Article
Multidisciplinary Sciences
Chiara Ghezzi, Bao Ying Chen, Robert Damoiseaux, Peter M. Clark
Summary: In this study, a new compound called pacritinib was discovered to inhibit glucose consumption in squamous cell lung cancer cells, and FLT3 inhibitors were identified as a potential new class of drugs that can block glucose consumption in squamous cell lung cancer.
SCIENTIFIC REPORTS
(2023)
Article
Hematology
Sangeetha Venugopal, John Mascarenhas
Summary: Myelofibrosis (MF) can lead to splenomegaly and thrombocytopenia. Currently approved JAK1/2 inhibitors have not been evaluated in patients with platelets <= 50 x 109/L. Pacritinib (PAC), a selective JAK2 inhibitor, has shown efficacy in MF patients, especially in splenic response and symptom improvement.
Article
Oncology
Jiao Wei, Ai-Min Hui, Nitika
Summary: This article is a summary of biomarkers for FLT3 inhibitors in acute myeloid leukemia (AML) and alternative approaches to overcome resistance to current therapies. AML is a type of leukemia where FLT3 gene mutations are common, making it an attractive target for treatment. However, the current inhibitors face challenges due to multiple mutations in the FLT3 gene. Therefore, the identification of biomarkers and finding alternative approaches are important.
Review
Medicine, General & Internal
Cristina Negotei, Andrei Colita, Iuliana Mitu, Anca Roxana Lupu, Mihai-Emilian Lapadat, Constanta Elena Popovici, Madalina Crainicu, Oana Stanca, Nicoleta Mariana Berbec
Summary: Acute myeloid leukemia (AML) is an aggressive disease characterized by the accumulation of abnormal hematopoietic precursors. FLT3 gene mutations increase the risk of relapse and mortality. FLT3 mutation screening is mandatory for AML patients, and FLT3 inhibitors are crucial for treatment. FLT3-ITD is the most common mutation type, while FLT3-TKD affects a smaller percentage. FLT3 inhibitors are now vital in treating AML patients with FLT3 mutations.
JOURNAL OF CLINICAL MEDICINE
(2023)
Article
Oncology
Jad Othman, Nicola Potter, Katya Mokretar, David Taussig, Anjum Khan, Pramila Krishnamurthy, Anne-Louise Latif, Paul Cahalin, James Aries, Mariam Amer, Edward Belsham, Eibhlin Conneally, Charles Craddock, Dominic Culligan, Mike Dennis, Caroline Duncan, Sylvie D. Freeman, Caroline Furness, Amanda Gilkes, Paraskevi Gkreka, Katherine Hodgson, Wendy Ingram, Manish Jain, Andrew King, Steven Knapper, Panagiotis Kottaridis, Mary Frances McMullin, Unmesh Mohite, Loretta Ngu, Jenny O'Nions, Katharine Patrick, Tom Rider, Wing Roberts, Marianne Tang Severinsen, Neill Storrar, Tom Taylor, Nigel H. Russell, Richard Dillon
Summary: Patients with FLT3-mutated AML are at high risk of relapse and poor outcomes. Monitoring measurable residual disease (MRD) can help identify patients destined to relapse, providing an opportunity for pre-emptive intervention. In this study, 56 patients with molecular failure were treated with FLT3 inhibitors (FLT3i), resulting in a molecular response rate of 60% and an overall survival rate of 80% at 2 years. High-sensitivity next-generation sequencing identified patients more likely to benefit from FLT3i monotherapy. Further prospective studies are warranted to evaluate this promising treatment strategy.
Article
Multidisciplinary Sciences
Jarno Kivioja, Disha Malani, Ashwini Kumar, Mika Kontro, Alun Parsons, Olli Kallioniemi, Caroline A. Heckman
Summary: The study demonstrated a significant association between FLT3 internal tandem duplication allelic ratio (ITD-AR) and ex vivo response to FLT3 inhibitors in adult AML, while ITD length showed no correlation. Patients with high HLF gene expression and ITD-AR had better clinical response to the FLT3 inhibitor sorafenib compared to those with low ITD-AR and HLF expression.
SCIENTIFIC REPORTS
(2021)
Article
Immunology
Varvara Maiorova, Murad D. Mollaev, Polina Vikhreva, Elena Kulakovskaya, Dmitry Pershin, Dmitriy M. Chudakov, Alexey Kibardin, Michael A. Maschan, Sergey Larin
Summary: A CAR-T cell targeted at AML's full-length Flt3 ligand recognition module is shown to have specific killing effects on Flt3-positive leukemia cells without cytotoxicity towards Flt3-negative cells. The cytolytic capacity of T cells plays a crucial role in the killing, and the targeting authenticity is confirmed through competitive inhibition. The developed system, functioning as a non-immunogenic equivalent of scFv-mediated targeting, shows promising antitumor effects with low off-target cytotoxicity for AML treatment.
Article
Oncology
Anudishi Tyagi, Appalaraju Jaggupilli, Stanley Ly, Bin Yuan, Fouad El-Dana, Venkatesh L. Hegde, Vivek Anand, Bijender Kumar, Mamta Puppala, Zheng Yin, Stephen T. C. Wong, Alexis Mollard, Hariprasad Vankayalapati, Jason M. Foulks, Steven L. Warner, Naval Daver, Gautam Borthakur, V. Lokesh Battula
Summary: The study identified ACVR1 as a factor favoring AML growth and a potential therapeutic target. ACVR1 was found to be overexpressed in FLT3-mutated AML and inhibition of ACVR1 expression increased the sensitivity of AML cells to FLT3 inhibitors. A novel ACVR1 inhibitor, TP-0184, was developed and shown to selectively arrest the growth of FLT3-mutated AML cells.
Article
Oncology
Jiquan Jiang, Jing Feng, Xiangnan Song, Qing Yang, Hongbo Zhao, Rui Zhao, Xinrui He, Yaoyao Tian, Lianjie Wang, Yanhong Liu
Summary: The FLT3-ITD mutation in acute myeloid leukemia (AML) poses a serious threat to human health, with a poor prognosis and high risk of recurrence. Ferroptosis, an iron-dependent regulated cell death, plays a role in the development and progression of AML. This study identified a circRNA, hsa_circ_0015278, that regulates ferroptosis-related genes through miRNA sponge, promoting FLT3-ITD AML progression. This finding contributes to the identification of biomarkers for diagnosis and prognosis, and provides insights into the pathogenesis and therapeutic targets of AML with FLT3-ITD mutation.
Article
Hematology
Mohammad Azhar, Zachary Kincaid, Meenu Kesarwani, Arhama Ahmed, Mark Wunderlich, Tahir Latif, Daniel Starczynowski, Mohammad Azam
Summary: The JAK2 inhibitor momelotinib is a potent type 1 FLT3 inhibitor that effectively suppresses FLT3 mutations and growth factor signaling, showing better efficacy in suppressing leukemia in a preclinical murine model of AML.
Article
Pharmacology & Pharmacy
Yvette N. Lamb
Summary: Pacritinib is an orally administered kinase inhibitor developed for the treatment of myelofibrosis and graft-versus-host disease. It has received accelerated approval in the USA for the treatment of specific types of myelofibrosis based on clinical trial results.
Review
Biochemistry & Molecular Biology
Michael Loschi, Rinzine Sammut, Edmond Chiche, Thomas Cluzeau
Summary: FLT3-mutated acute myeloid leukemia, accounting for around 30% of AML cases, has seen improved prognosis with the emergence of tyrosine kinase inhibitors. However, challenges such as drug resistance still exist in the treatment of this disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Oncology
Jayastu Senapati, Tapan Mahendra Kadia
Summary: Treatment options in acute myeloid leukemia (AML) have significantly improved over the last decade, with better understanding of disease biology and availability of targeted therapies. The use of FLT3 inhibitors (FLT3i) in FLT3-mutated (FLT3(mut)) AML is an important development, but the clinical decisions and choice of FLT3i are still evolving.
CURRENT TREATMENT OPTIONS IN ONCOLOGY
(2022)
Article
Chemistry, Medicinal
Zhijie Wang, Donglin Wu, Xiaofei Zhao, Canlin Liu, Siming Jia, Qindi He, Fei Huang, Zitian Cheng, Tao Lu, Yadong Chen, Yun Chen, Pei Yang, Shuai Lu
Summary: AML patients need new therapies due to poor outcomes and relapse with single-target drugs. Inhibiting multiple oncogenic signals simultaneously is a promising strategy. This study developed novel dual FLT3/HDAC inhibitors through rational drug design and demonstrated their potential for AML treatment. The inhibitors blocked FLT3 and HDAC pathways, induced apoptosis, and arrested cell cycle.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Cell Biology
Jun Long, Xinjie Chen, Yan Shen, Yichen Lei, Lili Mu, Zhen Wang, Rufang Xiang, Wenhui Gao, Lining Wang, Ling Wang, Jieling Jiang, Wenjun Zhang, Huina Lu, Yan Dong, Yi Ding, Honghu Zhu, Dengli Hong, Yi Eve Sun, Jiong Hu, Aibin Liang
Summary: FLT3 inhibitors reduce the stability of the anti-cancer protein p53, leading to drug resistance. Blocking p53 degradation with proteasome inhibitors restores p53 protein levels and, when combined with FLT3-ITD inhibitors, shows superior therapeutic effects, suggesting a promising treatment strategy.
CELL REPORTS MEDICINE
(2023)
Article
Chemistry, Medicinal
Athisayamani Jeyaraj Duraiswamy, May Ann Lee, Babita Madan, Shi Hua Ang, Eldwin Sum Wai Tan, Wei Wen Vivien Cheong, Zhiyuan Ke, Vishal Pendharkar, Li Jun Ding, Yun Shan Chew, Vithya Manoharan, Kanda Sangthongpitag, Jenefer Alam, Anders Poulsen, Soo Yei Ho, David M. Virshup, Thomas H. Keller
JOURNAL OF MEDICINAL CHEMISTRY
(2015)
Review
Oncology
Babita Madan, David M. Virshup
MOLECULAR CANCER THERAPEUTICS
(2015)
Article
Biochemistry & Molecular Biology
B. Madan, Z. Ke, N. Harmston, S. Y. Ho, A. O. Frois, J. Alam, D. A. Jeyaraj, V. Pendharkar, K. Ghosh, I. H. Virshup, V. Manoharan, E. H. Q. Ong, K. Sangthongpitag, J. Hill, E. Petretto, T. H. Keller, M. A. Lee, A. Matter, D. M. Virshup
Article
Oncology
Sebastian Ribi, Daniel Baumhoer, Kristy Lee, Edison, Audrey S. M. Teo, Babita Madan, Kang Zhang, Wendy K. Kohlmann, Fei Yao, Wah Heng Lee, Qiangze Hoi, Shaojiang Cai, Xing Yi Woo, Patrick Tan, Gernot Jundt, Jan Smida, Michaela Nathrath, Wing-Kin Sung, Joshua D. Schiffman, David M. Virshup, Axel M. Hillmer
Article
Oncology
Kyle David Proffitt, Babita Madan, Zhiyuan Ke, Vishal Pendharkar, Lijun Ding, May Ann Lee, Rami N. Hannoush, David M. Virshup
Article
Developmental Biology
Zahra Kabiri, Gediminas Greicius, Babita Madan, Steffen Biechele, Zhendong Zhong, Hamed Zaribafzadeh, Edison, Jamal Aliyev, Yonghui Wu, Ralph Bunte, Bart O. Williams, Janet Rossant, David M. Virshup
Article
Chemistry, Medicinal
Anthony D. William, Angeline C. -H. Lee, Anders Poulsen, Kee Chuan Goh, Babita Madan, Stefan Hart, Evelyn Tan, Haishan Wang, Harish Nagaraj, Dizhong Chen, Chai Ping Lee, Eric T. Sun, Ramesh Jayaraman, Mohammad Khalid Pasha, Kantharaj Ethirajulu, Jeanette M. Wood, Brian W. Dymock
JOURNAL OF MEDICINAL CHEMISTRY
(2012)
Article
Oncology
Stefan Hart, Veronica Novotny-Diermayr, Kee Chuan Goh, Meredith Williams, Yong Cheng Tan, Lai Chun Ong, Albert Cheong, Bee Kheng Ng, Chithra Amalini, Babita Madan, Harish Nagaraj, Ramesh Jayaraman, Khalid M. Pasha, Kantharaj Ethirajulu, Wee Joo Chng, Nurulhuda Mustafa, Boon Cher Goh, Cyril Benes, Ultan McDermott, Mathew Garnett, Brian Dymock, Jeanette M. Wood
MOLECULAR CANCER THERAPEUTICS
(2013)
Article
Medicine, Research & Experimental
Babita Madan, Nathan Harmston, Gahyathiri Nallan, Alex Montoya, Peter Faull, Enrico Petretto, David M. Virshup
JOURNAL OF CLINICAL INVESTIGATION
(2018)
Article
Biochemistry & Molecular Biology
Muhammad Idris, Nathan Harmston, Enrico Petretto, Babita Madan, David M. Virshup
Review
Oncology
Zheng Zhong, Jia Yu, David M. Virshup, Babita Madan
CANCER AND METASTASIS REVIEWS
(2020)
Article
Oncology
Jia Yu, Permeen A. Mohamed Yusoff, Danielle T. J. Woutersen, Pamela Goh, Nathan Harmston, Ron Smits, David M. Epstein, David M. Virshup, Babita Madan
Article
Genetics & Heredity
Shiyang Liu, Nathan Harmston, Trudy Lee Glaser, Yunka Wong, Zheng Zhong, Babita Madan, David M. Virshup, Enrico Petretto
Article
Medicine, Research & Experimental
Amanpreet Kaur, Jun Yi Stanley Lim, Sugunavathi Sepramaniam, Siddhi Patnaik, Nathan Harmston, May Ann Lee, Enrico Petretto, David M. Virshup, Babita Madan
Summary: The study reveals that Wnt signaling plays a critical role in regulating DNA repair genes in stem cells and cancer, maintaining genomic integrity. Blocking Wnt signaling may sensitize cancers to radiation and other DNA damaging agents.
EMBO MOLECULAR MEDICINE
(2021)
Article
Medicine, Research & Experimental
Zheng Zhong, Nathan Harmston, Kris C. Wood, Babita Madan, David M. Virshup
Summary: Wnt signaling plays a crucial role in regulating the balance between stemness and differentiation. RNF43-mutant pancreatic cancers are resistant to PORCN inhibitors due to genetic alterations that silence EP300 and downregulate GATA6 expression, leading to a shift in phenotype and resistance to Wnt inhibition.
JOURNAL OF CLINICAL INVESTIGATION
(2022)
