Article
Oncology
Igor Bychkov, Iuliia Topchu, Petr Makhov, Alexander Kudinov, Jyoti D. Patel, Yanis Boumber
Summary: Lung cancer is a common and deadly form of cancer, with non-small cell lung cancer (NSCLC) being the most diagnosed subtype. The VEGFR2 protein, a member of the VEGF receptor tyrosine kinase family, and Musashi-2 (MSI2) RNA-binding protein play important roles in NSCLC progression. This study demonstrates that MSI2 positively regulates VEGFR2 protein and impacts AKT signaling through negative regulation of PTEN mRNA translation. MSI2 directly binds to both VEGFR2 and PTEN mRNAs. Additionally, MSI2 expression correlates with VEGFR2 and VEGF-A protein levels in human lung adenocarcinoma samples. These findings suggest that the MSI2/VEGFR2 axis is involved in lung adenocarcinoma progression and should be further investigated as a potential therapeutic target.
Article
Biochemistry & Molecular Biology
Hyun-Dong Cho, Nguyen Thi Thanh Nhan, Christopher Zhou, Kayeman Tu, Tara Nguyen, Nicolene A. Sarich, Kaori H. Yamada
Summary: Excessive VEGF-A signaling induces vascular leakage and angiogenesis. KIF13B-mediated recycling of internalized VEGFR2 through Rab11-positive recycling vesicle regulates endothelial permeability. Inhibition of KIF13B-mediated VEGFR2 trafficking mitigates vascular leakage in models of blinding eye disease wet AMD.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2023)
Review
Oncology
Agnese Montanino, Anna Manzo, Guido Carillio, Giuliano Palumbo, Giovanna Esposito, Vincenzo Sforza, Raffaele Costanzo, Claudia Sandomenico, Gerardo Botti, Maria C. Piccirillo, Priscilla Cascetta, Giacomo Pascarella, Carmine La Manna, Nicola Normanno, Alessandro Morabito
Summary: Inhibition of angiogenesis has shown efficacy in treating SCLC, with anlotinib being the only drug that has demonstrated improvement in both overall survival (OS) and progression-free survival (PFS) in Chinese patients. Future challenges include evaluating angiogenesis inhibitors in combination with immune-checkpoint inhibitors and chemotherapy in SCLC patients, as well as identifying predictive biomarkers of response to these agents.
FRONTIERS IN ONCOLOGY
(2021)
Article
Oncology
Kenji Nakahama, Hiroyasu Kaneda, Masahiko Osawa, Mitsuru Fukui, Motohiro Izumi, Naoki Yoshimoto, Akira Sugimoto, Hiroaki Nagamine, Koichi Ogawa, Yoshiya Matsumoto, Kenji Sawa, Yoko Tani, Shigeki Mitsuoka, Tetsuya Watanabe, Kazuhisa Asai, Tomoya Kawaguchi
Summary: This study found that the expression of vascular endothelial growth factor receptor 2 in immune cells can affect the therapeutic efficacy of immune-checkpoint inhibitors in patients with advanced non-small cell lung cancer, while the expression in tumor cells does not significantly impact the treatment outcome.
Article
Oncology
Tomoyuki Naito, Yuji Minegishi, Hideaki Shiraishi, Tatsuhiko Hoshino, Junichi Maeda, Toshiya Yokota, Shingo Ikeda, Miyanaga Akihiko, Masahiro Seike
Summary: The study explores the impact of background cardiovascular risk factors on VEGF inhibitor-related adverse vascular events (AVEs) in NSCLC patients. It found that male gender, smoking history, hypertension, dyslipidemia, diabetes, and cardiovascular disease were associated with increased risk of VEGF-related AVEs. Hypertension and chronic kidney disease were associated with discontinuation due to VEGF-related AVEs. The study recommends caution in using VEGF inhibitors for patients with ≥3 cardiovascular risk factors.
JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Jun-Ping Shiau, Cheng-Che Wu, Shu-Jyuan Chang, Mei-Ren Pan, Wangta Liu, Fu Ou-Yang, Fang-Ming Chen, Ming-Feng Hou, Shen-Liang Shih, Chi-Wen Luo
Summary: The study found a positive correlation between FAK and VEGFR2 in TNBC patients, and FAK promotes angiogenesis in TNBC cells by regulating VEGFR2 expression. Therefore, targeting FAK could be a potential strategy for TNBC treatment.
Review
Biochemistry & Molecular Biology
Aaron C. Tan, Nick Pavlakis
Summary: The management of advanced lung cancer has been transformed by the identification of targetable oncogenic driver alterations, including ALK gene rearrangements. ALK tyrosine kinase inhibitors have become the first-line treatment options for advanced ALK rearranged NSCLC. However, drug resistance remains a challenge, and the role of anti-angiogenic therapy in ALK rearranged NSCLC needs further exploration.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell Biology
Yingzhuo Xu, Jian Wang, Xu Wang, Xiaoshu Zhou, Jing Tang, Xiaohua Jie, Xijie Yang, Xinrui Rao, Yunhong Xu, Biyuan Xing, Zhenyu Li, Gang Wu
Summary: Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) tyrosine kinase inhibitors (TKIs) have achieved significant progress in the treatment of non-small-cell lung cancer, but resistance limits their efficacy. The study found that the use of ADRB2 antagonist propranolol can enhance the therapeutic effect of VEGFR2-TKIs by inhibiting ADRB2 signaling pathway. This research contributes to the understanding of VEGF-TKI and ICI resistance mechanisms and provides a new direction for developing effective treatment strategies.
CELL DEATH DISCOVERY
(2022)
Article
Oncology
YanJie Lu, HanZheng Zhao, Ying Liu, YanZhen Zuo, Qian Xu, Lei Liu, XiaoMin Li, HongBin Zhu, Ying Zhang, Shuling Zhang, XiangYang Zhao, YuHong Li
Summary: Chronic stress can exacerbate tumor angiogenesis, primarily through elevating stress-related hormone levels and causing behavioral changes in individuals. Utilizing isoprenaline as an agonist of beta 2-adrenergic receptor, the study demonstrated the molecular mechanisms of stress in tumor angiogenesis both in vivo and in vitro. Isoprenaline promotes VEGF autocrine in HUVECs, up-regulating plexinA1 and VEGFR2 levels, leading to activation of the JAK2-STAT3 signaling pathway essential for angiogenesis.
FRONTIERS IN ONCOLOGY
(2021)
Article
Oncology
Senem Uzun, Yueksel Korkmaz, Nora Wuerdemann, Christoph Arolt, Behrus Puladi, Oliver G. Siefer, Hanife G. Doenmez, Martin Hufbauer, Baki Akguel, Jens P. Klussmann, Christian U. Huebbers
Summary: This study investigated the impact of HPV infection on VEGFR2 expression and vascularization in oropharyngeal squamous cell carcinoma (OPSCC). Results showed that HPV-positive OPSCC exhibit upregulated VEGFR2 in tumor-supporting blood vessels, while HPV-negative tumors upregulate VEGFR2 in tumor cells, indicating potential different signaling pathways of VEGFR2 depending on the HPV-status.
Article
Cell Biology
Chike Osude, Leo Lin, Meet Patel, Adam Eckburg, Joseph Berei, Adijan Kuckovic, Namrata Dube, Aayush Rastogi, Shruti Gautam, Thomas J. Smith, Shylendra B. Sreenivassappa, Neelu Puri
Summary: This study elucidated the mechanism of EGFR-TKI resistance mediated by VEGF/VEGFR in NSCLC cell lines with EGFR mutations or acquired resistance to Erlotinib. Combination treatment of Erlotinib with a VEGFR-2 inhibitor showed increased efficacy in Erlotinib-resistant cell lines. NSCLC patients with high expression of VEGFR-2 had shorter survival times. These results suggest that VEGFR-2 may play a key role in EGFR-TKI resistance and that combination treatment may be effective in NSCLC patients with EGFR mutations.
Article
Biotechnology & Applied Microbiology
Xinlong Xie, Qiying Wu, Yuhong Liu, Chunyang Chen, Zeguo Chen, Chao Xie, Mingzhe Song, Zhenlin Jiang, Xiaoke Qi, Sixi Liu, Zhenjie Tang, Zhongshi Wu
Summary: This study evaluated the effect of VEGF on neointimal hyperplasia and local inflammatory responses in decellularized small-diameter vascular grafts. The results showed that local administration of VEGF attenuated neointimal hyperplasia by inducing macrophage M2 polarization and modulating the inflammatory response.
FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY
(2022)
Article
Medicine, Research & Experimental
Benjamin M. Kahn, Alfredo Lucas, Rohan G. Alur, Maximillian D. Wengyn, Gregory W. Schwartz, Jinyang Li, Kathryn Sun, H. Carlo Maurer, Kenneth P. Olive, Robert B. Faryabi, Ben Z. Stanger
Summary: Through studying the tumor vascular environment, the use of the endothelial index (EI) and vascular microenvironment signatures (VMS) can better assess tumor vascular density, which is associated with prognosis in certain cancer types. These findings suggest that these metrics may enable more precise deployment of antiangiogenesis therapy.
JOURNAL OF CLINICAL INVESTIGATION
(2021)
Article
Chemistry, Medicinal
Chaofan Wang, Xiaoyun Lu
Summary: MET is a promising drug target for the treatment of MET-dependent diseases, especially NSCLC. Small molecule MET inhibitors with three types of binding modes have been developed. This review provides an overview of MET's structural features, activation mechanism, dysregulation pathway, and the development strategies of MET inhibitors, as well as the acquired resistance mechanisms. These insights will accelerate the discovery of new generation MET inhibitors to overcome clinical acquired resistance.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biology
Stephen B. Waters, Joseph R. Dominguez, Hyun-Dong Cho, Nicolene A. Sarich, Asrar B. Malik, Kaori H. Yamada
Summary: Research demonstrates that KAI has protective effects in VEGF-A-induced vascular leakage and cancer metastasis, while an EC-specific KIF13B knockout mouse model reveals the role of KIF13B in regulating pathological angiogenesis, vascular leakage, tumor growth, and cancer metastasis induced by VEGF-A.
LIFE SCIENCE ALLIANCE
(2021)
Article
Oncology
Ping Zhang, Isaac Kitchen-Smith, Lingyun Xiong, Giovanni Stracquadanio, Katherine Brown, Philipp H. Richter, Marsha D. Wallace, Elisabeth Bond, Natasha Sahgal, Samantha Moore, Svanhild Nornes, Sarah De Val, Mirvat Surakhy, David Sims, Xuting Wang, Douglas A. Bell, Jorge Zeron-Medina, Yanyan Jiang, Anderson J. Ryan, Joanna L. Selfe, Janet Shipley, Siddhartha Kar, Paul D. Pharoah, Chey Loveday, Rick Jansen, Lukasz F. Grochola, Claire Palles, Andrew Protheroe, Val Millar, Daniel Ebner, Meghana Pagadala, Sarah P. Blagden, Timothy S. Maughan, Enric Domingo, Ian Tomlinson, Clare Turnbull, Hannah Carter, Gareth L. Bond
Summary: Insights from cancer susceptibility loci suggest potential for improved cancer management through precision oncology, highlighting the importance of understanding interactions between germline variants and somatic mutations in tumorigenesis. This study proposes that cancer risk-associated germline variants interact with somatic TP53 mutations to modify cancer risk, progression, and therapy response, offering a novel approach for therapeutic targeting of p53 activities and identifying new combinatorial therapies.
Article
Oncology
Guillaume Rieunier, Xiaoning Wu, Letitia E. Harris, Jack Mills, Ashwin Nandakumar, Laura Colling, Elena Seraia, Stephanie B. Hatch, Daniel Ebner, Lisa K. Folkes, Ulrike Weyer-Czernilofsky, Thomas Bogenrieder, Anderson J. Ryan, Valentine M. Macaulay
Summary: Inhibition of IGF1R delays repair of radiation-induced DNA damage and influences endogenous DNA damage by regulating RRM2 expression. IGF axis blockade induces replication stress and reciprocal codependence on ATM, providing a potential therapeutic approach for ATM-deficient cancers.
Article
Oncology
Yanyan Jiang, Jennifer Martin, Maryam Alkadhimi, Kay Shigemori, Paul Kinchesh, Stuart Gilchrist, Veerle Kersemans, Sean Smart, James M. Thompson, Mark A. Hill, Mark J. O'Connor, Barry R. Davies, Anderson J. Ryan
Summary: The study found that the addition of olaparib increased the therapeutic index of hemithoracic radiation in a mouse model of lung cancer, enhancing anti-tumour efficacy without increasing lung toxicity.
BRITISH JOURNAL OF CANCER
(2021)
Review
Biotechnology & Applied Microbiology
Peter Kok-Ting Wan, Anderson J. Ryan, Leonard W. Seymour
Summary: Cancer gene therapies targeting the tumor microenvironment have shown promising results by focusing on strategies that target the cancer stroma, reduce tumor vasculature, and repolarize the immunosuppressive microenvironment. This approach is appealing because the genetically stable TME plays a crucial role in promoting cancer growth, immune tolerance, and resistance to therapies, especially in the presence of multiple mutations in cancers.
Article
Oncology
T. Cascone, R. L. Sacks, I. M. Subbiah, N. Drobnitzky, S. A. Piha-Paul, D. S. Hong, K. R. Hess, B. Amini, T. Bhatt, S. Fu, A. Naing, F. Janku, D. Karp, G. S. Falchook, A. P. Conley, S. Sherman, F. Meric-Bernstam, A. J. Ryan, J. Heymach, V Subbiah
Summary: The combination therapy of VAN + EV shows promising antitumor activity in advanced solid cancers, with manageable toxicities. Further studies are needed to explore its efficacy in tumors with RET pathway aberrations.
Article
Oncology
Yanyan Jiang, Elaine Willmore, Stephen R. Wedge, Anderson J. Ryan
Summary: The inhibition of DNAPK has been shown to enhance the sensitivity of chronically hypoxic tumor cells to radiation, with a more pronounced inhibitory effect on DNA DSB repair, suggesting a broader therapeutic window for transient DNAPK inhibition combined with radiotherapy.
MOLECULAR CANCER THERAPEUTICS
(2021)
Article
Medicine, Research & Experimental
Florian J. Groelly, Manuela Porru, Jutta Zimmer, Hugo Benainous, Yanti De Visser, Anastasiya A. Kosova, Serena Di Vito, Violeta Serra, Anderson Ryan, Carlo Leonetti, Alejandra Bruna, Annamaria Biroccio, Madalena Tarsounas
Summary: The compound pyridostatin shows high specificity against BRCA1/2-deficient tumors and tumors resistant to PARP inhibitors. It disrupts replication leading to DNA double-stranded breaks and can be repaired in the absence of BRCA1/2 by non-homologous end joining. Additionally, pyridostatin triggers immune responses and can be further potentiated by combining it with paclitaxel. Overall, pyridostatin has potential for therapeutic development in cancer patients with BRCA1/2 mutations.
EMBO MOLECULAR MEDICINE
(2022)
Article
Biochemistry & Molecular Biology
Xiaoning Wu, Elena Seraia, Stephanie B. Hatch, Xiao Wan, Daniel V. Ebner, Francesca Aroldi, Yanyan Jiang, Anderson J. Ryan, Thomas Bogenrieder, Ulrike Weyer-Czernilofsky, Guillaume Rieunier, Valentine M. Macaulay
Summary: Inhibition of both IGF and CHK1 leads to synergistic suppression of cell viability and tumor growth by downregulating RRM2 expression and reducing dNTP supply, resulting in delayed DNA replication and accumulation of unreplicated single-stranded DNA. This study highlights the therapeutic potential of targeting the IGF:CHK1 interaction and identifies RRM2 as a key target for synthetic lethality in cancer therapy.
Article
Biochemical Research Methods
Stephen M. Stribbling, Anderson J. Ryan
Summary: Tumor-bearing experimental animals are crucial for preclinical cancer drug development, with the subcutaneous tumor model being the most commonly used. This article provides an overview of different in vivo tumor models, including their advantages and disadvantages and their role in drug development. It then details the establishment and key steps of the subcutaneous tumor model.
Article
Engineering, Biomedical
Frank van den Heuvel, Anna Vella, Francesca Fiorini, Mark Brooke, Mark Hill, Anderson Ryan, Tim Maughan, Amato Giaccia
Summary: A methodology for predicting tissue sparing effects in pulsed ultra-high dose rate radiation exposures is introduced and illustrated using published experiments. The proposed system quantifies the effects by formalizing the variability of oxygen levels as an oxygen dose histogram and calculating the change in DNA-damage induction based on the oxygen fixation concept. The results show that the FLASH-effect depends on the initial oxygenation level in tissue, the total dose delivered, pulse length, and pulse repetition rate.
PHYSICS IN MEDICINE AND BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Katharine J. Herbert, Rathi Puliyadi, Remko Prevo, Gonzalo Rodriguez-Berriguete, Anderson Ryan, Kristijan Ramadan, Geoff S. Higgins
Summary: The study confirms the potential of TOPK as a target for treating solid tumors, shows that TOPK inhibitor in combination with radiation treatment can enhance efficacy, and reveals a previously unknown role of TOPK during S phase supporting cancer cell survival.
CELL DEATH AND DIFFERENTIATION
(2021)