Keyword: Targeted Therapy

ABSTRACT: Introduction: Cdc42 is a small Rho GTPase that regulates various cellular functions controlling cell motility, shape, and growth through actin cytoskeleton dynamics. This protein is also known to be overexpressed in various diseases, particularly in cancer. Colorectal cancer is a common malignancy with a high mortality rate. Elevated Cdc42 expression is observed in colorectal cancer. Inhibition of Cdc42 can significantly slow the growth and metastasis of colorectal cancer but often causes severe side effects. To address this issue, PLGA-PEG nanoparticles functionalized with DNA aptamers were developed to selectively deliver the Cdc42 inhibitor CASIN to tumor cells by targeting nucleolin—a protein that is overexpressed in colorectal cancer.
Materials and Methods: The nucleolin-targeting aptamer AS1411 (5'-FAM–GGT GGT GGT GGT TGT GGT GGT GGT GG–3'-NH2) was synthesized as a 28-base single-stranded DNA oligonucleotide modified with a fluorescein label at the 5' end and an amine group at the 3' end. PLGA-PEG-NHS nanoparticles conjugated with the AS1411 aptamer were prepared using the nanoprecipitation method. Conjugation efficiency was assessed by DNA quantification, as well as by fluorescence microscopy and Raman spectroscopy. Binding affinity and specificity of aptamer-functionalized nanoparticles to nucleolin-positive cancer cells were confirmed by flow cytometry.
Results: AS1411-functionalized PLGA-PEG-NHS nanoparticles loaded with CASIN had an average size of approximately 129 nm (polydispersity index 0.259) and a zeta potential of –52.3 mV. Encapsulation efficiency was 38.1%, and drug loading content was 7.35%. CASIN release occurred in two phases: an initial burst release followed by a gradual release over 48 hours. In vitro, these nanoparticles significantly suppressed the growth of colorectal cancer cells (HT29, SW620, HCT116) and substantially reduced HT29 cell migration, while AS1411-modified nanoparticles without CASIN had minimal effects. Furthermore, the nanoparticles significantly reduced the migratory and invasive capacity of colorectal cancer cells.
Conclusion: Overall, this targeted nanoparticle system represents a promising strategy for improving the precision and efficacy of colorectal cancer treatment. This research was funded by the Science Committee of the Ministry of Science and Higher Education of the Republic of Kazakhstan (Grant No. AP26100973) and Nazarbayev University under Collaborative Research Project (CRP) No. 211123CRP1611.

ABSTRACT: Background: The introduction of targeted therapy and immune checkpoint inhibitors has significantly improved treatment outcomes in patients with locally advanced and metastatic renal cell carcinoma (mRCC). However, tumor heterogeneity and the development of alternative signaling pathways may contribute to treatment resistance, emphasizing the need for effective combination strategies.
Objective: To evaluate the efficacy of contemporary immunotherapy-based combinations in the first-line treatment of metastatic renal cell carcinoma and identify clinical factors relevant to treatment selection.
Materials and Methods: Published data from randomized phase III studies of first-line systemic therapy for advanced and metastatic renal cell carcinoma were analyzed. Particular attention was given to nivolumab plus ipilimumab and lenvatinib plus pembrolizumab compared with sunitinib. Treatment efficacy was assessed using progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and outcomes according to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups.
Results: In the CLEAR trial, lenvatinib plus pembrolizumab significantly prolonged median PFS compared with sunitinib (23.9 vs 9.2 months) and improved overall survival. In patients with intermediate/poor IMDC risk, median PFS was 22.1 months with lenvatinib plus pembrolizumab versus 5.9 months with sunitinib, while ORR was 72.4% versus 28.8%, respectively. Long-term results of the CheckMate 214 trial demonstrated a sustained survival benefit with nivolumab plus ipilimumab compared with sunitinib. The final analysis after a median follow-up of 9.3 years showed an OS hazard ratio of 0.71 in the intention-to-treat population and 0.69 in patients with intermediate/poor IMDC risk. Durable responses were maintained across long-term follow-up.
Conclusions: Immunotherapy-based combinations have substantially improved the treatment of metastatic renal cell carcinoma. Lenvatinib plus pembrolizumab provides significant improvements in PFS and objective response compared with sunitinib, while nivolumab plus ipilimumab demonstrates durable long-term survival benefits. Selection of first-line therapy should consider IMDC risk group, tumor burden, metastatic sites, clinical condition, histological characteristics, and individual patient factors.

ABSTRACT: Introduction: Despite the relatively low mutational burden of most pediatric tumors, molecular genetic studies are increasingly being used in pediatric oncology. They enable confirmation of diagnosis, assessment of prognosis, and identification of potential targets for molecularly targeted therapy. Analysis of molecular diagnostic results in real-world clinical practice allows us to assess the capabilities and limitations of molecular diagnostics across different pediatric tumors.
Materials and Methods: Targeted sequencing of tumor DNA using a customized QIAseq panel (Qiagen, Germany) was performed in 334 patients with extracranial solid tumors treated at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology between 2018 and 2023.
Results: The highest diagnostic yield was observed in malignant rhabdoid tumors (n=23): diagnostically significant alterations were identified in 91.3% of patients.
In most cases, these alterations were highly specific to this tumor type and could be used to confirm the diagnosis alongside morphological and immunohistochemical data.
Prognostically significant molecular alterations were most frequently detected in neuroblastoma – in 66.7% of patients (112/168). The majority of these consisted of mutations in genes of the RAS/p53 signaling pathways, allowing further characterization of tumor biology and identification of patients with molecular features potentially associated with disease course and response to therapy.
Potentially therapeutically significant alterations were identified in 36% of patients (120/334). However, the presence of a molecular target did not always lead to the administration of the corresponding drug, as evidence for the efficacy of targeted therapy in children remains limited for a significant proportion of these alterations.
Targeted therapy based on molecular genetic testing results was administered in 6.3% of cases (21/334), predominantly in neuroblastoma (n=13).
It was used in the first-line setting or at first relapse in 66.7% of cases (14/21). In 61.9% (13/21) of patients, targeted agents were used in combination with standard antitumor therapy.
An objective response or disease stabilization lasting more than 6 months was observed in 66.7% (14/21) of patients. The median time to best response or stabilization was 6 months (range 0.8–12.3). The median duration of targeted therapy as monotherapy was 10.9 months (range 0.8–43.5), and in combination with chemotherapy – 12.3 months (range 0.3–61.5). In 42.8% (9/21) of patients, the response was maintained at the time of last follow-up.
Conclusion: Thus, molecular genetic plays an important role in improving the diagnosis and treatment of pediatric tumors. Futher accumulation of clinical and molecular data will provide a deeper understanding of tumor biology and expand opportunities of personalized treatment.