American Association for Cancer Research (AACR)

Clinical Cancer Research

, том 31 , издание 8 , страницы OF1-OF12

Results of the phase I/II study and preliminary B cell gene signature of combined inhibition of glutamine metabolism and EGFR in colorectal cancer

Kristen K Ciombor ^{1, 2}

Seong-Woo Bae ^{3, 4}

Jennifer G. Whisenant ^{2, 5}

Gregory D. Ayers ^{1, 6}

Quanhu Sheng ^{5, 6}

Todd E Peterson ^{5, 7, 8}

G T Smith ^{5, 8}

Kangyu Lin ^{3, 9}

Saikat Chowdhury ^{9, 10}

Preeti Kanikarla ^{9, 10}

Alexey V. Sorokin ^{3, 9}

Allison S. Cohen ^{11, 12}

Laura W. Goff ^{2, 13}

Dana Cardin ^{2, 13}

John Paul Shen ^{9, 10}

Scott Kopetz ^{9, 14}

C. Eng ^{2, 13}

Y.-M. Shyr ^{6, 13}

J A Berlin ^{2, 13}

H. Charles Manning ^{3, 4}

Скрыть аффилиации авторов Показать аффилиации авторов: 14 аффилиаций

Vanderbilt University, Nashville, TN, United States |

1Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. |

The University of Texas MD Anderson Cancer Center, Houston, Tx, United States |

⁴

2Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas. |

⁵

Vanderbilt University Medical Center, Nashville, United States |

⁶

3Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee. |

⁷

4Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, Tennessee. |

⁸

5Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee. |

⁹

6Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. |

¹⁰

The University of Texas MD Anderson Cancer Center, HOUSTON, TEXAS, United States |

¹¹

Washington University in St. Louis, United States |

¹²

7Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri. |

¹³

Vanderbilt University Medical Center, Nashville, TN, United States |

¹⁴

University of Texas MD Anderson Cancer Center, Houston, TX, United States |

Тип публикации: Journal Article

Дата публикации: 2025-02-10

American Association for Cancer Research (AACR)

Clinical Cancer Research

scimago Q1

wos Q1

БС1

SJR: 4.800

CiteScore: 19.0

Impact factor: 10.2

ISSN: 10780432, 15573265

DOI: 10.1158/1078-0432.ccr-24-3133

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Purpose:

EGFR-targeting mAbs are essential for managing rat sarcoma virus wild-type metastatic colorectal cancer (mCRC), but their limited efficacy necessitates exploring immunologic and metabolic factors influencing response. This study evaluated glutamine metabolism targeting with EGFR inhibition to identify response biomarkers in patients with prior anti-EGFR treatment progression.

Patients and Methods:

We conducted a phase I/II trial in patients with KRAS wild-type mCRC, combining panitumumab (6 mg/kg) and CB-839 (600 mg/kg or 800 mg/kg), hypothesizing that the dual inhibition of glutamine metabolism and MAPK signaling would enhance outcomes. As study correlatives, we investigated the B-cell activation signature “B-score” and glutamine PET as potential treatment response biomarkers.

Results:

The combination of panitumumab and CB-839 was tolerable with manageable side effects, including grade 4 hypomagnesemia in four patients, a known panitumumab-related event. Two patients achieved partial response, and five had stable disease, with a 41% disease control rate. Median progression-free survival and overall survival were 1.84 and 8.87 months, respectively. A positive correlation between “B-score” and lesion size reduction suggested its association with clinical benefit (partial response and stable disease). Lower “B-score” correlated with greater tumor avidity for glutamine by PET, indicating B-cell activation sensitivity to glutamine depletion.

Conclusions:

The combination of CB-839 and panitumumab showed safety and promising preliminary responses, but the study closed early due to CB-839 development termination. The B-cell activation signature “B-score” emerged as a potential biomarker for EGFR and glutaminase inhibition in mCRC, warranting further studies. These findings suggest opportunities to improve immune response and therapies in glutaminolysis-dependent tumors.

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Bioorganic Chemistry	Bioorganic Chemistry, 1, 12.5% Bioorganic Chemistry 1 публикация, 12.5%
Cellular Signalling	Cellular Signalling, 1, 12.5% Cellular Signalling 1 публикация, 12.5%
International Journal of Molecular Sciences	International Journal of Molecular Sciences, 1, 12.5% International Journal of Molecular Sciences 1 публикация, 12.5%
MedComm	MedComm, 1, 12.5% MedComm 1 публикация, 12.5%
Frontiers in Immunology	Frontiers in Immunology, 1, 12.5% Frontiers in Immunology 1 публикация, 12.5%
Gastric Cancer	Gastric Cancer, 1, 12.5% Gastric Cancer 1 публикация, 12.5%
Frontiers in Pharmacology	Frontiers in Pharmacology, 1, 12.5% Frontiers in Pharmacology 1 публикация, 12.5%
Seminars in Cancer Biology	Seminars in Cancer Biology, 1, 12.5% Seminars in Cancer Biology 1 публикация, 12.5%
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Ciombor K. K. et al. Results of the phase I/II study and preliminary B cell gene signature of combined inhibition of glutamine metabolism and EGFR in colorectal cancer // Clinical Cancer Research. 2025. Vol. 31. No. 8. p. OF1-OF12.

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Ciombor K. K., Bae S., Whisenant J. G., Ayers G. D., Sheng Q., Peterson T. E., Smith G. T., Lin K., Chowdhury S., Kanikarla P., Sorokin A. V., Cohen A. S., Goff L. W., Cardin D., Shen J. P., Kopetz S., Eng C., Shyr Y., Berlin J. A., Manning H. C. Results of the phase I/II study and preliminary B cell gene signature of combined inhibition of glutamine metabolism and EGFR in colorectal cancer // Clinical Cancer Research. 2025. Vol. 31. No. 8. p. OF1-OF12.

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TY - JOUR

DO - 10.1158/1078-0432.ccr-24-3133

UR - https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-24-3133/751687/Results-of-the-phase-I-II-study-and-preliminary-B

TI - Results of the phase I/II study and preliminary B cell gene signature of combined inhibition of glutamine metabolism and EGFR in colorectal cancer

T2 - Clinical Cancer Research

AU - Ciombor, Kristen K

AU - Bae, Seong-Woo

AU - Whisenant, Jennifer G.

AU - Ayers, Gregory D.

AU - Sheng, Quanhu

AU - Peterson, Todd E

AU - Smith, G T

AU - Lin, Kangyu

AU - Chowdhury, Saikat

AU - Kanikarla, Preeti

AU - Sorokin, Alexey V.

AU - Cohen, Allison S.

AU - Goff, Laura W.

AU - Cardin, Dana

AU - Shen, John Paul

AU - Kopetz, Scott

AU - Eng, C.

AU - Shyr, Y.-M.

AU - Berlin, J A

AU - Manning, H. Charles

PY - 2025

DA - 2025/02/10

PB - American Association for Cancer Research (AACR)

SP - OF1-OF12

IS - 8

VL - 31

SN - 1078-0432

SN - 1557-3265

ER -

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@article{2025_Ciombor,

author = {Kristen K Ciombor and Seong-Woo Bae and Jennifer G. Whisenant and Gregory D. Ayers and Quanhu Sheng and Todd E Peterson and G T Smith and Kangyu Lin and Saikat Chowdhury and Preeti Kanikarla and Alexey V. Sorokin and Allison S. Cohen and Laura W. Goff and Dana Cardin and John Paul Shen and Scott Kopetz and C. Eng and Y.-M. Shyr and J A Berlin and H. Charles Manning},

title = {Results of the phase I/II study and preliminary B cell gene signature of combined inhibition of glutamine metabolism and EGFR in colorectal cancer},

journal = {Clinical Cancer Research},

year = {2025},

volume = {31},

publisher = {American Association for Cancer Research (AACR)},

month = {feb},

url = {https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-24-3133/751687/Results-of-the-phase-I-II-study-and-preliminary-B},

number = {8},

pages = {OF1--OF12},

doi = {10.1158/1078-0432.ccr-24-3133}

}

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Ciombor, Kristen K., et al. “Results of the phase I/II study and preliminary B cell gene signature of combined inhibition of glutamine metabolism and EGFR in colorectal cancer.” Clinical Cancer Research, vol. 31, no. 8, Feb. 2025, pp. OF1-OF12. https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-24-3133/751687/Results-of-the-phase-I-II-study-and-preliminary-B.