A Phase I Study of [18F]DASA-23 as a PET Tracer for Evaluating Pyruvate Kinase M2 (PKM2) Expression in Healthy Volunteers and in Patients With Intracranial Tumors

This phase I trial studies how well [18F]DASA-23 and positron emission tomography (PET) scan work in evaluating pyruvate kinase M2 (PKM2) expression in patients with intracranial tumors or recurrent glioblastoma and healthy volunteers. PKM2 regulates brain tumor metabolism, a key factor in glioblastoma growth. [18F]DASA-23 is a radioactive substance with the ability to monitor PKM2 activity. A PET scan is a procedure in which a small amount of a radioactive substance, such as [18F]DASA-23, is injected into a vein, and a scanner is used to make detailed, computerized pictures of areas inside the body where the substance is used. Tumor cells usually pick up more of these radioactive substances, allowing them to be found. Giving [18F]DASA-23 with a PET scan may help doctors evaluate PKM2 expression in healthy volunteers and in participants with intracranial tumors or recurrent glioblastoma.

开始日期2018-04-23

申办/合作机构

Stanford University

100 项与 [18F] DASA-23 相关的临床结果

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100 项与 [18F] DASA-23 相关的转化医学

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100 项与 [18F] DASA-23 相关的专利（医药）

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项与 [18F] DASA-23 相关的文献（医药）

2021-12-01·Clinical cancer research : an official journal of the American Association for Cancer Research1区 · 医学

A Clinical PET Imaging Tracer ([18F]DASA-23) to Monitor Pyruvate Kinase M2–Induced Glycolytic Reprogramming in Glioblastoma

1区 · 医学

Article

作者: Haywood, Tom ; Davidzon, Guido ; Naya, Lewis ; Liu, Daniel Dan ; Khalighi, Mehdi ; Iagaru, Andrei ; Gambhir, Sanjiv Sam ; Reyes, Samantha T. ; Shen, Bin ; Beinat, Corinne ; He, Joy Q. ; Murty, Surya ; Patel, Chirag B. ; Nagpal, Seema ; Warnock, Geoffrey I. ; Hayden-Gephart, Melanie ; Johnson, Eli ; Park, Jun Hyung ; Halbert, Kim ; Thomas, Reena ; Sinha, Rahul ; Castillo, Jessa B. ; Born, Donald E. ; Chu, Pauline ; Uchida, Nobuko ; Massoud, Tarik F. ; Recht, Lawrence D. ; Holley, Dawn ; Gandhi, Harsh ; Buccino, Pablo ; Koran, Mary Ellen I. ; Weissman, Irving ; Alam, Israt S. ; Granucci, Monica ; James, Michelle L. ; Phillips, Megan

Abstract:

Purpose::

Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, a key process of cancer metabolism. PKM2 is preferentially expressed by glioblastoma (GBM) cells with minimal expression in healthy brain. We describe the development, validation, and translation of a novel PET tracer to study PKM2 in GBM. We evaluated 1-((2-fluoro-6-[18F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA-23) in cell culture, mouse models of GBM, healthy human volunteers, and patients with GBM.

Experimental Design::

[18F]DASA-23 was synthesized with a molar activity of 100.47 ± 29.58 GBq/μmol and radiochemical purity >95%. We performed initial testing of [18F]DASA-23 in GBM cell culture and human GBM xenografts implanted orthotopically into mice. Next, we produced [18F]DASA-23 under FDA oversight, and evaluated it in healthy volunteers and a pilot cohort of patients with glioma.

Results::

In mouse imaging studies, [18F]DASA-23 clearly delineated the U87 GBM from surrounding healthy brain tissue and had a tumor-to-brain ratio of 3.6 ± 0.5. In human volunteers, [18F]DASA-23 crossed the intact blood–brain barrier and was rapidly cleared. In patients with GBM, [18F]DASA-23 successfully outlined tumors visible on contrast-enhanced MRI. The uptake of [18F]DASA-23 was markedly elevated in GBMs compared with normal brain, and it identified a metabolic nonresponder within 1 week of treatment initiation.

Conclusions::

We developed and translated [18F]DASA-23 as a new tracer that demonstrated the visualization of aberrantly expressed PKM2 for the first time in human subjects. These results warrant further clinical evaluation of [18F]DASA-23 to assess its utility for imaging therapy–induced normalization of aberrant cancer metabolism.

2020-08-01·European Journal of Nuclear Medicine and Molecular Imaging

Human biodistribution and radiation dosimetry of [18F]DASA-23, a PET probe targeting pyruvate kinase M2

Article

作者: Haywood, Tom ; Iagaru, Andrei ; Gandhi, Harsh ; Naya, Lewis ; Davidzon, Guido ; Patel, Chirag B ; Shen, Bin ; Khalighi, Mehdi ; Beinat, Corinne ; Holley, Dawn ; Gambhir, Sanjiv Sam

PURPOSE:

To assess the safety, biodistribution, and radiation dosimetry of the novel positron emission tomography (PET) radiopharmaceutical 1-((2-fluoro-6-[[¹⁸F]]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([¹⁸F]DASA-23) in healthy volunteers.

METHODS:

We recruited 5 healthy volunteers who provided a written informed consent. Volunteers were injected with 295.0 ± 8.2 MBq of [¹⁸F]DASA-23 intravenously. Immediately following injection, a dynamic scan of the brain was acquired for 15 min. This was followed by serial whole-body PET/MRI scans acquired up to 3 h post-injection. Blood samples were collected at regular intervals, and vital signs monitored pre- and post-radiotracer administration. Regions of interest were drawn around multiple organs, time-activity curves were calculated, and organ uptake and dosimetry were estimated with OLINDA/EXM (version 1.1) software.

RESULTS:

All subjects tolerated the PET/MRI examination, without adverse reactions to [¹⁸F]DASA-23. [¹⁸F]DASA-23 passively crossed the blood-brain barrier, followed by rapid clearance from the brain. High accumulation of [¹⁸F]DASA-23 was noted in organs such as the gallbladder, liver, small intestine, and urinary bladder, suggesting hepatobiliary and urinary clearance. The effective dose of [¹⁸F]DASA-23 was 23.5 ± 5.8 μSv/MBq.

CONCLUSION:

We successfully completed a pilot first-in-human study of [¹⁸F]DASA-23. Our results indicate that [¹⁸F]DASA-23 can be used safely in humans to evaluate pyruvate kinase M2 levels. Ongoing studies are evaluating the ability of [¹⁸F]DASA-23 to visualize intracranial malignancies, NCT03539731.

TRIAL REGISTRATION:

ClinicalTrials.gov , NCT03539731 (registered 28 May 2018).

2020-02-01·Molecular imaging and biology3区 · 医学

Evaluation of Glycolytic Response to Multiple Classes of Anti-glioblastoma Drugs by Noninvasive Measurement of Pyruvate Kinase M2 Using [18F]DASA-23

3区 · 医学

Article

作者: Patel, Chirag B ; Beinat, Corinne ; Xie, Yuanyang ; Gambhir, Sanjiv S

PURPOSE:

Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, the key process of tumor metabolism. PKM2 is found in high levels in glioblastoma (GBM) cells with marginal expression within healthy brain tissue, rendering it a key biomarker of GBM metabolic re-programming. Our group has reported the development of a novel radiotracer, 1-((2-fluoro- 6-[¹⁸F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([¹⁸F]DASA- 23), to non-invasively detect PKM2 levels with positron emission tomography (PET).

PROCEDURE:

U87 human GBM cells were treated with the IC50 concentration of various agents used in the treatment of GBM, including alkylating agents (temozolomide, carmustine, lomustine, procarbazine), inhibitor of topoisomerase I (irinotecan), vascular endothelial and epidermal growth factor receptor inhibitors (cediranib and erlotinib, respectively) anti-metabolite (5-fluorouracil), microtubule inhibitor (vincristine), and metabolic agents (dichloroacetate and IDH1 inhibitor ivosidenib). Following drug exposure for three or 6 days (n = 6 replicates per condition), the radiotracer uptake of [¹⁸F]DASA-23 and 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) was assessed. Changes in PKM2 protein levels were determined via Western blot and correlated to radiotracer uptake.

RESULTS:

Significant interactions were found between the treatment agent (n = 12 conditions total comprised 11 drugs and vehicle) and the duration of treatment (3- or 6-day exposure to each drug) on the cellular uptake of [¹⁸F]DASA-23 (p = 0.0001). The greatest change in the cellular uptake of [¹⁸F]DASA-23 was found after exposure to alkylating agents (p < 0. 0001) followed by irinotecan (p = 0. 0012), erlotinib (p = 0. 02), and 5-fluorouracil (p = 0. 005). Correlation of PKM2 protein levels and [¹⁸F]DASA-23 cellular uptake revealed a moderate correlation (r = 0.44, p = 0.15).

CONCLUSIONS:

These proof of principle studies emphasize the superiority of [¹⁸F]DASA-23 to [¹⁸F]FDG in detecting the glycolytic response of GBM to multiple classes of anti-neoplastic drugs in cell culture. A clinical trial evaluating the diagnostic utility of [¹⁸F]DASA-23 PET in GBM patients (NCT03539731) is ongoing.

100 项与 [18F] DASA-23 相关的药物交易

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