Sarah A. Hayes

From mice to men: GEMMs as trial patients for new NSCLC therapies

Given the large socio-economic burden of cancer, there is an urgent need for in vivo animal cancer models that can provide a rationale for personalised therapeutic regimens that are translatable to the clinic. Recent developments in establishing mouse models that closely resemble human lung cancers involve the application of genetically engineered mouse models (GEMMs) for use in drug efficacy studies or to guide patient therapy. Here, we review recent applications of GEMMs in non-small cell lung cancer research for drug development and their potential in aiding biomarker discovery and understanding of biological mechanisms behind clinical outcomes and drug interactions.

Exhaled breath condensate for lung cancer protein analysis: a review of methods and biomarkers.

Lung cancer is a leading cause of cancer-related deaths worldwide, and is considered one of the most aggressive human cancers, with a 5 year overall survival of 10-15%. Early diagnosis of lung cancer is ideal; however, it is still uncertain as to what technique will prove successful in the systematic screening of high-risk populations, with the strongest evidence currently supporting low dose computed tomography (LDCT). Analysis of exhaled breath condensate (EBC) has recently been proposed as an alternative low risk and non-invasive screening method to investigate early-stage neoplastic processes in the airways. However, there still remains a relative paucity of lung cancer research involving EBC, particularly in the measurement of lung proteins that are centrally linked to pathogenesis. Considering the ease and safety associated with EBC collection, and advances in the area of mass spectrometry based profiling, this technology has potential for use in screening for the early diagnosis of lung cancer. This review will examine proteomics as a method of detecting markers of neoplasia in patient EBC with a particular emphasis on LC, as well as discussing methodological challenges involving in proteomic analysis of EBC specimens.

Treatment of ALK-rearranged non-small cell lung cancer: A review of the landscape and approach to emerging patterns of treatment resistance in the Australian context

Since the identification of anaplastic lymphoma kinase (ALK) gene rearrangements in non‐small cell lung cancer (NSCLC) in 2005, the treatment of ALK‐rearranged NSCLC (ALK+ NSCLC) has evolved at a rapid pace. This molecularly distinct subset of NSCLC has uniquely important biology, clinicopathologic features and mechanisms of drug resistance which impact on the choice of treatment for a patient with this disease. There are multiple ALK tyrosine kinase inhibitors now available in clinical practice with efficacy data continuing to emerge and guide the optimal treatment algorithm. A detailed search of medical databases and clinical trial registries was conducted to capture all relevant articles on this topic enabling an updated detailed overview of the landscape of management of ALK‐rearranged NSCLC.

The role of proteomics in the age of immunotherapies

The antigenic landscape of the adaptive immune response is determined by the peptides presented by immune cells. In recent years, a number of immune-based cancer therapies have been shown to induce remarkable clinical responses through the activation of the patient’s immune system. As a result, there is a need to identify immune biomarkers capable of predicting clinical response. Recent advances in proteomics have led to considerable developments in the more comprehensive profiling of the immune response. “Immunoproteomics” utilises a rapidly increasing collection of technologies in order to identify and quantify antigenic peptides or proteins. This includes gel-based, array-based, mass spectrometry (MS), DNA-based, or computer-based (in silico) approaches. Immunoproteomics is yielding an understanding of disease and disease progression, vaccine candidates, and biomarkers to a depth not before understood. This review gives an overview of the emerging role of proteomics in improving personalisation of immunotherapy treatment.

Pattern of care and survival of anaplastic lymphoma kinase rearranged non-small cell lung cancer (ALK+ NSCLC) in an Australian Metropolitan Tertiary Referral Centre: A retrospective cohort analysis

To report on the pattern of care and survival of anaplastic lymphoma kinase rearranged non–small cell lung cancer (ALK+NSCLC) in a real‐world retrospective cohort from an Australian tertiary referral center.

Abstract 3886: Protein mapping of NSCLC cell lines: Defining mechanisms of acquired erlotinib resistance

Lung cancer is one of the most common and lethal malignancies globally, with non-small cell lung cancer (NSCLC) accounting for 85% of all lung cancer cases. Patients generally have a poor prognosis without treatment as most patients are diagnosed with advanced metastatic disease, when curative therapeutic options are limited. However, there has been a recent emphasis on identifying driver mutations responsible for patient tumours, which has paved the way for more effective targeted therapies in the treatment of NSCLC. One such targeted therapy, erlotinib, is used as standard‐of‐care treatment in NSCLC patients with sensitising EGFR mutations. Although use of these tyrosine kinase inhibitors (TKIs) often leads to dramatic and prolonged response, acquired resistance eventually ensues. Understanding and overcoming the molecular basis of resistance to erlotinib remains a challenge for successful long-term treatment. To identify mechanisms of erlotinib resistance, we used latest-generation mass spectrometry to comprehensively map the proteomes of two NSCLC cell lines: a parental NSCLC cell line sensitive to erlotinib (HCC827, contains a deletion in EGFR exon 19) and its matched erlotinib-resistant subline (HCC827_ER). Cell lines were treated with an IC50 dose of erlotinib or mock treatment. Three days after treatment, each cell line was profiled using the Sequential Windowed data independent Acquisition of the Total High-resolution Mass Spectra (SWATH-MS 2.0) algorithm, conducted on the Sciex 6600 TripleTOF. LC-MS/MS data was extracted for 3416 proteins (peptide confidence >99%) following a Sciex ProteinPilot database search. Overall, 33 proteins were differentially expressed between HCC827 mock and erlotinib treated cells, while expression levels of 59 proteins were significantly different between HCC827er mock and erlotinib treated cells (Fold Change>2, p This is the first time that lung cancer cell lines have been comprehensively profiled by SWATH-MS. Protein mapping will help to increase the understanding of the mechanisms involved in the acquisition of TKI resistance, which is crucial for the development of rational strategies to overcome resistance in the clinic. Citation Format: Sarah A. Hayes, Christoph Krisp, Amanda L. Hudson, Rozelle Harvie, Csilla Hasovits, Stephen Clarke, Mark P. Molloy, Viive M. Howell. Protein mapping of NSCLC cell lines: Defining mechanisms of acquired erlotinib resistance. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3886.