and SKMES) were screened for NP1 at the mRNA and protein levels by RT-PCR and Western blotting, respectively. Cellular expression and localisation of NP1 was further examined by immunocytochemistry, while a panel of retrospective resected lung tumours and matched normal tissues were stained by immunohistochemistry. The effects of targeting NP1 on cell proliferation (BrdU ELISA), apoptosis (FACS, HCS) and downstream survival signalling pathways (Western Blot) were examined under normoxic and hypoxic (0.1% O~2~) cell growth using anti-NP1 neutralising antibodies. Cell survival was assessed in response to treatment of NSCLC cells with a range of chemotherapeutic agents in combination with NP1 neutralising antibodies. Using a human xenograft model, tumour growth studies were carried out in nude mice following subcutaneous injection of NP1 over-expressing cells relative to empty vector controls.
Result:
All lung cancer cell lines examined expressed NP1 with the exception of the H460 cell line. Immunocytochemistry analysis confirmed cellular expression and localisation of this receptor, particularly in the leading edges of migrating cells, suggesting a possible role in cell migration. In a small cohort of resected NSCLC patients, tumour expression of NP1 was high relative to their matched normal lung tissues in adenocarcinoma, squamous cell and large cell neuroendocrine carcinomas. Cell proliferation and apoptosis were significantly altered in NSCLC cells expressing NP1. While hypoxia induced the expression of NP1, treatment of cells with NP1 neutralising antibodies reduced hypoxia-mediated cell proliferation and decreased expression of PI3K and MAPK signalling pathways. In a preliminary study, treatment with NP1 neutralising antibodies sensitised NSCLC cells to the cytotoxic effects of chemotherapy. In vivo, H460 cells over-expressing NP1 significantly increased tumour growth in NOD/SCID mice relative to empty vector controls.
Conclusion:
These data suggest a role for the Neuropilin-1 receptor in promoting cell survival and tumour growth in NSCLC and may offer potential as a therapeutic biological strategy in lung cancer.
-
+
P2.07 - Immunology and Immunotherapy (ID 708)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 2
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
-
+
P2.07-032 - Outcomes of Nivolumab in Metastatic NSCLC Patients via the Access Program Across Multiple Tertiary Oncology Centres. (ID 9298)
09:30 - 09:30 | Presenting Author(s): Kenneth Obyrne
- Abstract
Background:
Immune checkpoint inhibitors are the standard of care for non-small cell lung cancer (NSCLC) patients following first line therapy. There is limited information available on the outcomes of patients receiving these therapies for NSCLC outside of a clinical trial.
Method:
We retrospectively collected data from patients who received Nivolumab for advanced NSCLC on the Bristol-Myers Squibb (BMS) Access Program across four tertiary oncology institutions in Brisbane, Australia, to analyse their outcomes in a real-world setting, and compare these outcomes to those in Phase III randomised clinical trials.
Result:
85 patients were enrolled to this Ethics Committee approved audit - 32 females (37.6%); 53 males (62.4%); 54, PS 0-1 (63.5%); 30, PS 2-3 (35.3%); median age 67 yrs (range 42-84). 84 patients were evaluable for progression. 20% (17/84) of patients had a radiological partial response (PR) during the course of their treatment, and an additional 22.4% (19/84) patients had stable disease (SD) as their best response. In PS 0-1, 24% (13/54) had a PR, compared with only 10% (3/30) in PS 2-3 patients. The overall median progression-free survival (PFS) was 1.8 months, being 2.7 months in PS 0-1 versus 1.2 months in PS 2-3 patients. Median overall survival (OS) was 5.9 months; 6.5 months in PS 0-1 versus 2.3 months in PS 2-3 patients. Median OS for adenocarcinoma was 6.2 months, versus 4.7 months for squamous cell carcinoma. At 12 months after initiation of nivolumab 34% of patients were alive; 44% PS 0-1 versus 16% PS 2-3 patients. Grade 3 or 4 treatment related adverse events were observed in 10% of patients. Analysis of the prognostic relevance of routine haematological and biochemical parameters is ongoing.
Conclusion:
Nivolumab has clinically significant long term benefits in the treatment of relapsed NSCLC with 12 month survival rates in keeping with clinical trials in PS 0-1 patients. The development of predictive biomarkers remains central to identifying those patients, particularly with poor performance, most likely to benefit from immune checkpoint inhibitors.
-
+
P2.07-033 - Anti-PD1-Induced Rotator Cuff Injury: A Case Series (ID 9339)
09:30 - 09:30 | Presenting Author(s): Kenneth Obyrne
- Abstract
Background:
Immunotherapy is now part of the standard of care for the treatment of metastatic non-small cell lung cancer (NSCLC). Immune checkpoint blockers, including anti-PD1 and anti-PDL1 therapies are generally well tolerated, but pose a risk of immune-related toxicities. With 40-50% of patients surviving at 12 months post second-line nivolumab treatment, survivorship concerns such as quality of life need to start being considered in these patients. Immune-related musculoskeletal symptoms are often overlooked, but can result in significant morbidity for a patient.
Method:
We present a case series of four patients who developed significant anti-PD1-induced rotator cuff injury during treatment for either metastatic NSCLC or metastatic mesothelioma.
Result:
Three patients were given nivolumab for advanced NSCLC, and one patient was given pembrolizumab for metastatic epithelioid mesothelioma. The severity of rotator cuff injuries ranged from tendonitis and bursitis, to a full thickness rotator cuff tear. One patient had bilateral rotator cuff injuries. The symptoms began 6-12 weeks after commencing immune checkpoint anti-PD1 therapy and resulted in significant morbidity for the patients in terms of daily activities. All injuries were managed conservatively with a combination of steroid injections, anti-inflammatories and physiotherapy. Pembrolizumab was ceased in the mesothelioma patient after 6 cycles, and the musculoskeletal symptoms rapidly resolved. Two of the NSCLC patients ceased nivolumab due to progressive disease, at 5 months and 9 months respectively. The third NSCLC patient continues on nivolumab, with stable disease at 17 months. In the NSCLC patients who had continued on nivolumab despite musculoskeletal symptoms, the rotator cuff injuries settled over time with conservative management.
Conclusion:
Immune-related musculoskeletal symptoms are inadequately reported in clinical trials, but can result in significant morbidity for patients, and therefore may impact on their compliance with immune checkpoint blockade therapy. Increased vigilance and prompt management of this condition within the context of multi-disciplinary care may assist with symptom-control.
-
+
P2.14 - Radiotherapy (ID 715)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Radiotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
-
+
P2.14-020b - Prognostic factors in unresectable stage III NSCLC treated with concurrent chemoradiotherapy (ID 10233)
09:30 - 09:30 | Presenting Author(s): Kenneth Obyrne
- Abstract
Background:
Despite recent advances in combined chemoradiotherapy for the management of locally advanced, unresectable, stage III non-small cell lung cancer, the majority of patients treated ultimately relapse from their disease. Identifying prognostic factors that predict outcome may improve patient selection for definitive therapy and provide relevant clinical information for their future care.
Method:
This retrospective analysis assessed survival data for a consecutive series of patients with stage III non-small cell lung cancer treated with 6 weeks of curative-intent carboplatin (AUC 2) - paclitaxel (45mg/m[2]) plus radiotherapy at the Princess Alexandra Hospital, Brisbane, between January 2009 and December 2015. Kaplan-Meier analysis on an intention-to-treat basis was used to assess survival data, with attention to a number of clinicopathologic subgroups. Cox proportional hazards regression was performed on continuous and discrete patient covariates to identify those with an independent association with survival.
Result:
The study included 171 patients, with a median follow-up time of 30.5 months. Median overall survival (mOS) was 27.3 months (95% CI = 22.6 - 33.0) for the entire cohort. An improved mOS was seen in stage IIIA (34.3mo) vs IIIB (13.1mo, p<0.001) patients, and with non-squamous compared to squamous histologic subtype (35.5mo vs 22.7mo, p = 0.022). A longer mOS in females compared to males did not meet statistical significance (27.7mo vs 23.2mo, p = 0.21). Multivariate analysis revealed four factors most strongly and independently associated with poor survival: serum neutrophil:lymphocyte ratio (HR 1.15 for each unit increase, p <0.001), lactate dehydrogenase (HR 1.28 for each 50 U/L increase, p = 0.005), alkaline phosphatase (HR 1.1 for each 20 IU/L increase, p = 0.045), and albumin (inverse relationship, HR 0.76 for each 5 g/L increase, p = 0.047).
Conclusion:
This analysis confirms that outcomes for our cohort of stage III non-small cell cancer patients are consistent with international best practice. Our subgroup analyses were also in keeping with recognised clinical factors asociated with improved survival including earlier stage tumours and non-squamous histopathology. A number of pre-treament blood parameters, less well established as prognostic factors, independently influenced survival including the neutrophil:lymphocyte ratio, and lactate dehydrogenase, alkaline phosphatase and albumin levels. Analysis of oncogenic driver mutation status, PD-L1 expression and degree of tumor-infiltrating lymphocytes in available tumor samples is planned, with the goal of establishing a prognostic model to stratify and direct treatment options in this cohort of potentially curable patients.
-
+
P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
-
+
P3.01-026 - Analysis of Long-Term Response to First-Line Afatinib in the LUX-Lung 3, 6 and 7 Trials in Advanced EGFRm+ NSCLC (ID 9051)
09:30 - 09:30 | Author(s): Kenneth Obyrne
- Abstract
Background:
In patients with advanced EGFR mutation-positive (EGFRm+) NSCLC, first-line afatinib significantly improved PFS and objective response rate (ORR) versus platinum-doublet chemotherapy in the phase III LUX-Lung (LL) 3 and LL6 studies, and PFS, time-to-treatment failure (TTF) and ORR versus gefitinib in the phase IIb LL7 study. Here, we present post-hoc analyses of efficacy, safety and patient-reported outcomes (PROs) in afatinib long-term responders (LTRs) in LL3/6/7.
Method:
Treatment-naïve patients with stage IIIb/IV EGFRm+ NSCLC who were randomized to 40mg/day afatinib in LL3/6/7 and remained on treatment for ≥3 years were defined as LTRs. In these patients, we assessed efficacy and safety outcomes, as well as PROs measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) Questionnaire and the EQ-5D™ health status self-assessment questionnaire; these included scores on the EORTC Global Health [GH]/QoL scale (0–100), EORTC Performance Functioning scale (PF; 0–100), EQ Visual Analogue Scale (VAS; 0–100) and EQ-5D UK utility scale (EQ UK utility; 0–1).
Result:
In LL3/6/7, there were 24/229 (10%)/ 23/239 (10%)/ 19/160 (12%) afatinib-treated LTRs; 6/9/14 remained on treatment at time of analysis. Baseline characteristics were similar to the overall study populations, except for the proportion of women (LL3/6 only [LTRs versus overall]: 92/78% vs 64/64%) and Del19+ patients (LL3/6/7: 63–79% vs 49–58%). In LL3/6/7, 4–11% of LTRs had brain metastases at enrolment. Median (range) duration of treatment in LL3/6/7 LTRs was 50 (41–73)/56 (37–68)/42 (37–50) months. Due to few deaths, median OS could not be estimated. Median follow-up for OS in LL3/6/7 was 64.6/57.0/42.1 months. ORR among LTRs in LL3/6/7 was 70.8% (complete response: 4.2%; n=1)/78.3% (13.0%; n=3)/89.5% (5.3%; n=1). The frequency of afatinib dose reductions due to treatment-related AEs, and the frequency/duration of subsequent treatments were similar to the overall LL3/6/7 populations. In afatinib-treated LTRs in LL3/6/7, PROs appeared stable between ~Week 24 to ~Week 160, with slight improvements after ~3 years afatinib treatment versus scores at the start of treatment.
Conclusion:
In LL3/6/7, 10%–12% of afatinib-treated patients were LTRs. Afatinib was well tolerated among these patients. Long-term treatment was independent of tolerability-guided dose adjustment or presence of brain metastases at time of enrolment, and had no detrimental impact on subsequent treatment. In afatinib-treated LTRs, PROs were not negatively affected by long-term treatment, and were slightly improved after ~3 years of treatment versus scores at treatment initiation.
-
+
P3.01-075 - Afatinib Dose Adjustment: Effect on Safety, Efficacy and Patient-Reported Outcomes in the LUX-Lung 3/6 Trials in EGFRm+ NSCLC (ID 9365)
09:30 - 09:30 | Author(s): Kenneth Obyrne
- Abstract
Background:
Afatinib 40mg/day is approved globally for first-line treatment of EGFR mutation-positive (EGFRm+) NSCLC. Afatinib is available in several tablet strengths (20/30/40/50mg), and tolerability-guided dose adjustment schemes are well established. Here, we evaluate the impact of afatinib dose reduction on safety (AEs), pharmacokinetics, PFS and patient-reported outcomes (PROs) in the Phase III LUX-Lung (LL) 3 and 6 trials.
Method:
Treatment-naïve patients with stage IIIB/IV EGFRm+ NSCLC in LL3/6 received either 40mg/day afatinib or chemotherapy. In case of any treatment-related grade ≥3 AEs or selected prolonged grade 2 AEs, afatinib dose was reduced by 10mg decrements (minimum dose 20mg/day). In this post-hoc analysis of all afatinib-treated patients in LL3/6 (n=229/n=239), we compared incidence and severity of common AEs before and after dose reduction, afatinib plasma concentrations in patients who reduced to 30mg versus those remaining on 40mg, and PFS in patients with/without dose reductions in the first 6 months of treatment. PROs were measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire and the EQ-5D™ health status self-assessment questionnaire, and pooled data from both trials were assessed before/after dose reduction; these included scores on the EORTC Global Health/Quality of Life scale (GH/QoL; 0–100), EORTC Performance Functioning scale (PF; 0–100), EQ Visual Analogue Scale (VAS; 0–100) and EQ-5D UK utility scale (EQ UK utility; 0–1).
Result:
Dose reductions occurred in 122/229 (53.3%) patients in LL3 and 67/239 (28.0%) in LL6; >80% of dose reductions occurred in the first 6 months of treatment. Dose reductions decreased the incidence of treatment-related AEs (grade ≥3 AEs before/after dose reduction: LL3, 73%/20%; LL6, 81%/12%), and were more likely among patients who had higher afatinib plasma concentrations prior to subsequent dose reduction (Day 22). On Day 43, geometric mean afatinib plasma concentrations were comparable between patients who had dose reduced (n=59; 23.3ng/mL) and patients who remained on 40mg (n=284; 22.8ng/mL). Median PFS was comparable between patients with or without dose reductions in the first 6 months (LL3: 11.3 versus 11.0 months; HR [95% CI] 1.25 [0.91–1.72]; p=0.175; LL6: 12.3 versus 11.0 months; 1.00 [0.69–1.46]; p=0.982). There were no clinically meaningful changes in PROs following afatinib dose reduction: GH (40/30mg: 59.1/66.9; n=136); PF (79.4/83.0; n=136); EQ VAS (70.1/75.1; n=135); EQ UK utility (0.70/0.78; n=135).
Conclusion:
Tolerability-guided dose adjustments effectively reduced afatinib-related AEs without negatively affecting therapeutic efficacy and PROs.
