Metabolic Profiling for Chronic Lymphocytic Leukemia

Overseen By Christina Sheehan

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of Wisconsin, Madison

Must not be taking: Antihyperglycemics

Disqualifiers: Diabetes, Carbohydrate diets, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 2

16 Participants Needed

Trial Summary

What is the purpose of this trial?

Metabolic reprogramming has been identified as a hallmark of cancer. Almost a century after Otto Warburg initially discovered increased glycolytic activity in tumor tissue ("Warburg effect"), therapeutic targeting of cancer metabolism has become a field of intense research effort in cancer biology. A growing appreciation of metabolic heterogeneity and complexity is currently reshaping investigators "simplistic" understanding of metabolic reprogramming in cancer. Discovering metabolic vulnerabilities as new treatment targets for cancer requires systematic dissection of metabolic dependencies, fuel preferences, and underlying mechanisms in the specific physiological context. However, today's data on cancer cell metabolic signatures and heterogeneity in their physiological habitat of the human organism is sparse to non-existent representing a critical knowledge gap in designing effective metabolic therapies. Here, the investigators propose a "top-down" approach studying cancer cell metabolism in patients followed by mechanistic in-depth studies in cell culture and animal models to define metabolic vulnerabilities. Investigators will develop a metabolic tracing method to quantitatively characterize metabolic signatures and fuel preferences of leukemic lymphocytes in patients with chronic lymphocytic leukemia (CLL). Isotopic metabolic tracers are nutrients that are chemically identical to the native nutrient. Incorporated stable, non-radioactive isotopes allow investigators to follow their metabolic fate by monitoring conversion of tracer nutrients into downstream metabolites using cutting-edge metabolomics analysis. Using this method, investigators propose to test the hypothesis that leukemic lymphocytes show tissue-specific metabolic preferences that differ from non-leukemic lymphocytes and that ex vivo in-plasma labeling represents a useful model for assaying metabolic activity in leukemic cells in a patient-specific manner.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot be on antihyperglycemic therapy (medications for diabetes) or follow carbohydrate-restricting diets.

What data supports the effectiveness of the treatment for chronic lymphocytic leukemia?

The research shows that using labeled nutrients like [13C]glucose and [U-13C]glutamine can help understand cancer cell metabolism, which is important for developing targeted treatments. In chronic lymphocytic leukemia, understanding metabolic differences can guide therapy choices, as cells with different metabolic profiles respond differently to drugs. ^{1 2 3 4 5}

Is the use of 13C-labeled glutamine and glucose safe for humans?

Research on similar compounds, like 11C-glutamine and 18F-fluoroglutamine, used in imaging studies, shows they are generally safe for humans with no observed safety concerns in the studies conducted. ^{3 6 7 8 9}

How does this treatment for chronic lymphocytic leukemia differ from other treatments?

This treatment is unique because it focuses on understanding the metabolic profile of leukemia cells, particularly how they process nutrients like glucose and glutamine, which can reveal new therapeutic targets. Unlike traditional treatments that may not consider the metabolic environment, this approach uses advanced techniques like stable isotope tracing to study cell metabolism in its natural setting, potentially leading to more effective interventions. ^{10 11 12 13 14}

Research Team

Christopher Fletcher, MD

Principal Investigator

School of Medicine and Public Health, University of Wisconsin, Madison

Eligibility Criteria

This trial is for adults over 18 with or without Chronic Lymphocytic Leukemia (CLL). Group A includes healthy adults, Group B includes those newly diagnosed with low-burden CLL, and Group C has individuals with high-burden CLL affecting bone marrow. All must consent to participate.

Inclusion Criteria

Routine history of normal blood counts and vital signs

I am 18 years old or older.

I have never had cancer before.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Metabolic Profiling

Participants undergo metabolic profiling using isotopic metabolic tracers to characterize metabolic signatures and fuel preferences of leukemic lymphocytes.

1 day

1 visit (in-person)

Ex Vivo Labeling

Development and validation of an ex vivo labeling model to assay metabolism under conditions closest to the physiological setting.

10 minutes

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after metabolic profiling.

4 weeks

Treatment Details

Interventions

• [13C5]glutamine
• [U-13C]glucose

Trial Overview The study tests how leukemic cells process nutrients differently from normal cells by using special forms of glucose and glutamine ([13C5]glutamine, [U-13C]glucose) that can be tracked in the body to understand cancer cell metabolism.

Participant Groups

Group I: Group C:Treatment naïve CLL patients with high systemic disease burden Experimental Treatment 1 Intervention

Treatment naïve CLL patients with high systemic disease burden

Group II: Group B subset-2: Treatment naïve CLL patients with low disease burden Experimental Treatment 1 Intervention

Participants with low disease burden CLL (Chronic Lymphocytic Leukemia) defined as confined to Rai stage 0.

Group III: Group B subset-1: Treatment naïve CLL(Chronic Lymphocytic Leukemia) patients with low disease burden Experimental Treatment 1 Intervention

Participants with low disease burden CLL (Chronic Lymphocytic Leukemia) defined as confined to Rai stage 0.

Group IV: Group A: Healthy volunteers Experimental Treatment 1 Intervention

Healthy volunteers are defined as people without a history of cancer

Who Is Running the Clinical Trial?

University of Wisconsin, Madison

Lead Sponsor

Trials

1,249

Recruited

3,255,000+

Findings from Research

The study demonstrated that [18F]4F-Gln PET imaging can effectively measure cellular glutamine pool sizes in different breast cancer types, particularly highlighting the differences between triple-negative breast cancers (TNBC) and MCF-7 tumors.

Inhibition of glutaminase (GLS) in TNBC tumors significantly increased glutamine pool size, and this change was detectable using [18F]4F-Gln PET, suggesting its potential as a pharmacodynamic marker for drugs targeting glutaminolysis in aggressive cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[18F](2S,4R)4-Fluoroglutamine PET Detects Glutamine Pool Size Changes in Triple-Negative Breast Cancer in Response to Glutaminase Inhibition. Zhou, R., Pantel, AR., Li, S., et al.[2019]

The study introduces a novel method using stable isotope-labeled nutrients, like [13C]glucose, to analyze metabolic activity in intact tumors in vivo, providing insights that are not possible with traditional culture models.

This technique allows researchers to assess how cancer cells adapt their metabolism in response to various factors, which can help in understanding tumor behavior and potentially guide therapeutic strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stable isotope tracing to assess tumor metabolism in vivo. Faubert, B., Tasdogan, A., Morrison, SJ., et al.[2023]

Using (13)C metabolic flux analysis, researchers identified that [1,2-(13)C(2)]glucose is the most effective tracer for accurately estimating metabolic fluxes in cancer cell metabolism, particularly for glycolysis and the pentose phosphate pathway.

The study also found that [U-(13)C(5)]glutamine is the best tracer for analyzing the tricarboxylic acid (TCA) cycle, providing essential insights for designing more effective metabolic flux analysis experiments in mammalian cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of 13C isotopic tracers for metabolic flux analysis in mammalian cells. Metallo, CM., Walther, JL., Stephanopoulos, G.[2021]

In a study of 140 chronic lymphocytic leukemia patients, it was found that leukemic cells with mutated immunoglobulin variable heavy-chain had significantly lower glycolytic activity compared to those with unmutated chains, indicating a link between genetic mutations and energy metabolism.

The research also revealed that higher glycolytic activity in leukemic cells was associated with increased resistance to certain drugs and that glycolytic capacity could serve as an independent predictor of overall survival, suggesting potential for tailoring therapies based on metabolic profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Energy metabolism is co-determined by genetic variants in chronic lymphocytic leukemia and influences drug sensitivity. Lu, J., Böttcher, M., Walther, T., et al.[2020]

This study presents a detailed protocol for using 13C-stable isotope tracing to analyze the metabolic processes in HER2+ breast cancer brain metastases in mice, which is crucial for understanding tumor cell dependencies.

The method includes steps for injecting cancer cells to create brain metastases, infusing stable isotopes, and analyzing metabolites, providing a comprehensive approach for future cancer research and potential treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimized protocol for stable isotope tracing and steady-state metabolomics in mouse HER2+ breast cancer brain metastasis. Parida, PK., Marquez-Palencia, M., Kaushik, AK., et al.[2022]

The first-in-human study of the PET tracer 11C-glutamine in nine patients with metastatic colorectal cancer showed it was well tolerated with no safety concerns, indicating its potential for safe use in cancer imaging.

11C-glutamine effectively visualized metastatic lesions in organs such as the lung, brain, bone, and liver, suggesting its utility for noninvasive imaging and monitoring of cancer treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-Human PET Imaging and Estimated Radiation Dosimetry of l-[5-11C]-Glutamine in Patients with Metastatic Colorectal Cancer. Cohen, AS., Grudzinski, J., Smith, GT., et al.[2023]

In a study involving 25 adult cancer patients, the radiologic imaging agent fluorine 18-(2S,4R)-4-fluoroglutamine (FGln) was safely administered with no adverse effects, demonstrating its potential as a tumor imaging agent.

FGln PET scans successfully identified tumors in 17 out of 25 patients, particularly in aggressive cancers with mutations affecting glutamine metabolism, suggesting that FGln could serve as a valuable biomarker for targeted imaging in various cancer types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In Vivo PET Assay of Tumor Glutamine Flux and Metabolism: In-Human Trial of 18F-(2S,4R)-4-Fluoroglutamine. Dunphy, MPS., Harding, JJ., Venneti, S., et al.[2019]

The study developed two novel PET tracers, [18F]fluorophenylglutamine and [18F]fluorobiphenylglutamine, which showed potential for imaging tumors that utilize glutamine for growth, with [18F]fluorophenylglutamine demonstrating moderate tumor uptake in vivo.

[18F]fluorophenylglutamine is the first glutamine radiotracer with a phenyl group that prevents in vivo defluorination, making it a promising candidate for further optimization to enhance its imaging capabilities in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiosynthesis, in vitro and preliminary in vivo evaluation of the novel glutamine derived PET tracers [18F]fluorophenylglutamine and [18F]fluorobiphenylglutamine. Baguet, T., Verhoeven, J., Pauwelyn, G., et al.[2021]

The glutamine analog 18F-(2 S,4 R)4-fluoroglutamine (18F-(2 S,4 R)4-FGln) was successfully synthesized with high radiochemical purity (>98%) and showed rapid and higher uptake in breast cancer cells compared to the standard imaging agent 18F-FDG.

In a preliminary clinical study involving 10 breast cancer patients, 18F-(2 S,4 R)4-FGln/PET detected more lesions than 18F-FDG/PET (90% vs 80%), suggesting it may be a more effective tool for noninvasive imaging of breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PET Imaging of 18F-(2 S,4 R)4-Fluoroglutamine Accumulation in Breast Cancer: From Xenografts to Patients. Liu, F., Xu, X., Zhu, H., et al.[2019]

This study used advanced metabolomic technologies to track how glucose is processed in HeLa cancer cells, revealing that cancer cells not only secrete lactate but also convert glucose into various important metabolites.

After 48 hours of glucose labeling, the research quantified how much of the consumed glucose is transformed into proteins, peptides, sugars, glycerol, and lipids, providing insights into the metabolic pathways active in cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential incorporation of glucose into biomass during Warburg metabolism. Chen, YJ., Huang, X., Mahieu, NG., et al.[2021]

In breast cancer MCF-7 cells, the availability of glucose and glutamine significantly affects the levels of key metabolites, indicating that tumor cells can adapt their metabolism to fluctuating nutrient conditions.

Despite engaging similar metabolic pathways under both limiting and standard nutrient conditions, the specific concentrations of metabolites like serine and alanine vary greatly, highlighting the metabolic flexibility of cancer cells in response to nutrient scarcity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diverse Roads Taken by 13C-Glucose-Derived Metabolites in Breast Cancer Cells Exposed to Limiting Glucose and Glutamine Conditions. Gkiouli, M., Biechl, P., Eisenreich, W., et al.[2020]

Intermediary metabolism is crucial for regulating cell fate and function, especially in cancer, where targeting metabolic pathways can lead to new treatment options.

The study presents a protocol for in vivo stable isotope tracing of glutamine metabolism in acute myeloid leukemia (AML) cells in mice, highlighting the importance of studying metabolic profiles in their natural bone marrow environment rather than just in cell cultures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of Leukemia Cell Metabolism through Stable Isotope Tracing in Mice. van Gastel, N., Spinelli, JB., Haigis, MC., et al.[2022]

In a study using a MYC-inducible human Burkitt lymphoma cell line, it was found that MYC expression and hypoxic conditions increased glucose consumption and lactate production, highlighting the metabolic adaptations of cancer cells in challenging environments.

The research revealed that under glucose deprivation, glutamine metabolism became crucial for cell survival, suggesting that targeting glutamine pathways with inhibitors like BPTES could be a promising strategy for cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Le, A., Lane, AN., Hamaker, M., et al.[2022]

The PEPA method enhances the sensitivity and speed of detecting carbon labels in isotopically enriched metabolites in human cancer cells, making it a valuable tool for metabolomics studies.

By using 1D-1H-NMR spectra, PEPA allows for better quantification of stable isotope enrichment compared to traditional 13C-NMR techniques, thus broadening the range of metabolites that can be analyzed in cellular extracts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Positional Enrichment by Proton Analysis (PEPA): A One-Dimensional 1 H-NMR Approach for 13 C Stable Isotope Tracer Studies in Metabolomics. Vinaixa, M., Rodríguez, MA., Aivio, S., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

[18F](2S,4R)4-Fluoroglutamine PET Detects Glutamine Pool Size Changes in Triple-Negative Breast Cancer in Response to Glutaminase Inhibition. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Stable isotope tracing to assess tumor metabolism in vivo. [2023]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Evaluation of 13C isotopic tracers for metabolic flux analysis in mammalian cells. [2021]

4. Italy pubmed.ncbi.nlm.nih.gov

Energy metabolism is co-determined by genetic variants in chronic lymphocytic leukemia and influences drug sensitivity. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Optimized protocol for stable isotope tracing and steady-state metabolomics in mouse HER2+ breast cancer brain metastasis. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

First-in-Human PET Imaging and Estimated Radiation Dosimetry of l-[5-11C]-Glutamine in Patients with Metastatic Colorectal Cancer. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

In Vivo PET Assay of Tumor Glutamine Flux and Metabolism: In-Human Trial of 18F-(2S,4R)-4-Fluoroglutamine. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Radiosynthesis, in vitro and preliminary in vivo evaluation of the novel glutamine derived PET tracers [18F]fluorophenylglutamine and [18F]fluorobiphenylglutamine. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

PET Imaging of 18F-(2 S,4 R)4-Fluoroglutamine Accumulation in Breast Cancer: From Xenografts to Patients. [2019]

10. United States pubmed.ncbi.nlm.nih.gov

Differential incorporation of glucose into biomass during Warburg metabolism. [2021]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Diverse Roads Taken by 13C-Glucose-Derived Metabolites in Breast Cancer Cells Exposed to Limiting Glucose and Glutamine Conditions. [2020]

12. United States pubmed.ncbi.nlm.nih.gov

Analysis of Leukemia Cell Metabolism through Stable Isotope Tracing in Mice. [2022]

13. United States pubmed.ncbi.nlm.nih.gov

Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. [2022]

14. Germany pubmed.ncbi.nlm.nih.gov

Positional Enrichment by Proton Analysis (PEPA): A One-Dimensional 1 H-NMR Approach for 13 C Stable Isotope Tracer Studies in Metabolomics. [2021]