Precision Therapy for Solid Tumors: Synergistic CDK4/6 Inhibition and Anti-VEGF Targeting LncRNA

Overview

Solid tumors pose significant challenges in current therapeutic approaches. Targeted therapy has emerged as a promising avenue, aiming to enhance treatment efficacy while minimizing adverse effects. This clinical trial focuses on an innovative combination of two targeted inhibitors, Palbociclib and Bevacizumab, for their potential synergistic effects in addressing these challenging malignancies. Moreover, this study incorporates a molecular approach by considering Long Non-Coding RNAs (LncRNAs) as biomarkers. Initiating with a focus on colorectal cancer, the study aims to expand its scope to other solid tumors, including lung, breast, ovarian and other cancers. Palbociclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, disrupts the cell cycle progression, particularly in cancer cells with specific molecular characteristics. Bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, targets angiogenesis-a critical process for tumor growth and metastasis. The rationale behind combining these agents lies in their complementary mechanisms of action, potentially leading to enhanced antitumor effects. LncRNAs have shown promise in predicting treatment response and prognosis in various cancers, providing an additional layer of precision to the treatment strategy. By elucidating the molecular basis through LncRNA analysis, the trial aims to tailor the treatment to the specific molecular profile of each patient, ultimately striving for better outcomes and improved survival rates. This novel combination therapy, coupled with a personalized biomarker-driven approach, represents a cutting-edge strategy in the pursuit of more effective and individualized treatment for solid tumors.

This innovative clinical trial applies a comprehensive strategy to study the complex interplay of biomarkers, immune responses, angiogenesis, and proliferation in solid tumor progression. This approach integrates the selective cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, such as Palbociclib, with the angiogenesis inhibitor, like Bevacizumab. This dual-targeted therapy holds promise for treating various solid tumors, including colorectal cancer, breast cancer, lung cancer, ovarian cancer, and others. A focal point of the study is the investigation of Long Non-Coding RNA (LncRNA) , chosen for its potential as a prognostic and predictive biomarker. LncRNA plays a multifaceted role in cellular processes, influencing cell cycle checkpoints, angiogenesis, and metastasis. Its aberrant expression across different cancers positions as a key subject of investigation, particularly considering its potential association with polymorphisms. Beyond its involvement in proliferation and angiogenesis. It also adds an additional layer of complexity, crucial for understanding patient outcomes. The investigation initiates with colorectal cancer and extends to other solid cancers, including lung, ovarian, and breast cancers. Patients are stratified into carriers or non-carriers of the risk allele, forming the foundation for precision-driven treatments. The study design comprises two distinct groups within the colorectal cancer cohort, Group 1 and Group 2, involving patients with and without the risk allele. These groups undergo combined therapy with a CDK4/6 inhibitor and anti-VEGF. Similarly, the distribution is maintained for patients with and without the risk allele in other solid tumors (lung, breast, ovarian, etc.), receiving the same combined therapy tailored to their molecular profiles whether taken as 1st line of treatment or 2nd line of treatment. Precise pre-treatment assessments establish baseline parameters, while post-treatment evaluations cover outcomes such as tumor progression, cancer regression, survival rates, and thromboembolic events. The interdependent relationship between proliferative tumor cells and angiogenesis, coupled with the potential impact of thromboembolism, is pivotal for cancer progression. Dysregulated cell cycle machinery, often involving overactive cyclin-dependent kinases (CDKs) like CDK4/6, drives uncontrolled proliferation, leading to a hypoxic microenvironment that triggers angiogenesis. Recognizing this symbiosis, the rationale for combining Palbociclib, a CDK4/6 inhibitor, with Bevacizumab, an anti-VEGF agent, becomes evident. While Palbociclib disrupts the cell cycle progression of proliferating tumor cells, hindering their uncontrolled growth, Bevacizumab concurrently targets the angiogenic process by inhibiting VEGF. This dual-targeted approach aims to comprehensively address both the proliferative, angiogenic, and thromboembolic facets of tumor biology, potentially leading to a more effective and synergistic anti-tumor response. Four groups will be considered: Carrier Groups: Group 1: "Carrier First-line Combined Therapy Group", C-FL-CT; Group 2: "Carrier Second-line Combined Therapy Group", C-SL-CT Non-carrier Groups: Group 3: "Non-carrier First-line Combined Therapy Group", NC-FL-CT; Group 4: "Non-carrier Second-line Combined Therapy Group", NC-SL-CT "Carrier"" denotes the patient who possesses the risk allele of the LncRNA CDKN2B-AS1. Group 1: This group of patients, who are carriers of the risk alleles, will receive combined therapy as the initial first-line treatment without prior chemotherapy. Group 2: This group of patients, who are carriers of the risk alleles, will receive combined therapy after having undergone prior chemotherapy, making it the second-line treatment. Group 3: This group of patients, who are non-carriers of the risk alleles, will receive combined therapy as the initial first-line treatment without prior chemotherapy. Group 4: This group of patients, who are non-carriers of the risk alleles, will receive combined therapy after having undergone prior chemotherapy, making it the second-line treatment. In summary, the study integrates precision medicine, biomarker-driven therapies, and a comprehensive understanding of the molecular basis of tumor progression, including thromboembolism. This approach offers a promising avenue for the development of personalized and effective treatments for various solid tumors, emphasizing not only efficacy and safety but also the overall effectiveness of the proposed therapeutic interventions.