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Pyruvate

Participants will receive an injection of 250 mM of hyperpolarized 13-C pyruvate intravenously after standard of care imaging sequences are performed. Then participants will undergo HP-MR imaging.

Imaging tumors pre and post administration of hyperpolarized 13-C pyruvate injection.

Hyperpolarized 13C-Pyruvate

Nikita Rednam, BA

Many human diseases are characterized by their ability to alter existing metabolic pathways and interrupt cellular processes. Cancer exploits the Warburg effect and utilizes greater glucose than normal cells and within this process uses anaerobic respiration, leading to increased conversion of pyruvate to lactate. This can be exploited by hyperpolarized imaging. Hyperpolarized 13C MRI imaging is an approach that utilizes a stable isotope of Carbon (13C) linked to pyruvate. MRI spectroscopy is used in conjunction with hyperpolarized 13C pyruvate in order to temporally detect pyruvate and its conversion to lactate in-vivo, in order to visualize downstream metabolic (glycolytic) activity secondary to the Warburg effect, which should be useful in detecting and characterizing tumors of various types. Hyperpolarized 13C pyruvate MR imaging has not been tested in most cancers. In this preliminary survey, we will test the hypothesis that hyperpolarized 13C pyruvate MR imaging can be used to image various cancers.

Most cancers exhibit the Warburg effect, which involves synthesis of lactate via glycolytic pathways. The present method of using 18F-FDG to image metabolic events only evaluates early glycolysis and does not investigate late glycolytic effects which can be examined by 13C pyruvate. The ability to detect cancer using 13C pyruvate has been shown using ovarian cancer models and in the prostate in humans, however its utility in other tumors needs clarification. Because cancers of various types affect metabolic pathways, it is necessary to improve imaging techniques to better investigate downstream metabolism. Many studies have shown that there are higher lactate levels in cancer tissue and higher levels of glycolysis. 13C pyruvate imaging takes advantage of these pathways by imaging the tumors while undergoing pyruvate to lactate conversion . From this modality, a three dimensional visualization of the tumor and metabolic products created by the pyruvate can be investigated.

Participants will be evaluated pre and post hyperpolarized 13-C pyruvate injection for change in pyruvate signal compared to background.

HP Pyruvate MRI in Cancers

Hyperpolarized 13-C Pyruvate MRI Surveillance of Multiple Cancers

University of Maryland, Baltimore

Chief of Oncologic Imaging

Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Lung Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Patients who have diagnosed with lung cancer before treatment

high risk patients who are age and co-morbidity matched controls without proof of lung cancer.

Nir Peled, MD PhD

Naomi Gai Mor, M.Sc.

Eve Keret

Dr. Nir Peled, PhD,MD, FCCP

Nir Peled, MD PhD FCCP

Lung cancer is the most lethal cancer, killing \~1.3 million people worldwide every year. Early diagnosis could increase its survival by 3-4 folds. Therefore the yield of screening for lung cancer is not a question anymore and the urgent unmet need is to define the group that is under a high risk for lung cancer.

Our lab is focusing on revealing non-invasive biomarkers as for early detection of lung cancer. This study specifically focuses on biomarkers that are found in exhaled breath. These biomarkers are known as volatile organic compounds (VOCs).The VOCs' profile can discriminate between those who suffer from lung cancer and healthy individuals.

It is well established that a cancer cell can activate their glycolysis (glucose degradation) pathway in order to survive. This links malignant processes with this basic biochemical, metabolic cycle. This study will focus on the unique processes incurred by glycolysis in the tumor cells and its effect on the surrounding environment. By better understanding and revealing the exact mechanism, it will become possible to identify the biomarkers released by malignant cells that use glycolysis as a source of energy.

This study's goal is to identify and analyze those distinguishing VOCs. The hope is that these VOCs will provide a new innovative possibility of developing the so desperately needed, early-detection lung cancer screening method.

This research will collect and analyze the exhaled breath of participants. The exhaled breath will be obtained before and after a glucose challenge test, in which the participant is asked to drink a solution containing water and glucose. This study will involve a total of seventy participants, fifty of which currently suffer from active lung cancer, while the remaining participants belong to a high-risk group.

The Contribution of induced Glycolysis to the Exhaled Volatile Organic Compounds' (VOCs) Signature in Lung Cancer

Abstract:

Lung cancer is infamous for its cruel mortality rates as it is the most lethal cancer in both men and women. Unfortunately, most lung cancers are detected and diagnosed at a very advanced stage and this complicates treatment options. Therefore, there is dire, unmet need to develop an effective, highly sensitive, highly specific and non-invasive screening method. The solution to this problem may be found in volatile organic compounds (VOCs) which are organic molecules identified in exhaled breath. These VOCs differ between those individuals who suffer from lung cancer and healthy individuals. Seeing as increased glycolysis is one of the characteristic patterns of malignancies, the purpose of this study is to determine the contribution of induced glycolysis to these exhaled VOCs. Therefore, this study will compare exhaled breath samples in individuals who suffer from lung cancer before and after a glucose challenge test. This study aims to better understand the mechanisms involved in order to identify the distinguishing VOCs. This may aid in developing the so necessary diagnostic means for lung cancer screening.

1. Introduction:

   Lung cancer is the moth lethal cancer in both men and women. \[1\] There are two main classes of lung cancer: the first, Small Cell Lung Cancer (SCLC) which is often referred to as Oat Cell Cancer, and the second being Non-Small Cell Lung Cancer (NSCLC), which constitutes the majority of cases of lung cancer. \[2\] Unfortunately, most lung cancer detection and diagnosis is performed when the cancer is in an advanced, metastatic stage in which surgery is not a viable treatment option. \[3\] Thus, detection and diagnosis its early stages may significantly improve the five year survival rate as well as provide the possibility of a cure.

   An effective, non-invasive lung cancer screening method for distinguishing biological markers found in high-risk groups has yet to be developed. Lately, researchers have begun considering Volatile Organic Compounds' (VOCs) templates as a possible means for early detection. These VOCs can be retrieved and isolated from exhaled breath samples. The VOCs reflect the unique metabolic and biochemical activity in malignant cells. This association has been proven in several researchers as well as in our own group \[4\] who has shown that not only can VOCs distinguish between healthy and affected individuals, but they can even discern between SCLC and NSCLC. \[5, 6\] The current research will focus on the detection, identification and the characterization of these unique biological markers found in the exhaled breath of those who suffer from lung cancer. Amongst those VOCs which are detected, this research will specifically focus on those VOCs which hold the potential to be incorporated into an effective, non-invasive screening method for lung cancer.

   Carcinogenesis is a process that is bound to somatic evolution. One of the most popular evolutionary advantages found in malignant, metastatic cells is the increased uptake of glucose through the process of glycolysis. This glycolysis process is unique to malignant cell because it is most pronounced in anaerobic conditions, whereas healthy cells most often perform glycolysis in aerobic conditions. Anaerobic glycolysis- the process of the conversion of glucose to lactic acid in the presence of oxygen- is also known as the "Warburg Effect" after Otto Warburg who discovered this characteristic. \[7\]

   Thus, some of the distinguishing processes found in malignant cells are the exceeded rate of substance exchange and increased glucose degradation (Warburg Effect). These processes release organic compounds, some of which are released into exhaled breath. Therefore, this research will examine the relationship between a glucose challenge test and its effect on the pattern on VOCs in exhaled breath.
2. Research Goals:

   The template for organic particles in exhaled breath discriminates between those individuals who suffer from active lung cancer from those individuals who are considered healthy. The purpose of this study is to examine the contribution of the process of glycolysis to this unique template. Being that the process of glycolysis is accelerated in malignant cells, we hypothesize that the glucose challenge test will express VOC in those individuals who suffer from the disease. These findings can contribute to the development of diagnostic tools for lung cancer.
3. Hypothesis:

   We hypothesize that the Warburg Effect is an essential component in the creation of VOCs that are unique to lung cancer, and therefore, that the glucose challenge test will increase the production of these VOCs. These markers hold the potential to create a more effective, non-invasive screening method with improved sensitivity and specificity.
4. Methods:

4.1 Research Design: This research is an observational case-control study assesses the comparison between the VOCs samples obtained from exhaled breath samples and blood tests taken before and after a glucose challenge test. The glucose challenge test involves drinking a solution which contains 75 grams of glucose and a waiting period of 90 minutes between the collection of exhaled breath and blood samples. There is a need to fast for six hours before this test. In addition, a clinical assessment will be performed based on the medical anamnesis and on existing, current medical information.

4.2 Study Population: The goal of this research is to determine if the process of glycolysis contributes to the unique VOC pattern in the exhaled breath of those who are affected with lung cancer. The participants will be chosen from individuals that are currently being treated in pulmonology clinics for various reasons. The control group will include participants that have been identified as high-risk individuals for lung cancer, whereas the study group will include participants who suffer from active lung cancer but have not yet begun any form of medical treatment.

The recruitment process will be performed in two consecutive stages. In the first stage, twenty patients from the study group will be compared to the twenty participants from the control group. At this point, a preliminary assessment of the data will be performed to find differences in the VOCs between these two groups. Only in the event that these differences are found will the research go on to the second stage, in which 30 more participants will be recruited and tested for the study group.

The control group as previously mentioned will include 20 participants that do not have lung cancer, but are similar to the research group in terms of age, gender, medical history, and history of smoking. This classification will be performed based off the self-report surveys completed by the participants.

Exclusion criterions for the study population are as follows:

1. Patients that are uninterested to participant and/or unable to sign a consent form
2. Lung Cancer patients who have begun treatment prior to this research
3. Patients who are unable to complete this research and/or the follow up visits
4. Individuals that suffer from diabetes

4.3 Research Variables:

The main variables which will be used to test our hypothesis are as follows:

* Epidemiological variables of the participants
* Quantitative data defining the malignant cells ( TMN, the size of the tumor, number of metastases and their location)
* The glucose levels( via a dipstick) before and after the glucose challenge test (requires a fast of 6 hours prior to the test)
* The VOCs pattern obtained from the exhaled breath samples and the characterization of these molecules via the GCMS method.

4.4 Research Methods:

Medical Anamnesis:

A collection of the details of the patient's medical history will be obtained. Information such as gender, age, medical history, consumption of tobacco and family history will be noted. In addition, information which quantifies and qualifies the malignant cells (if present) will be collected and recorded. This includes details such as the type of tumor as well as its place, volume, histological characteristics and imaging results. Some of the medical information will be obtained from pre-existing updated medical records.

Exhaled Breath Test:

Each participant will undergo an exhaled breath test before and after the glucose challenge test with a lay period of 90 minutes in between the tests.

The detailed explanation regarding the process of collection of the exhaled breath samples:

The patient will exhale 3 breaths (with 750 ml in each exhaled breath) into appropriate Mylar bags in a sterile area with technology that ensures that the exhaled breath is isolated and unaffected from the external environment. The contents of the Mylar bags will be stored in TENAX samples which preserves the samples for a period of six months. The samples will undergo additional analysis at the Israel Institute of Technology (Technion) under the auspices of Professor Haim Hussam. Each sample will be analyzed for the purposes of identifying VOCs via the GC-MS method. The sample will undergo additional processing such as SPME (pre-concentration into solid-phase micro extraction). The SPME will be transferred to the GC-MS. The GC-MS method allows for the identification of the compounds in a short period of time via the use of chromatographic and spectroscopic instruments. The spectroscopic instrument will undergo additional analysis via the AOS instrument. The AOS includes detectors which are conjugated to nano-particles of gold. Each detector identifies a wide variety of VOCs in accordance to their location and concentration which cause varying levels of resistance. This response is recorded and will undergo statistical analysis via PCA to focus on the specific VOC patterns found in the sample.

The detailed explanation of the process of the glucose challenge test is as follows:

The participant is requested to drink a sugary solution (273 ml) constituted from 75 grams of glucose and water. The test requires that the participant fast for a period of 6 hours before the test. After drinking the solution, the participant must wait a lay period of 90 minutes before the retest of his or her exhaled breath. In addition, the level of glucose will be tested by a dipstick before drinking the solution, and after the 90 minute lay period.

4.5 Statistical Analysis: The sample size is 70 persons ( 40 persons in the first stage, and an additional 30 participants in the second stage as explained above).

The expectation is that there will be a significant difference between the VOC template before and after the glucose challenge test. The estimated difference of effect is around 30%, with the assumption that the sampling error stands at around 10% and with a confidence interval of 95%. The number of necessary participants needed in order to achieve results with statistical significance and size effect ranges from approximately 20-25 persons.

The information from the AOS which recorded the changes in resistance will be analyzed via PCA to focus on the specific VOC pattern changes obtained in each sample.

The remaining variables which were measured quantitatively will be presented in averages with their corresponding standard deviations. Those variables that were obtained quantitatively will be presented as percentages.

Statistical analysis for significance will be performed by the following statistical tests: Student's T Test, Chi-Square, Analysis of Variance (ANOVA), and the Kruskal-Wallis test. All statistical tests will be performed on the SPSS computer program.

The Contribution of Induced Glycolysis to the Exhaled Volatile Organic Compounds' (VOCs) Signature in Lung Cancer

Each breath sample will be analyzed to identify VOCs via the GC-MS and Artificaial olfactory System AOS. We expect a significant difference between the VOC template before and after the glucose challenge test. The estimated difference of effect \~ 30%, with a sampling error \~ 10% and CI \~ 95% and sample size of 20-25 persons.

The information from the AOS which recorded the changes in resistance will be analyzed via PCA to focus on the specific VOC pattern changes obtained in each sample.

The remaining variables which were measured quantitatively will be presented in averages with their corresponding standard deviations. Those variables that were obtained quantitatively will be presented as percentages.

Statistical analysis for significance will be performed by the following statistical tests: Student's T Test, Chi-Square, Analysis of Variance (ANOVA), and the Kruskal-Wallis test.

Sheba Medical Center

Head, Thoracic Cancer Research and Detection Center- MD PhD FCCP

Skin and Connective Tissue Diseases

Keratosis, Actinic

Keratosis

Skin Diseases

Precancerous Conditions

Anti-Inflammatory Agents

Antirheumatic Agents

Analgesics

Hyaluronic Acid

Diclofenac

Anti-Inflammatory Agents, Non-Steroidal

Analgesics, Non-Narcotic

Cyclooxygenase Inhibitors

Enzyme Inhibitors

Adjuvants, Immunologic

Immunologic Factors

Viscosupplements

Protective Agents

3 % diclofenac in 2.5% hyaluronic acid gel (Solaraze® 3% gel) is applied twice daily in the treatment area. 3 % diclofenac in 2.5% hyaluronic acid gel (Solaraze® 3% gel) is to be applied 1cm beyond the single AK.

3% diclofenac in 2.5% hyaluronic acid gel

The rationale of this study is to investigate the effects of topical diclofenac on tumor metabolism in the treatment of actinic keratoses in immunocompetent and immunocompromised patients.

Study hypothesis is that topical diclofenac lowers lactate level in skin biopsies of actinic keratoses. Planned number of patients is 38.

This study is a monocenter study investigating the effects of 3% diclofenac in 2.5% hyaluronic acid gel on tumor metabolism in the treatment of actinic keratoses. Treatment duration is 3 months. Skin biopsies will be obtained before treatment, at the end of the treatment and four weeks after the treatment. Control biopsies at visit 1 and 3 are performed in healthy, sun damaged and untreated skin. Evaluation of efficacy will be performed at the end of the treatment and four weeks after the treatment.

Duration of treatment is 3 months (±4 weeks). Approximately 0,5g Solaraze® 3% gel is applied on a 5cm x 5cm lesion. Solaraze® 3% gel is applied twice daily on the study lesions.

Neoplastic cells show an increased glucose metabolism and glycolysis which is associated with high lactate concentrations. There is also data for several tumor entities that high levels of lactate in the tumor are associated with tumor progression, metastasis and poor clinical outcome. Kreutz et al. demonstrated that diclofenac inhibits tumor cell proliferation in vitro and tumor growth in vivo via COX-independent effects on glucose metabolism. Diclofenac is taken up by tumor cells and inhibits tumor cell proliferation through inhibition of the oncogene MYC and subsequently glycolysis and block of lactate transport. MYC regulates genes involved in glycolysis and is upregulated in neoplastic cells, which is in line with the metabolic switch to glycolysis, the so called "Warburg effect", that cancer cells show. Although these results were found in vitro using human melanoma cells and in vivo in a mouse model, a similar mechanism of action is assumed to be relevant for the treatment of actinic keratoses with topical diclofenac. However tumor metabolism in diclofenac-treated actinic keratoses has never been investigated. To investigate the mechanism of action of diclofenac in the treatment of actinic keratoses, a clinical study analyzing particularly lactate levels, glycolysis and inflammatory infiltrate is needed.

Effects of Topical Diclofenac on Tumor Metabolism

Prospective, Controlled and Monocentric Study to Evaluate the Effects of Topical 3% Diclofenac in 2.5% Hyaluronic Acid Gel on Tumor Metabolism in the Treatment of Actinic Keratoses in Immunocompetent and Immunocompromised Patients

Assessment of the effects of topical 3% diclofenac in 2.5% hyaluronic acid gel on lactate level in skin biopsies of actinic keratoses. Skin biopsies of actinic keratoses are obtained prior to treatment and 4 weeks after the treatment.

Assessment of the effects of topical 3% diclofenac in 2.5% hyaluronic acid gel on lactate level in skin biopsies of actinic keratoses compared to untreated sun damaged, healthy skin in a subpopulation

Glycolysis-relevant proteins evaluated using PCR and Westernblot techniques

Metabolic changes (e.g. glucose, amino acids) evaluated by NMR methods and bioluminescence imaging techniques

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
HP Pyruvate MRI in Cancers	NCT05697406	Image Warburg Effect Tumors	Hyperpolarized ...	18 Years - 88 Years	University of Maryland, Baltimore
The Contribution of Induced Glycolysis to the Exhaled Volatile Organic Compounds' (VOCs) Signature in Lung Cancer	NCT01852838	Lung Cancer		18 Years - 95 Years	Sheba Medical Center
Effects of Topical Diclofenac on Tumor Metabolism	NCT01935531	Actinic Keratos...	3% diclofenac i...	18 Years -	University Hospital Regensburg
The Contribution of Induced Glycolysis to the Exhaled Volatile Organic Compounds' (VOCs) Signature in Lung Cancer	NCT01852838	Lung Cancer		18 Years - 95 Years	Sheba Medical Center
HP Pyruvate MRI in Cancers	NCT05697406	Image Warburg Effect Tumors	Hyperpolarized ...	18 Years - 88 Years	University of Maryland, Baltimore
The Contribution of Induced Glycolysis to the Exhaled Volatile Organic Compounds' (VOCs) Signature in Lung Cancer	NCT01852838	Lung Cancer		18 Years - 95 Years	Sheba Medical Center

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