Synthesis and Preclinical Evaluation of Novel 68Ga-DOTA-RBB as Potential PET Radiotracer for Imaging CDK4/6 in Tumors DOI

Zhen-Peng Yu,

Xin Wang, Zhiqiang Yu

et al.

ACS Medicinal Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(6), P. 938 - 944

Published: May 14, 2024

Many malignant tumors, including breast cancer, exhibit amplification and overexpression of cyclin-dependent kinase 4 6 (CDK4/6). Ribociclib, approved used in clinical treatment, acts as a highly selective CDK4/6 inhibitor for ER+/HER2- cancer. By modifying ribociclib with the chelator DOTA, we designed synthesized novel CDK4/6-positive PET imaging agent, which was radiolabeled by 68Ga radioactive tagging. The radiotracer demonstrates high radiochemical purity, excellent stability vitro vivo, favorable pharmacokinetic characteristics. Cell uptake experiments using MCF-7 cells indicate that an excess (RBB) can inhibit cellular 68Ga-DOTA-RBB. Imaging biodistribution tumor-bearing nude mice show significant accumulation tumor. However, preadministration results substantial reduction within On basis our explorations, 68Ga-DOTA-RBB, targeted agent holds potential application values.

Language: Английский

Therapeutic Strategies for Targeting CDKN2A Loss in Melanoma DOI Creative Commons
Inger Z. M. Kreuger, Roderick C. Slieker, Tim van Groningen

et al.

Journal of Investigative Dermatology, Journal Year: 2022, Volume and Issue: 143(1), P. 18 - 25.e1

Published: Sept. 16, 2022

Loss of the tumor suppressor gene CDKN2A, encoding p16 and p14, is a frequent event driving melanoma progression. Therefore, therapeutic strategies aimed at CDKN2A loss hold great potential to improve treatment. Pharmacological inhibition targets CDK4/6 prime example such strategy. Other approaches exploit cell cycle deregulation, target metabolic rewiring, epigenetically restore expression, act on dependencies resulting from co-deleted genes, or are directed effects immune responses. This review explores these targeting loss, which potentially open up new avenues for precision medicine in melanoma.

Language: Английский

Citations

42
CDK4/6 inhibitors in lung cancer: current practice and future directions DOI Creative Commons

Shuoshuo Lv,

Jie Yang, Jiayuh Lin

et al.

European Respiratory Review, Journal Year: 2024, Volume and Issue: 33(171), P. 230145 - 230145

Published: Jan. 31, 2024

Lung cancer is the leading cause of cancer-related deaths worldwide, and ∼85% lung cancers are classified as nonsmall cell (NSCLC). These malignancies can proliferate indefinitely, in part due to dysregulation cycle resulting abnormal growth. The specific activation cyclin-dependent kinases 4 6 (CDK4/6) closely linked tumour proliferation. Approximately 80% human tumours exhibit abnormalities cyclin D-CDK4/6-INK4-RB pathway. Specifically, CDK4/6 inhibitors either monotherapy or combination therapy have been investigated pre-clinical clinical studies for treatment NSCLC, promising results achieved. This review article focuses on research regarding use including characteristics mechanisms action approved drugs progress research.

Language: Английский

Citations

10
Palbociclib Induces Senescence in Melanoma and Breast Cancer Cells and Leads to Additive Growth Arrest in Combination With Irradiation DOI Creative Commons
Tina Jost,

Lucie Heinzerling,

Rainer Fietkau

et al.

Frontiers in Oncology, Journal Year: 2021, Volume and Issue: 11

Published: Oct. 13, 2021

Several kinase inhibitors (KI) bear the potential to act as radiosensitizers. Little is known of radiosensitizing effects a wide range other KI like palbociclib, which approved in ER+/HER2- metastatic breast cancer.In our study, we used healthy donor fibroblasts and cancer skin cells investigate influence concomitant + radiation therapy. Cell death cell cycle distribution were studied by flow cytometry after Annexin-V/7-AAD Hoechst staining. Cellular growth arrest was colony-forming assays. Furthermore, C12-FDG staining (senescence) mRNA expression analysis (qPCR) clarify cellular mechanisms.The CDK4/6 inhibitor palbociclib induced G0/G1 phase. toxicity (cell death) only slightly increased not enhanced additional radiotherapy. As main outcome colony formation assays, found that improved radiotherapy an additive manner. Noticeably, treatment clearly senescence partly melanoma cells, but also fibroblasts. According these findings, downregulation senescence-related FOXM1 might be involved mechanism senescence-induction palbociclib.The effect on additive. Palbociclib induces permanent inducing fibroblasts, cancer, cells. Direct induction minor secondary action. Concomitant strategy worth studying clinical trials.

Language: Английский

Citations

50
Treatment of Metastatic Melanoma with a Combination of Immunotherapies and Molecularly Targeted Therapies DOI Open Access

Taylor Rager,

Adam Eckburg, Meet Patel

et al.

Cancers, Journal Year: 2022, Volume and Issue: 14(15), P. 3779 - 3779

Published: Aug. 3, 2022

Melanoma possesses invasive metastatic growth patterns and is one of the most aggressive types skin cancer. In 2021, it estimated that 7180 deaths were attributed to melanoma in United States alone. Once metastasizes, traditional therapies are no longer effective. Instead, immunotherapies, such as ipilimumab, pembrolizumab, nivolumab, treatment options for malignant melanoma. Several biomarkers involved tumorigenesis have been identified potential targets molecularly targeted therapy, tyrosine kinase inhibitors (TKIs). Unfortunately, quickly acquires resistance these therapies. To bypass resistance, combination with immunotherapies single or multiple TKIs employed shown improve prognosis patients compared monotherapy. This review discusses several target biomarkers, BRAF, MEK, RAS, c-KIT, VEGFR, c-MET PI3K. regimens already FDA-approved treating melanoma, while others still clinical trials. Continued research into causes factors influencing efficacy treatments, specific mutations oncogenic proteins, may further effectiveness therapies, providing a better patients.

Language: Английский

Citations

31
The spindle assembly checkpoint is a therapeutic vulnerability of CDK4/6 inhibitor–resistant ER + breast cancer with mitotic aberrations DOI Creative Commons
Isabel Soria‐Bretones, Kelsie L. Thu, Jennifer Silvester

et al.

Science Advances, Journal Year: 2022, Volume and Issue: 8(36)

Published: Sept. 7, 2022

Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) are standard first-line treatments for metastatic ER + breast cancer. However, acquired resistance to CDK4/6i invariably develops, the molecular phenotypes exploitable vulnerabilities associated with not yet fully characterized. We developed a panel CDK4/6i-resistant cancer cell lines patient-derived organoids demonstrate that subset resistant models accumulates mitotic segregation errors micronuclei, displaying increased sensitivity inhibitors checkpoint regulators TTK Aurora kinase A/B. RB1 loss, well-recognized mechanism resistance, causes such defects confers enhanced inhibition. In these models, inhibition CFI-402257 induces premature chromosome segregation, leading excessive errors, DNA damage, death. These findings nominate inhibitor as therapeutic strategy defined patients who develop CDK4/6i.

Language: Английский

Citations

31
The Genomic Landscape of Melanoma and Its Therapeutic Implications DOI Open Access
Ting‐Ting Yang, Sebastian Yu,

Chiao‐Li Khale Ke

et al.

Genes, Journal Year: 2023, Volume and Issue: 14(5), P. 1021 - 1021

Published: April 29, 2023

Melanoma is one of the most aggressive malignancies skin. The genetic composition melanoma complex and varies among different subtypes. With aid recent technologies such as next generation sequencing single-cell sequencing, our understanding genomic landscape its tumor microenvironment has become increasingly clear. These advances may provide explanation to heterogenic treatment outcomes patients under current therapeutic guidelines further insights development potential new targets. Here, we a comprehensive review on genetics related tumorigenesis, metastasis, prognosis. We also affecting relation progression treatment.

Language: Английский

Citations

17
Advances in Melanoma: From Genetic Insights to Therapeutic Innovations DOI Creative Commons
Fernando Valdez-Salazar,

Luis Alberto Jiménez-Del Río,

Jorge Ramón Padilla‐Gutiérrez

et al.

Biomedicines, Journal Year: 2024, Volume and Issue: 12(8), P. 1851 - 1851

Published: Aug. 14, 2024

Advances in melanoma research have unveiled critical insights into its genetic and molecular landscape, leading to significant therapeutic innovations. This review explores the intricate interplay between alterations, such as mutations BRAF, NRAS, KIT, pathogenesis. The MAPK PI3K/Akt/mTOR signaling pathways are highlighted for their roles tumor growth resistance mechanisms. Additionally, this delves impact of epigenetic modifications, including DNA methylation histone changes, on progression. microenvironment, characterized by immune cells, stromal soluble factors, plays a pivotal role modulating behavior treatment responses. Emerging technologies like single-cell sequencing, CRISPR-Cas9, AI-driven diagnostics transforming research, offering precise personalized approaches treatment. Immunotherapy, particularly checkpoint inhibitors mRNA vaccines, has revolutionized therapy enhancing body’s response. Despite these advances, mechanisms remain challenge, underscoring need combined therapies ongoing achieve durable comprehensive overview aims highlight current state transformative impacts advancements clinical practice.

Language: Английский

Citations

7
Development of Personalized Strategies for Precisely Battling Malignant Melanoma DOI Open Access
Armond J. Isaak, G Clements, Rand Gabriel M. Buenaventura

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(9), P. 5023 - 5023

Published: May 4, 2024

Melanoma is the most severe and fatal form of skin cancer, resulting from multiple gene mutations with high intra-tumor inter-tumor molecular heterogeneity. Treatment options for patients whose disease has progressed beyond ability surgical resection rely on currently accepted standard therapies, notably immune checkpoint inhibitors targeted therapies. Acquired resistance to these therapies treatment-associated toxicity necessitate exploring novel strategies, especially those that can be personalized specific and/or populations. Here, we review current landscape progress explore what oncology techniques may entail in scope melanoma. Our purpose provide an up-to-date summary tools at our disposal work circumvent common barriers faced when battling

Language: Английский

Citations

6
Targeting PD-1/PD-L1 in tumor immunotherapy: Mechanisms and interactions with host growth regulatory pathways DOI

Songyu Shen,

Yihan Hong,

Jiajun Huang

et al.

Cytokine & Growth Factor Reviews, Journal Year: 2024, Volume and Issue: 79, P. 16 - 28

Published: Aug. 10, 2024

Language: Английский

Citations

6
Multi-center retrospective review of vitiligo-like lesions in breast cancer patients treated with cyclin-dependent kinase 4 and 6 inhibitors DOI
Alexander Bang, Christopher J. Fay, Nicole R. LeBoeuf

et al.

Breast Cancer Research and Treatment, Journal Year: 2024, Volume and Issue: 204(3), P. 643 - 647

Published: Jan. 15, 2024

Language: Английский

Citations

6