Unveiling Prognosis Cancer-Associated Thromboembolism Biomarkers and Their Related Polymorphisms: Exploring Their Involvement With Immune Circulating Cells and Therapeutic Reversibility
Overview
- Phase
- Phase 1
- Intervention
- SNP
- Conditions
- Cancer
- Sponsor
- Lebanese University
- Enrollment
- 500
- Locations
- 2
- Primary Endpoint
- Venous Thromboembolism (VTE) Events including: Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and other Thromboembolic Events (Vein Thrombosis, Portal Vein Thrombosis, Superior Mesenteric Vein Thrombosis, and Renal Vein Thrombosis)
- Status
- Recruiting
- Last Updated
- 2 years ago
Overview
Brief Summary
This study aims to assess biomarkers and their related polymorphisms in the context of cancer-associated thromboembolism, with a particular focus on their interaction with the immune system. The roles of immune checkpoints, inflammatory and angiogenesis factors, as well as circulating immune cells will be elucidated. Additionally, our investigation extends to the exploration of long non-coding RNAs (LncRNAs) and genes associated with the coagulation vascular system. Initially, these aspects will be evaluated in the context of colorectal cancer, with the intention to expand our research to other solid tumors.
The identification of these biomarkers and genetic factors holds the potential to revolutionize therapeutic approaches for patients with cancer-associated thromboembolism, shedding light on their chemotherapy resistance. The effectiveness of combining immunotherapy with targeted inhibitors like Palbociclib and anticoagulants such as Rivaroxaban, among other potential interventions, will be assessed.
This study aims to make significant contributions to the understanding of these critical aspects, ultimately leading to the development of more effective treatment strategies for cancer patients.
Detailed Description
Cancer, especially solid tumors, remains a significant global health challenge despite ongoing advancements in risk factor identification and targeted therapies. Among the various complexities of cancer treatment, the relationship between cancer and thromboembolism, characterized by arterial and venous thrombosis, has attracted attention due to its significant impact on patient outcomes. Cancer cells activate the coagulation system, leading to prothrombotic disorders in the vascular wall and promoting tumor progression. Patients with cancer, particularly those undergoing systemic chemotherapy, face an increased risk of thromboembolism due to abnormal blood clotting mechanisms. Recent research has emphasized the importance of identifying novel biomarkers for risk assessment, prognosis determination, and treatment selection in cancer. Among these biomarkers, long non-coding RNAs (LncRNAs) and those of the vascular coagulation system have emerged as pivotal players in cancer development and progression. However, their role as prognostic and predictive biomarkers for cancer risk and treatment response remains relatively unexplored. Understanding the complex interplay between cancer, immune responses, and thromboembolism is crucial. Immunological subsets, including central immune effector T cells (CD8+, CD25+), NK cells, and macrophages, have been linked to cancer prognosis. Furthermore, therapies that modulate the immune system, such as immunotherapy and cell-based therapies, hold promise for improving cancer treatment outcomes. Most notably, these therapies exhibit immunomodulatory effects, triggering immunogenic cell death and preventing immunosuppression. However, their efficacy may be compromised in cases of cancer associated with clotting abnormalities within the circulatory system. Progenitor cells, including stem cells and endothelial progenitor cells (EPCs), are emerging as potential players in cancer therapy, offering new avenues for research. Among the innovative approaches is the assessment of circulating immune and endothelial progenitor cells (termed "CIEs"), which may play significant roles in the mechanisms underlying cancer-associated thromboembolism. Understanding the relationship between these cells, inflammatory and angiogenic factors, immune checkpoint, and cancer progression could pave the way for improved cancer risk assessment and treatment strategies. This study seeks to contribute to our understanding of the intricate connections between LncRNA, coagulation-related biomarkers, thromboembolism, immune responses, and cancer, using solid tumors as a representative example. By shedding light on these complex interactions, this study aims to identify potential biomarkers that can guide risk assessment and treatment decisions, ultimately improving the management of cancer patients.
Investigators
Nehman Makdissy
Principal Investigator, Professor
Lebanese University
Eligibility Criteria
Inclusion Criteria
- •Individuals of white ethnicity.
- •Age between \> 18
- •Both males and females.
- •Diagnosis of selected cancer type (e.g., colorectal cancer).
- •Cancer stage 0/I/II without metastasis or lymph node dissemination at the time of enrollment.
- •No previous cancer therapy (radiotherapy, chemotherapy, or immunotherapy) received before study enrollment.
- •Unrelated patients.
Exclusion Criteria
- •Cancer stage III/IV.
- •History of hematological cancer types or previous cancers, recurrent or relapse.
- •Diagnosis of inflammatory bowel diseases.
- •Pre-existing cardiovascular diseases or coronary artery diseases.
- •Confirmed treated or untreated autoimmune diseases.
- •Metabolic disorders, diabetes, or hypertension.
- •Neurological diseases.
- •Evidence of cardiac, renal, bone, or cerebral damage.
- •Presence of more than one type of malignancies.
- •Active infections or myositis.
Arms & Interventions
Non-Carriers of Targeted Gene-Related Polymorphisms (GRPs) in Cancer Patients
Cancer patients without any incidence of thromboembolism will be included if they are non-carriers of the targeted gene-related polymorphism (GRP).
Intervention: SNP
Carriers of Targeted GRPs in Cancer Patients
Cancer patients without any incidence of thromboembolism will be included if they are carriers of the targeted gene-related polymorphism.
Intervention: SNP
Carriers of Targeted GRPs in Cancer-Associated Thromboembolism Patients
Cancer patients with incidence of thromboembolism will be included if they are carriers of the targeted gene-related polymorphism.
Intervention: SNP
Carriers of Targeted GRPs in Cancer-Associated Thromboembolism Patients Treated with Palbociclib
Cancer patients with incidence of thromboembolism will be included if they are carriers of the targeted gene-related polymorphism and will be subjected to Palbociclib treatment.
Intervention: Palbociclib
Carriers of Targeted GRPs in Cancer-Associated Thromboembolism Patients Treated with Palbociclib
Cancer patients with incidence of thromboembolism will be included if they are carriers of the targeted gene-related polymorphism and will be subjected to Palbociclib treatment.
Intervention: SNP
Carriers of Targeted GRPs in Cancer-Associated Thromboembolism Treated with Anti-Coagulant
Cancer patients with incidence of thromboembolism will be included if they are carriers of the targeted gene-related polymorphism and will be subjected to anti-coagulant treatment.
Intervention: Rivaroxaban
Carriers of Targeted GRPs in Cancer-Associated Thromboembolism Treated with Anti-Coagulant
Cancer patients with incidence of thromboembolism will be included if they are carriers of the targeted gene-related polymorphism and will be subjected to anti-coagulant treatment.
Intervention: SNP
Outcomes
Primary Outcomes
Venous Thromboembolism (VTE) Events including: Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and other Thromboembolic Events (Vein Thrombosis, Portal Vein Thrombosis, Superior Mesenteric Vein Thrombosis, and Renal Vein Thrombosis)
Time Frame: up to 60 months
The outcome measure of VTE including DVT, PE, and other thromboembolic events will be assessed by : (1) Clinical Assessment: Clinical symptoms such as swelling and pain in the lower limbs, tenderness behind the lower leg and/or medial thigh, and supplementary evaluation with color ultrasound of the veins in both lower limbs (lower extremity venography); (2) Imaging: CT pulmonary arteriography (CTPA) will be employed in conjunction with related clinical manifestations such as dyspnea and shortness of breath for diagnosing PE; (3) Laboratory Criteria: Diagnostic criteria will also consider laboratory parameters, including elevated D-dimer levels (\> 1000 ng/mL), increased fibrinogen levels (\> 700 mg/dL), and shortened activated partial thromboplastin time (aPTT) (\< 20 sec).
Assessment of Cancer Progression
Time Frame: up to 60 months
The assessment of cancer progression will be conducted using the standardized TNM staging system and applying the Response Evaluation Criteria (RECIST) guideline (ver. 1.1). Clinical parameters, laboratory tests indicative of cancer progression (including tumor markers and histopathological analysis), and relevant imaging modalities (e.g., CT, MRI, or PET scans) will be employed to evaluate the extent of primary tumor growth, lymph node involvement, and the presence of distant metastases. Progression-Free Survival (PFS), a key primary clinical endpoint for assessing cancer progression, will be calculated as the duration (in months) from the date of enrollment in the study until the tumor progresses, new lesions appear, or until the participant's death from any cause. Cancer progression will be determined based on RECIST guidelines, considering an increase in tumor size or the appearance of new lesions according to imaging assessments and clinical evaluations.
Identification of Potential Biomarkers
Time Frame: Once at the moment of the patient's enrollment in the study
The objective of this outcome is to identify and characterize novel biomarkers associated with thromboembolism and cancer progression. Specifically, the assessment will focus on Long Non-Coding RNAs (LncRNAs) such as CDKN2B and CDKN2B-AS1, and markers related to the vascular coagulation system including ACE, PAI-1, FXIII, and Prothrombin. This identification process will involve collecting biological samples (e.g., blood, tissue) from enrolled patients at the time of study enrollment. The assessment will analyze and evaluate the expression and polymorphisms of the studied genes (CDKN2B, CDKN2B-AS1, ACE, PAI-1, FXIII, and Prothrombin) using quantitative PCR (qPCR), with Ct (Cycle threshold) as the common unit of measure for all genes. This comprehensive assessment aims to enhance our understanding of the molecular signatures linked to thromboembolism and cancer progression, illuminating potential diagnostic and therapeutic avenues for improved patient outcomes.
Evaluation of Treatment Response to Palbociclib
Time Frame: up to 60 months
This primary outcome assesses treatment response in patients undergoing Palbociclib therapy for controlling cancer progression and thromboembolism. The evaluation will employ RECIST criteria to measure the percentage change in tumor size, indicative of treatment effectiveness.
Secondary Outcomes
- Survival Rates(up to 60 months)
- Adverse Events(up to 60 months)
- Evaluation of Tumor-Infiltrating Lymphocytes (TILs)(up to 60 months)
- Examination of Genetic Variants, specifically rs1333049 G>C Polymorphism within the CDKN2B-AS1 Gene(Once at the moment of the patient's enrollment in the study)
- Immunophenotyping of Immune Cell Populations(up to 60 months)
- Assessment of Immune Checkpoint Expression (e.g., PD-1 and CTLA-4)(up to 60 months)
- Measurement of Angiogenic Factors (e.g., VEGF)(up to 60 months)
- Inflammatory Cytokine Profiling(up to 60 months)