Metabolic Profiling for Chronic Lymphocytic Leukemia

Overseen By Cancer Connect

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to understand how cancer cells in chronic lymphocytic leukemia (CLL) use nutrients differently from normal cells. Researchers will use special nutrients, including [13C5]glutamine and [U-13C]glucose (forms of labeled nutrients), to track how leukemic cells process energy and identify new treatment targets. Participants include healthy volunteers and those who have not yet received treatment for CLL, regardless of whether they have a low or high disease burden. Those with CLL who are treatment-naïve and experiencing symptoms related to bone marrow infiltration might be suitable candidates. As an unphased trial, this study offers participants the chance to contribute to foundational research that could lead to new treatment strategies.

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 prior data suggests that this metabolic tracing method is safe for patients with chronic lymphocytic leukemia?

Research shows that both [13C5]glutamine and [U-13C]glucose are generally safe for studying metabolism in humans.

For [13C5]glutamine, studies indicate it can trace nutrient use in the body without harm. No evidence suggests serious side effects from its use.

Regarding [U-13C]glucose, past research confirms its safety, even in cancer patients. It aids in studying energy processing without major issues.

These tracers are stable isotopes, meaning they are non-radioactive and safe for the body. They help researchers understand cellular nutrient use, crucial for studying diseases like cancer. Overall, both tracers have demonstrated safety in similar research settings. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it explores how [13C5]glutamine and [U-13C]glucose can be used to understand the metabolic processes in Chronic Lymphocytic Leukemia (CLL) patients. Unlike standard treatments, which typically focus on directly targeting cancer cells, this approach aims to map the metabolism of cancer and healthy cells. By using these specially labeled molecules, scientists hope to uncover unique metabolic pathways that could lead to new, targeted therapies. This technique could potentially reveal insights that go beyond current options, which largely involve chemotherapy and monoclonal antibodies.

What evidence suggests that this trial's treatments could be effective for chronic lymphocytic leukemia?

This trial will use special forms of glucose and glutamine to study how chronic lymphocytic leukemia (CLL) cells use these nutrients differently from normal cells. Participants will be divided into groups, including healthy volunteers and treatment-naïve CLL patients with varying disease burdens. Research has shown that CLL cells consume more glucose and glutamine, which are crucial for their growth and survival. Specifically, a form of glutamine can enter a key energy-producing process in cells. Meanwhile, a special form of glucose helps track how leukemia cells take in and use glucose. These methods help identify unique behaviors in CLL cells, potentially leading to targeted treatments. ^{2 5 6 7 8}

Who Is on the Research Team?

Christopher Fletcher, MD

Principal Investigator

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

Are You a Good Fit for This Trial?

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 have never had cancer before.

Group B

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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 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]

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]

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]

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]

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]

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 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]

Citations

1. withpower.com withpower.com/trial/early-phase-1-leukemia-lymphoid-9-2021-b3e0b

Metabolic Profiling for Chronic Lymphocytic Leukemia What data supports the effectiveness of the treatment for chronic lymphocytic leukemia? The research shows that using labeled nutrients like [13C]glucose ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04785989

In Vivo Metabolic Profiling of CLL (Chronic Lymphocytic ... It will reveal how CLL cells utilize glutamine compared to non-leukemic lymphocytes and how this changes with different disease burden and site of disease.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10118070/

Characterization of metabolic alterations of chronic ... The data so far demonstrate that both glucose and glutamine metabolism were upregulated in CLL cells stimulated in vitro with CD40 or BCR, mimicking the LN ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8358691/

Physiological impact of in vivo stable isotope tracing on ... [U–13C5]-glutamine fueling the TCA cycle through glutaminase activity has been demonstrated by the labeling pattern of glutamate M+5 and TCA cycle intermediates ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S0006497121056378

Inhibition of Glutamine Import Attenuates Venetoclax ... Our study highlights the role of glutamine, in addition to glucose, in the metabolic reprogramming that CLL cells undergo in the LN.

6. isotope.com isotope.com/product/attachment/CDNLM-6805-PK/SDS%20-%20CDNLM-6805.pdf

L-GLUTAMINE (13C5, 97-99% Self-contained breathing apparatus. Hand protection. : Wear suitable protective clothing and gloves. Eye protection. : Wear safety glasses with ...

7. medchemexpress.com medchemexpress.com/l-glutamine-13c5.html?srsltid=AfmBOoqq0y8preKcnpD5LyXO-PCaVKyW5uZOumgJb42wBtvJtuDKoE9n

L-Glutamine- 13 C 5 (Synonyms: L-Glutamic acid 5-amide L-Glutamine-13C5 (Synonyms: L-Glutamic acid 5-amide-13C5) ; Solubility · 16.67 mg/mL (110.32 mM); Clear solution; Need ultrasonic and warming and heat to 60°C.

8. isotope.com isotope.com/metabolomics-and-cellular-metabolism/l-glutamine-13c5-clm-1822-h-001

L-Glutamine (¹³C₅, 99%) L-Glutamine (13C5) is a canonical amino acid that is used as a quantitative standard or metabolic tracer in MS-based experiments.