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M. Ilouze
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MINI 12 - Biomarkers and Lung Nodule Management (ID 109)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:J.M. Siegfried, H.I. Pass
- Coordinates: 9/07/2015, 16:45 - 18:15, 401-404
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MINI12.07 - Exhaled Breath Analysis in Lung Cancer - One Stop Shop for Diagnosis, Staging and EGFR Analysis (ID 2431)
16:45 - 18:15 | Author(s): M. Ilouze
- Abstract
- Presentation
Background:
Lung cancer (LC) is the leading cause of cancer death in the United States with more than 158,000 estimated deaths in 2015. Early detection of LC has been well established as a significant key point in patients' survival and prognosis, yet unfortunately, the vast majority of new LC patients are being diagnosed at advanced disease stages. Exhaled breath analysis can serve as a non-invasive method in early detection of LC. The tumor's micro-environment releases various compounds to blood, some of which are then exhaled at breath as Volatile Organic Compounds (VOCs). This study evaluates the potential of exhaled breath analysis in LC detection and to further diagnose histology, EGFR mutational status and to discriminate early from advanced disease in a multinational study.
Methods:
Breath samples were taken from untreated LC patients and matching controls. Patients were enrolled in a large tertiary referral hospital in Israel. Analysis was performed by gold nanoparticle-based Artificial Olfactory System (NaNose®) and Pattern recognition methods were used to analyze the results obtained from the NaNose®. Histology, EGFR mutation status and staging was taken from patient's files.
Results:
A total of 174 patients participated in this study, and Inter-group analysis of 80 LC patients (64 advanced stage) and 31 matched controls showed a significant discrimination between disease and control. Among all patients, 83 were adenocarcinoma and 11 were squamous. EGFR mutations were detected in 24 patients. The comparisons resulted in: early LC versus control: p < 0.0001; accuracy 85.11%, advanced LC versus control: p < 0.0001; accuracy 82.11%, early LC versus advanced LC: p < 0.0001; accuracy 78.75%. Histology (Adenocarcinoma vs. Squamous cell carcinoma) and EGFR status was also significantly determined by the volatile signature.
Conclusion:
Breath analysis may support early detection of cancer as well as histological diagnoses, staging and mutational testing in lung cancer. This innovative method may pose as an important non-invasive tool for lung cancer early detection, thus promoting better prognosis and therapeutic possibilities for patients.
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MINI 15 - Chemotherapy Developments for Lung Cancer (ID 128)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:L. Crinò, C.P. Belani
- Coordinates: 9/08/2015, 16:45 - 18:15, Mile High Ballroom 1a-1f
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MINI15.14 - The Role of Breath Sampling in Monitoring Response to Treatment in Lung Cancer (ID 2551)
16:45 - 18:15 | Author(s): M. Ilouze
- Abstract
- Presentation
Background:
The current available method to monitor response to treatment in lung cancer patient is by Computerized Tomography (CT) scans. However, time intervals between consecutive CT scans might be too long to allow early identification of treatment failure. The aim of this study is to examine the use of breath sampling as a tool for monitoring response to anti-cancerous treatment in patients with advanced lung cancer.
Methods:
In a prospective study, repeated exhaled breath samples were collected from patients with advanced lung cancer before and under systemic therapy. VOCs[1] profiles were determined by GC-MS[2] and nanomaterial-based array of sensors and correlated with response to therapy, assessed by CT scans as Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD). [1] Volatile Organic Compounds [2] gas-chromatography/mass-spectrometry
Results:
One hundred forty three breath samples were collected from 39 patients with stage III/IV lung cancer. GC-MS anaylsis identified 3 VOCs as significantly indicating PR/SD samples. One of them was also significantly discriminated between PR/SD and PD. Further, the NA-NOSE signals were able to alarm per a change in tumor response across therapy, i.e. indicating lack of further response to therapy, or developement of resistance to therapy. PR/SD was detected in a sensitivity of 93%, specificity of 85% and accuracy of 89% and ppositive/negative predictive values (PPV; NPV) of 86% and 92% respectively. PD was detected with 100% specificity and 92% accuracy, but the sensitivity was only 28%. The PPV and NPV were 100% and 91%, respectively. The achieved results indicate high reliability in predicting a progression of the disease and detecting patient's lack of response to treatment (i.e., PD).
Conclusion:
Breath analysis may serve as a serogate marker for response to systemic therapy in lung cancer. Such a monitoring tool can provide the oncologist with a quick and simple method to identify patient's response to anti-cancerous treatment in shorter intervals than currently available by CT scans.
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P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-067 - Mitochondrial Respiration Capacity and Sensitivity to Glycolysis Blockade in Lung Cancer (ID 2360)
09:30 - 17:00 | Author(s): M. Ilouze
- Abstract
Background:
One of the metabolic perturbations in cancer cells is the Warburg effect; glycolysis is preferred over oxidative phosphorylation (OXPHOS), even in the presence of oxygen. The precise mitochondrial alterations that underlie the increased dependence of cancer cells on aerobic glycolysis for energy generation may serve as an escape mechanism from apoptosis. Here, we aimed to profile the mitochondrial activity in different lung cancer cell lines in reference to their glycolytic activity and to their sensitivity to metabolic modifications.
Methods:
The metabolic profile of A549 and H358 cell lines were tested before and after glycolysis blockade (glucose starvation, 2DG) and mitochondrial induction (FCCP). Glycolysis inhibition and mitochondrial activity were assessed by western-blot quantification of key enzymes involved in the glycolysis pathway (e.g. Hexokinase I/II, glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase 2) and of mitochondrial coded proteins (e.g. ND1, ATP6 synthase). The oxygen consumption rates (OCR) and extra cellular acidification rate (ECAR) were measured by XF[e]24 extracellular flux analyzer. Further, mitochondrial index was compared to the cells' sensitivity to glycolysis inhibition.
Results:
A549 cells were highly affected by glucose inhibition/starvation accompanied by ineffective mitochondrial compensation. On the other hand, H358 cells recovered completely from glucose starvation through mitochondrial hyper-activation (Fig 1); At the basal level (when no material was applied), A549 cells that were starved had a decrease of 68% in the ECAR, as compared to non-treated cells. Their recovery was limited after glucose injection (23 vs.41 mpH/min). In comparison, H358 cells had a 43% decrease in their glycolysis rate with a full recovery after glucose injection (44-46 mpH/min; pre & post respectively). Mitochondrial respiration was very low for A549 cells under starvation, while significantly increased in H358 cells (223 vs.143 pmol/min, *Pv<0.0001). Respectively, the expression level of mitochondrial coded proteins was higher in the cells that demonstrated higher mitochondrial capacity (Fig 2). Figure 1
Conclusion:
Cells with high mitochondrial capacity may tolerate glucose starvation/ blockade, while a limited mitochondrial reserve exposes the cells to higher sensitivity to glycolysis stress. This might suggest a potential therapeutic avenue with a companion predictive test.
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-047 - Mitochondrial Activation- A Potential Therapy in Lung Cancer (ID 2359)
09:30 - 17:00 | Author(s): M. Ilouze
- Abstract
Background:
Lung cancer is the leading cause of cancer related deaths in the United States with an overall 5- year survival rate of all stages of~ 17%. Radiation therapy plays a key role in lung cancer treatment. However, many lung cancer patients show resistance to radiation. There is a growing body of evidence indicating that mitochondria may be the primary targets for cancer therapeutics: The unique metabolism of most solid tumors, including lung cancer, stems from remodeling mitochondrial functions to produce a glycolytic phenotype and a strong resistance to apoptosis (Warburg effect). Cancer specific remodeling can be reversed by a small molecule named dichloroacetate (DCA) which promote mitochondrial activation by increasing the influx of pyruvate. Sodium oxamate- another molecule that interferes with cells metabolism, inhibits the formation of the lactate-the end product of glycolysis. Here, we tested whether mitochondrial induction (using DCA and sodium oxamate) may increase the sensitivity of non-small cell lung cancer (NSCLC) cells to radiation through this mechanism. Moreover we tested whether sodium oxamate, increases the effect of DCA on radiation.
Methods:
Two representative NSCLC cell lines (A549 and H1299) were tested for their sensitivity to radiation with and without pre-exposure to DCA and sodium oxamate. The treatment efficacy was evaluated using a clonogenic survival assay. An extracellular flux analyzer was used to assess the effect of DCA on cellular oxygen consumption as a surrogate marker for mitochondrial activity.
Results:
We found that DCA increases the oxygen consumption rate in both A549 and H1299 cells by 60 % (p = 0.0037) and 20 % (p = 0.0039), respectively. Pre-exposure to DCA one hour before radiation increased the cytotoxic death rate 4-fold in A549 cells (55 to 13 %, p = 0.004) and 2-fold in H1299 cells (35 to 17 %, p = 0.28) respectively, compared to radiation alone. Sodium Oxamate radisosensitized H1299 cells as well. Double treatment with DCA and Sodium Oxamate enhances the radiosensitivity of H1299 cells.
Conclusion:
Mitochondrial activation may serve as a radio-sensitizer in the treatment of non-small cell lung cancer. Inhibition of the end stage of glycolysis increases the effect of mitochondrial activation on radiation.
