Plasma Sphingolipid Metabolites and Radiotherapy Efficacy in Hepatocellular Carcinoma

Официальное название

Correlation Between Plasma Sphingolipid Metabolites and the Efficacy of Radiotherapy in Hepatocellular Carcinoma

Обзор

Plasma contains a variety of metabolites, among which sphingolipids, including ceramide, sphingosine, and sphingosine-1-phosphate, serve as important intracellular second messengers and are involved in various cellular signaling pathways, such as apoptosis. We hypothesize that plasma sphingolipid levels may be associated with the efficacy of radiotherapy for liver cancer. This study will utilize LC-MS/MS technology for qualitative and quantitative analysis of plasma sphingolipids in liver cancer patients undergoing radiotherapy. Clinical data related to patient prognosis will also be collected to investigate the correlation between plasma sphingolipid levels and the therapeutic efficacy of liver cancer radiotherapy. The aim is to establish the clinical diagnostic significance of plasma sphingolipid levels in predicting the efficacy of liver cancer radiotherapy, providing new insights to enhance the effectiveness of radiotherapy in liver cancer treatment.

Подробное описание

Liver cancer is one of the most common malignant tumors worldwide, posing a significant challenge to public health. Radiotherapy plays a crucial role in controlling local recurrence and metastasis in hepatocellular carcinoma (HCC) and improving patient survival. Advanced radiotherapy techniques such as Intensity-Modulated Radiation Therapy (IMRT) and Stereotactic Body Radiation Therapy (SBRT) have enhanced tumor dose precision, increasing local control rates while minimizing radiation-induced side effects. However, current methods for assessing radiotherapy efficacy, including CT, MRI, and PET-CT, require extended post-treatment observation periods, delaying clinical decision-making. Additionally, radiotherapy can lead to radiation-induced liver disease (RILD) and other adverse effects such as radiation enteritis and bone marrow suppression. Therefore, identifying early predictive biomarkers for radiotherapy response and toxicity is critical for optimizing treatment strategies.

Sphingolipids, including ceramide (CER), sphingosine (SPH), and sphingosine-1-phosphate (S1P), are essential cellular signaling molecules involved in apoptosis, proliferation, and inflammation. Studies have shown that radiotherapy influences sphingolipid metabolism by altering enzyme activity, thereby affecting the balance of CER, SPH, and S1P-key regulators of tumor cell apoptosis. With advancements in lipidomics, the role of sphingolipid metabolism in radiation sensitivity has become an area of growing interest. Sphingolipid levels have been correlated with radiotherapy sensitivity in various cancers, making them potential prognostic biomarkers and therapeutic targets.

This study is designed as a single-center, prospective observational study with a two-year follow-up period, enrolling 260 primary liver cancer patients receiving radiotherapy. Plasma samples will be collected before, during, and after radiotherapy for qualitative and quantitative analysis of sphingolipid metabolites using liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS). Clinical imaging and laboratory data related to treatment response and adverse events will also be collected. Patients will be classified according to the mRECIST 1.1 criteria into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) groups for further correlation analysis.

The primary objective is to investigate the relationship between plasma sphingolipid levels and radiotherapy efficacy by analyzing overall survival (OS), objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), disease-free survival (DFS), and time to progression (TTP). The secondary objective is to explore the association between sphingolipid levels and radiation-induced toxicity, including RILD, radiation enteritis, and bone marrow suppression, to assess their potential as predictive biomarkers for treatment-related complications.

Patients will be followed at 1, 2, 6, 12, 18, 24, 36, and 48 months post-radiotherapy. The study does not involve any interventional treatment beyond standard clinical care, and patient management decisions will remain at the discretion of treating physicians. This research aims to provide new insights into the clinical significance of sphingolipid metabolism in predicting radiotherapy outcomes and toxicity in liver cancer, potentially improving personalized radiotherapy strategies.

Первичные конечные точки

• Disease Control Rate (DCR) [Срок оценки: From the start of treatment to 12 weeks post-treatment assessment]

Вторичные конечные точки (3)

• Progression-Free Survival (PFS) [Срок оценки: From treatment initiation to the date of disease progression or death, up to 24 months.]
• Overall Survival (OS) [Срок оценки: From treatment initiation to death, up to 24 months]
• Safety and Tolerability [Срок оценки: From the start of treatment until 90 days after the last dose.]

Критерии участия

Критерии включения

• Patients voluntarily signed the informed consent form.
• Aged between 18 and 80 years.
• Clinically diagnosed with primary liver cancer according to the latest treatment guidelines.
• Determined by the treating physician to require radiotherapy.
• Expected survival time of more than 3 months.

Критерии исключения

• Patients who discontinued radiotherapy or did not complete the planned treatment.
• Presence of malignancies from other origins.
• Severe metabolic diseases such as uncontrolled diabetes, significant obesity, or fatty liver disease.
• Uncontrolled comorbidities, such as severe cardiovascular or pulmonary diseases, that may affect treatment or study outcomes.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Только случаи

Центры проведения

Китай · 1 центр

• Nanfang Hospital, Southern Medical University — Гуанчжоу

Публикации

• Deng X, Yin X, Allan R, Lu DD, Maurer CW, Haimovitz-Friedman A, Fuks Z, Shaham S, Kolesnick R. Ceramide biogenesis is required for radiation-induced apoptosis in the germ line of C. elegans. Science. 2008 Oct 3;322(5898):110-5. doi: 10.1126/science.1158111. PMID 18832646
• Kumar A, Oskouian B, Fyrst H, Zhang M, Paris F, Saba JD. S1P lyase regulates DNA damage responses through a novel sphingolipid feedback mechanism. Cell Death Dis. 2011 Feb 10;2(2):e119. doi: 10.1038/cddis.2011.3. PMID 21368890
• Taha TA, Osta W, Kozhaya L, Bielawski J, Johnson KR, Gillanders WE, Dbaibo GS, Hannun YA, Obeid LM. Down-regulation of sphingosine kinase-1 by DNA damage: dependence on proteases and p53. J Biol Chem. 2004 May 7;279(19):20546-54. doi: 10.1074/jbc.M401259200. Epub 2004 Feb 26. PMID 14988393
• Aureli M, Bassi R, Prinetti A, Chiricozzi E, Pappalardi B, Chigorno V, Di Muzio N, Loberto N, Sonnino S. Ionizing radiations increase the activity of the cell surface glycohydrolases and the plasma membrane ceramide content. Glycoconj J. 2012 Dec;29(8-9):585-97. doi: 10.1007/s10719-012-9385-2. Epub 2012 May 17. PMID 22592846
• Cheng JC, Bai A, Beckham TH, Marrison ST, Yount CL, Young K, Lu P, Bartlett AM, Wu BX, Keane BJ, Armeson KE, Marshall DT, Keane TE, Smith MT, Jones EE, Drake RR Jr, Bielawska A, Norris JS, Liu X. Radiation-induced acid ceramidase confers prostate cancer resistance and tumor relapse. J Clin Invest. 2013 Oct;123(10):4344-58. doi: 10.1172/JCI64791. Epub 2013 Sep 16. PMID 24091326
• Garcia-Barros M, Paris F, Cordon-Cardo C, Lyden D, Rafii S, Haimovitz-Friedman A, Fuks Z, Kolesnick R. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science. 2003 May 16;300(5622):1155-9. doi: 10.1126/science.1082504. PMID 12750523
• Liao WC, Haimovitz-Friedman A, Persaud RS, McLoughlin M, Ehleiter D, Zhang N, Gatei M, Lavin M, Kolesnick R, Fuks Z. Ataxia telangiectasia-mutated gene product inhibits DNA damage-induced apoptosis via ceramide synthase. J Biol Chem. 1999 Jun 18;274(25):17908-17. doi: 10.1074/jbc.274.25.17908. PMID 10364237
• Gomez-Larrauri A, Presa N, Dominguez-Herrera A, Ouro A, Trueba M, Gomez-Munoz A. Role of bioactive sphingolipids in physiology and pathology. Essays Biochem. 2020 Sep 23;64(3):579-589. doi: 10.1042/EBC20190091. PMID 32579188

Идентификаторы

NCT: NCT06864221 · NFEC-2024-389

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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