Article
Oncology
Soichiro Mori, Hirofumi Akita, Shogo Kobayashi, Yoshifumi Iwagami, Daisaku Yamada, Yoshito Tomimaru, Takehiro Noda, Kunihito Gotoh, Yutaka Takeda, Masahiro Tanemura, Yuichiro Doki, Hidetoshi Eguchi
Summary: Radiation therapy can induce increased c-Met expression in pancreatic cancer cells, leading to enhanced invasion and migration ability, promoting the risk of distant metastasis. Inhibiting c-Met can reverse this enhanced malignant potential.
Article
Chemistry, Medicinal
Dipti Kanabar, Mimansa Goyal, Emma Kane, Tejashri Chavan, Abbas Kabir, Xuechun Wang, Snehal Shukla, Joseph Almasri, Sona Goswami, Gizem Osman, Marino Kokolis, Donald E. Spratt, Vivek Gupta, Aaron Muth
Summary: This study reports the structure-based design of small molecules that can bind to Gankyrin and inhibit its overexpression in breast and lung cancers, showing potential therapeutic value.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Oncology
Kavya Ramkumar, Azusa Tanimoto, Carminia M. Della Corte, C. Allison Stewart, Qi Wang, Li Shen, Robert J. Cardnell, Jing Wang, Urszula M. Polanska, Courtney Andersen, Jamal Saeh, J. Elizabeth Pease, Jon Travers, Giulia Fabbri, Carl M. Gay, Jelena Urosevic, Lauren A. Byers
Summary: This study aims to develop therapeutic strategies and biomarkers of response for small cell lung cancer (SCLC). The researchers found that AURKB inhibitor showed promising therapeutic efficacy in SCLC, and high expression of BCL2 predicted resistance to the inhibitor. Therefore, targeting BCL2 can overcome resistance and enhance sensitivity to AURKB inhibition in SCLC.
CLINICAL CANCER RESEARCH
(2023)
Review
Medicine, Research & Experimental
Julie Ko, Monte M. Winslow, Julien Sage
Summary: Metastasis is a major cause of morbidity and mortality in cancer patients, especially with small cell lung cancer (SCLC) known for its remarkable metastatic proclivity. Recent advances in research, such as using circulating tumor cells and genetically engineered mouse models, are helping to overcome limitations in studying SCLC metastasis. New insights into cellular mechanisms associated with increased metastatic ability offer promise for future therapeutic options.
EMBO MOLECULAR MEDICINE
(2021)
Article
Chemistry, Medicinal
Zhenhao Liu, Kuan Liang, Wenlang Liu, Tao Jiang, Rui Zhou, Mojie Duan, Zheng Zheng
Summary: The tyrosine-protein kinase Met (c-Met) is a crucial signaling molecule involved in cellular growth and division. Dysregulation of c-Met can lead to various fatal diseases. Understanding the mechanisms of ligand binding and regulation of c-Met is important for developing effective drugs against drug tolerance.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Review
Oncology
Elena Michaels, Christine M. Bestvina
Summary: The MET pathway can be activated by various mechanisms in NSCLC, including mutations and amplifications. Detection methods for MET alterations include RNA-based NGS and FISH. Newer selective MET TKIs have shown improved efficacy, and MET amplification is a common resistance mechanism to EGFR inhibition.
FRONTIERS IN ONCOLOGY
(2022)
Article
Oncology
Jingya Wang, Tao Sun, Zhaoting Meng, Liuchun Wang, Mengjie Li, Jinliang Chen, Tingting Qin, Jiangyong Yu, Miao Zhang, Zhixin Bie, Zhiqiang Dong, Xiangli Jiang, Li Lin, Cuicui Zhang, Zhujun Liu, Richeng Jiang, Guang Yang, Lin Li, Yan Zhang, Dingzhi Huang
Summary: Combining a PARP inhibitor with an XPO1 inhibitor significantly improves efficacy and tolerability in treating small cell lung cancer, restoring the balance and activity of FOXO3a. This dual inhibition provides a new therapeutic approach for SCLC, warranting further investigation in potential clinical trials.
Article
Oncology
Yang Xia, Rui Jin, Miao Li, Fen Lan, Hao Zhu, Yinghui Yu, Da Miao, Qiyuan Wang, Yi Zhou, Giovanni Selvaggi, Songmin Ying, Jianjun Zhang, Huahao Shen, Xiuning Le, Wen Li
Summary: Met proto-oncogene exon 14 skipping (METex14) mutations are targetable driver genes in non-small-cell lung cancers. Ensartinib, a multi-kinase inhibitor, showed significant antitumor effects against METex14 mutant NSCLCs in preclinical and clinical trials, with low rates of adverse events.
Article
Cell Biology
Ke Li, Xinling Zhu, Conghu Yuan
Summary: The downregulation of miR-185-3p has been identified as a key factor responsible for EGFR TKI resistance in lung cancer cells, involving the upregulation of PFKL and MET. Combining PFKL/MET inhibitors with EGFR TKIs could be a promising therapeutic approach for lung cancer patients with EGFR mutations.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(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
Medicine, Research & Experimental
Christopher W. Schultz, Yang Zhang, Rajaa Elmeskini, Astrid Zimmermann, Haiqing Fu, Yasuhisa Murai, Darawalee Wangsa, Suresh Kumar, Nobuyuki Takahashi, Devon Atkinson, Liton Kumar Saha, Chien-Fei Lee, Brian Elenbaas, Parth Desai, Robin Sebastian, Ajit Kumar Sharma, Melissa Abel, Brett Schroeder, Manan Krishnamurthy, Rajesh Kumar, Nitin Roper, Mirit Aladjem, Frank T. Zenke, Zoe Weaver Ohler, Yves Pommier, Anish Thomas
Summary: Small-cell lung cancer (SCLC) is the most lethal type of lung cancer, and MYC-driven non-neuroendocrine SCLC is resistant to standard therapies. ATR inhibitors have been found to enhance the efficacy of lurbinectedin, an approved treatment for relapsed SCLC. The first-in-class ATR inhibitor berzosertib synergizes with lurbinectedin by causing mitotic catastrophe and cell death. Clinical trial NCT04802174 is assessing the combination of lurbinectedin and berzosertib.
EMBO MOLECULAR MEDICINE
(2023)
Article
Chemistry, Multidisciplinary
Qian Gou, Huiqing Chen, Mingjun Chen, Juanjuan Shi, Jianhua Jin, Qian Liu, Yongzhong Hou
Summary: Immune cells play a role in protecting against tumor progression, while aberrant expression of PD-L1 in cancer cells leads to tumor immune escape. This study found that ING4 induces the autophagic degradation of PD-L1, inhibiting immune escape in NSCLC. However, high expression of CK2 was found to correlate with low ING4 protein levels in NSCLC. Further analysis revealed that CK2 induces the phosphorylation of ING4-S150, leading to its degradation by JFK ubiquitin ligase. In contrast, CK2 gene knockout increased ING4 protein stability and T cell activity, inhibiting NSCLC immune escape. Additionally, the combination of a CK2 inhibitor and PD-1 antibody effectively enhanced antitumor immunotherapy.
Article
Cell Biology
Fangfei Qu, Siqi C. Brough, Wojciech Michno, Chioma J. Madubata, Griffin G. Hartmann, Alyssa Puno, Alexandros P. Drainas, Debadrita Bhattacharya, Erwin Tomasich, Myung Chang Lee, Dian Yang, Jun Kim, Maria Peiris-Pages, Kathryn L. Simpson, Caroline Dive, Matthias Preusser, Angus Toland, Christina Kong, Millie Das, Monte M. Winslow, Anca M. Pasca, Julien Sage
Summary: Small-cell lung cancer cells recruit reactive astrocytes to the brain metastases, mimicking the interactions between neurons and astrocytes during brain development. The secreted factor Reelin from SCLC cells plays a crucial role in recruiting astrocytes, which promote the growth of SCLC by secreting neuronal pro-survival factors.
NATURE CELL BIOLOGY
(2023)
Review
Oncology
Leylah M. Drusbosky, Richa Dawar, Estelamari Rodriguez, Chukwuemeka Ikpeazu
Summary: The MET exon 14 skipping mutation is present in a small percentage of lung cancer patients, but targeted inhibitors like capmatinib and tepotinib show promising clinical activity with tolerable toxicity profiles. Ongoing research aims to overcome acquired resistance and enhance the effectiveness of these agents.
JOURNAL OF HEMATOLOGY & ONCOLOGY
(2021)
Article
Cell Biology
Zhe Liu, Liang Ma, Yiming Sun, Wenying Yu, Xue Wang
Summary: The study demonstrated that the STAT3/ZEB1 axis is critical in gefitinib resistance in lung cancer, and a new potential therapeutic strategy targeting STAT3 has been identified with the inhibitor LL1. LL1 was shown to sensitize resistant cells to gefitinib by depleting STAT3 activity and blocking its signaling pathways, with little observed toxicity in animal models, indicating it could be a chemotherapeutic adjuvant for gefitinib resistance in NSCLC.
CELL DEATH & DISEASE
(2021)
Article
Oncology
David S. Hong, Kathleen N. Moore, Johanna C. Bendell, Daniel D. Karp, Judy S. Wang, Susanna Ulahannan, Suzanne Jones, Wenjuan Wu, Gregory P. Donoho, Yan Ding, Andrew Capen, Xuejing Wang, Aimee Bence Lin, Manish R. Patel
Summary: The combination of Prexasertib and Samotolisib showed antitumor activity in preclinical models and preliminary efficacy in heavily pretreated patients. However, the clinical combination was associated with toxicity, suggesting supportive measures may be required.
CLINICAL CANCER RESEARCH
(2021)
Article
Medicine, General & Internal
Peter Chen, Ajay Nirula, Barry Heller, Robert L. Gottlieb, Joseph Boscia, Jason Morris, Gregory Huhn, Jose Cardona, Bharat Mocherla, Valentina Stosor, Imad Shawa, Andrew C. Adams, Jacob Van Naarden, Kenneth L. Custer, Lei Shen, Michael Durante, Gerard Oakley, Andrew E. Schade, Janelle Sabo, Dipak R. Patel, Paul Klekotka, Daniel M. Skovronsky
Summary: LY-CoV555, a neutralizing antibody, showed promising results in reducing viral load, improving symptoms, and lowering the risk of hospitalization among patients with mild or moderate Covid-19. While one of the doses appeared to accelerate the decline in viral load, others did not show significant effects by day 11.
NEW ENGLAND JOURNAL OF MEDICINE
(2021)
Article
Cell Biology
Timothy B. Branigan, David Kozono, Amy E. Schade, Peter Deraska, Hembly G. Rivas, Larissa Sambel, Hunter D. Reavis, Geoffrey Shapiro, Alan D. D'Andrea, James A. DeCaprio
Summary: This study identified that knockout of MMB-FOXM1 complex components LIN54 and FOXM1 reduced CHK1 inhibitor-induced DNA replication stress markers and premature mitosis during Late S phase. Activation of a feedback loop between the MMB-FOXM1 complex and CDK1 is required for CHK1 inhibitor-induced premature mitosis in Late S phase and subsequent replication catastrophe. These findings offer mechanistic insights into small molecule inhibitors under clinical trials and support combination therapies.
Article
Oncology
Ioannis A. Vathiotis, Tyler MacNeil, Jon Zugazagoitia, Konstantinos N. Syrigos, Thazin Nwe Aung, Aaron M. Gruver, Peter Vaillancourt, Ina Hughes, Steve Hinton, Kyla Driscoll, David L. Rimm
Summary: The study revealed that the CD200/CD200R immune checkpoint is widely expressed in lung cancer patients and may serve as a potential target for immune therapy. Both CD200 and CD200R are abundantly expressed in NSCLC patients, with moderate correlation with PD-L1. This finding provides a basis for targeting the CD200/CD200R pathway for treating NSCLC patients.
Article
Medical Laboratory Technology
Jessica A. Baker, Anthony N. Sireci, Narasimha Marella, Holly Kay Cannon, Tyler J. Marquart, Timothy R. Holzer, Leslie O'Neill Reising, Joel D. Cook, Sameera R. Wijayawardana, Juraj Bodo, Eric D. Hsi, Andrew E. Schade, Gerard J. Oakley
Summary: This study validated and described the performance of Abbott Molecular RET break-apart FISH probes for detecting RET rearrangements. The results showed that using appropriate cutoffs can achieve high sensitivity and specificity. This helps to ensure that appropriate patients receive effective, timely therapy.
ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE
(2022)
Article
Pathology
Aaron M. Gruver, Matt D. Westfall, Bradley L. Ackermann, Salisha Hill, Ryan D. Morrison, Juraj Bodo, Keith K. Lai, David C. Gemperline, Eric D. Hsi, Daniel C. Liebler, Jochen Schmitz, Robert J. Benschop
Summary: This study successfully used targeted mass spectrometry to analyze the expression of various cells and proteins in 19 ulcerative colitis (UC) biopsies, and performed global proteome analysis to identify pathways associated with UC progression. Positive correlations were observed between histological scores of active colitis and certain measurements, while inverse relationships were detected with other targets due to crypt disruption. An exploratory accuracy assessment showed promising sensitivities and specificities with established cut-offs. Further studies are needed to verify the utility of this novel approach.
JOURNAL OF CLINICAL PATHOLOGY
(2022)
Article
Immunology
Michael Dougan, Masoud Azizad, Bharat Mocherla, Robert L. Gottlieb, Peter Chen, Corey Hebert, Russell Perry, Joseph Boscia, Barry Heller, Jason Morris, Chad Crystal, Awawu Igbinadolor, Gregory Huhn, Jose Cardona, Imad Shawa, Princy Kumar, Andra Blomkalns, Andrew C. Adams, Jacob Van Naarden, Kenneth L. Custer, Jack Knorr, Gerard Oakley, Andrew E. Schade, Timothy R. Holzer, Philip J. Ebert, Richard E. Higgs, Janelle Sabo, Dipak R. Patel, Matan C. Dabora, Mark Williams, Paul Klekotka, Lei Shen, Daniel M. Skovronsky, Ajay Nirula
Summary: Bamlanivimab and etesevimab together (700/1400 mg) reduced hospitalizations and viral load in patients with mild-to-moderate COVID-19.
CLINICAL INFECTIOUS DISEASES
(2022)
Article
Anatomy & Morphology
Monika D. Polewski, Gitte B. Nielsen, Ying Gu, Aaron T. Weaver, Gavin Gegg, Siena Tabuena-Frolli, Mariana Cajaiba, Debra Hanks, Michael Method, Michael F. Press, Claudia Gottstein, Aaron M. Gruver
Summary: The objective of this study was to develop a standardized Ki-67 immunohistochemistry method for precise assessment of patients with early breast cancer and to evaluate the prognostic value of Ki-67 expression in these patients. The results showed that patients with high Ki-67 expression had a higher risk of developing invasive disease within 2 years compared to those with low Ki-67 expression.
APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY
(2022)
Article
Oncology
Christopher J. Sweeney, Ivor J. Percent, Sunil Babu, Jennifer L. Cultrera, Bryan A. Mehlhaff, Oscar B. Goodman, David S. Morris, Ian D. Schnadig, Costantine Albany, Neal D. Shore, Paul R. Sieber, Susan C. Guba, Wei Zhang, Volker Wacheck, Gregory P. Donoho, Anna M. Szpurka, Sophie Callies, Boris Kin Lin, Johanna C. Bendell
Summary: In patients with metastatic castration-resistant prostate cancer (mCRPC) who had progressed on abiraterone treatment, the combination of samotolisib/enzalutamide showed tolerable side effects and significantly improved progression-free survival (PFS), especially in patients with intact PTEN and no androgen receptor splice variant 7.
CLINICAL CANCER RESEARCH
(2022)
Article
Medicine, Research & Experimental
Jonathan T. Sims, Josh Poorbaugh, Ching-Yun Chang, Timothy R. Holzer, Lin Zhang, Sarah M. Engle, Stephanie Beasley, Thompson N. Doman, Lynn Naughton, Richard E. Higgs, Nicole Kallewaard, Robert J. Benschop
Summary: This study aimed to monitor and characterize the immune response to SARS-CoV-2 infection in hospitalized patients with COVID-19 through analysis of peripheral blood and nasopharyngeal swab samples, with or without bamlanivimab treatment. The findings showed elevated levels of certain inflammatory protein biomarkers in the serum of COVID-19 patients, which were linked with inflammatory and viral-induced interferon response genes detected in nasopharyngeal swab samples.
JOURNAL OF TRANSLATIONAL MEDICINE
(2022)
Article
Anatomy & Morphology
Miglena Komforti, Erinn Downs-Kelly, Francisco Sapunar, Sameera R. Wijayawardana, Aaron M. Gruver, Sunil S. Badve
Summary: This study compared the concordance of Ki-67 immunohistochemistry results obtained from different automated staining instruments on breast cancer samples and found that good concordance can be achieved with reagents run on the ASL48 instrument, demonstrating the importance of optimized protocols and standardized scoring.
APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY
(2022)
Article
Oncology
Panagiotis A. Konstantinopoulos, Jung-Min Lee, Bo Gao, Rowan Miller, Jung-Yun Lee, Nicoletta Colombo, Ignace Vergote, Kelly M. Credille, Suzanne R. Young, Samuel McNeely, Xuejing Aimee Wang, Aimee Bence Lin, Ronnie Shapira-Frommer
Summary: This study aimed to evaluate the efficacy and safety of using prexasertib, a CHK1 inhibitor, in treating high-grade serous ovarian cancer. The results showed that prexasertib demonstrated durable single agent activity to a certain extent and its effects were not influenced by clinical characteristics, BRCA status, or prior therapies, including PARPi. The study also emphasized the need for alternative biomarker approaches to identify responders.
GYNECOLOGIC ONCOLOGY
(2022)
Article
Oncology
Alyssa C. Flint, Dana K. Mitchell, Steven P. Angus, Abbi E. Smith, Waylan Bessler, Li Jiang, Henry Mang, Xiaohong Li, Qingbo Lu, Brooke Rodriguez, George E. Sandusky, Andi R. Masters, Chi Zhang, Pengtao Dang, Jenna Koenig, Gary L. Johnson, Weihua Shen, Jiangang Liu, Amit Aggarwal, Gregory P. Donoho, Melinda D. Willard, Shripad Bhagwat, D. Wade Clapp, Steven D. Rhodes
Summary: By utilizing an integrated multi-omic approach, we identified novel therapeutic targets for the treatment of peripheral nerve sheath tumors, particularly plexiform neurofibromas (PNF), in individuals with neurofibromatosis type 1 (NF1). Through experimental studies on a mouse model, we discovered that inhibiting the CDK4/6 and RAS/MAPK pathways showed significant efficacy in reducing PNF tumor burden. These findings provide a promising rationale for clinical translation and treatment of PNF and other related tumors.
CLINICAL CANCER RESEARCH
(2023)
Meeting Abstract
Oncology
Loredana Puca, Michele S. Dowless, Carmen M. Perez-Ferreiro, Maria Jesus Ortiz-Ruiz, Gregory P. Donoho, Andrew Capen, Lysiane Huber, Sarah M. Bogner, Dongling Fei, Jason R. Manro, Chun Ping Yu, Wei Guo Xu, Rui Wang, Shuang Chen, Mark A. Hicks, Parisa Zolfaghari, Andrew Faber, Raymond Gilmour, Monica D. Ramstetter, Matthew T. Chang, Maria Jose Lallena, Xuequian Gong, David M. Hyman, Lillian M. Smyth, Barbara J. Brandhuber, Barry S. Taylor, Anke Klippel
Article
Oncology
Michael Crager, Sameera R. Wijayawardana, Aaron M. Gruver, Andrea Blacklock, Christy Russell, Frederick L. Baehner, Francisco Sapunar
Summary: This study assessed the correlation between Oncotype Dx (R) assay and Ki-67 IHC MIB-1 assay. The results showed a moderately positive correlation, suggesting that they should not be used interchangeably in clinical practice.
BREAST CANCER RESEARCH
(2022)