Article
Oncology
Angela McLigeyo, Jamilla Rajab, Peter Oyiro, Mohammed Ezzi, Yatich Bett, Matilda Ong'ondi, Andrew Odhiambo, Sitna Mwanzi, Nicholas Othieno-Abinya
Summary: This study analyzed the baseline characteristics and factors associated with cytopenia in Chronic Myeloid Leukemia patients treated with imatinib. The results showed no significant differences in gender, age, marital status, occupation, and education level between patients with and without cytopenia. Multivariable analysis revealed that baseline anemia, neutropenia, thrombocytopenia, and thrombocytosis increased the odds of developing cytopenia.
Article
Biochemistry & Molecular Biology
Elena V. Koroleva, Yuri V. Kornoushenko, Anna D. Karpenko, Ivan P. Bosko, Julia V. Siniutsich, Zhanna V. Ignatovich, Alexander M. Andrianov
Summary: An integrated computational approach was used to identify potential inhibitors of Bcr-Abl tyrosine kinase, an enzyme involved in chronic myeloid leukemia. Five compounds were found to effectively block the enzyme activity and exhibit high binding affinity comparable to FDA-approved kinase inhibitors. These compounds may serve as good scaffolds for the design of novel anticancer agents.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Multidisciplinary Sciences
Pelin Ayaz, Agatha Lyczek, YiTing Paung, Victoria R. Mingione, Roxana E. Iacob, Parker W. de Waal, John R. Engen, Markus A. Seeliger, Yibing Shan, David E. Shaw
Summary: The authors used molecular dynamics simulations to study the binding process of Abl kinase with the cancer drug imatinib. The simulations revealed that imatinib induces a large conformational change of the protein and identified a region in Abl kinase that is structurally unstable during binding. Mutations in this region confer imatinib resistance by exacerbating structural instability.
NATURE COMMUNICATIONS
(2023)
Article
Pharmacology & Pharmacy
Tingting Lu, Jiangyan Cao, Fengming Zou, Xixiang Li, Aoli Wang, Wenliang Wang, Huamin Liang, Qingwang Liu, Chen Hu, Cheng Chen, Zhenquan Hu, Wenchao Wang, Lili Li, Jian Ge, Yang Shen, Tao Ren, Jing Liu, Ruixiang Xia, Qingsong Liu
Summary: CHMFL-48 is a novel type II kinase inhibitor that potently inhibits the wild-type BCR-ABL kinase and a panel of imatinib-resistant mutants. This drug shows strong inhibitory activity in a cellular context, blocking autophosphorylation of BCR-ABL kinase, affecting downstream signaling mediators, and inducing cell cycle progression blockade and apoptosis.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Article
Multidisciplinary Sciences
Yosuke Tanaka, Reina Takeda, Tsuyoshi Fukushima, Keiko Mikami, Shun Tsuchiya, Moe Tamura, Keito Adachi, Terumasa Umemoto, Shuhei Asada, Naoki Watanabe, Soji Morishita, Misa Imai, Masayoshi Nagata, Marito Araki, Hitoshi Takizawa, Tomofusa Fukuyama, Chrystelle Lamagna, Esteban S. Masuda, Ryoji Ito, Susumu Goyama, Norio Komatsu, Tomoiku Takaku, Toshio Kitamura
Summary: Leukemia stem cells in chronic myeloid leukemia are resistant to imatinib, but can be eliminated by combining imatinib with IRAK1/4 inhibitors that inhibit the IRAK1/4-NF-kappa B-PD-L1 signaling pathway.
NATURE COMMUNICATIONS
(2022)
Article
Oncology
Ryan Yen, Sarah Grasedieck, Andrew Wu, Hanyang Lin, Jiechuang Su, Katharina Rothe, Helen Nakamoto, Donna L. Forrest, Connie J. Eaves, Xiaoyan Jiang
Summary: This study analyzed differentially expressed miRNAs in CML patients, showing that the combination of miR-145 and miR-708 effectively predicts response to NL in treatment-naive patients, while miR-150 and miR-185 are significant classifiers at 1 month and 3 months post-NL therapy.
Article
Biochemistry & Molecular Biology
Nafia Gokce Ulusoy, Safiye Emirdag, Ece Sozer, Mohamed O. Radwan, Halilibrahim Ciftci, Mehran Aksel, Ali Ozmen, Nurettin Yayli, Tamer Karayildirim, Ozgen Alankus, Hiroshi Tateishi, Masami Otsuka, Mikako Fujita, Belgin Sever, Serap Sahin Bolukbasi
Summary: In this study, new gypsogenin derivatives were synthesized and their anticancer effects against CML cells were evaluated. Compound 6l was found to be the most effective anti-leukemic agent against CML cells, with less cytotoxicity towards healthy cells compared to imatinib. Furthermore, compound 6l significantly enhanced apoptosis in CML cells and inhibited Abl TK activity.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2022)
Article
Oncology
Yun Xu, Ziting Wang, Lei Zhang, Congying Gao, Fahui Li, Xueming Li, Yu Ke, Hong-Min Liu, Zhenbo Hu, Liuya Wei, Zhe-Sheng Chen
Summary: The compound JOA can inhibit the proliferation of chronic myeloid leukemia cells, including those with the BCR-ABL-T315I mutation, and induce cell differentiation. This effect may be mediated by the inhibition of the BCR-ABL/c-MYC signaling pathway. JOA shows potential as a lead compound for overcoming imatinib resistance in CML therapy.
Article
Hematology
Huimin Feng, Yue Fu, Zelong Cui, Minran Zhou, Lu Zhang, Zhenxing Gao, Sai Ma, Chunyan Chen
Summary: This study shows that PHF8 is significantly increased in CML patients and inhibits cell differentiation while promoting cell proliferation. Targeting PHF8, which directly regulates BCR::ABL1 expression, may be a useful therapeutic approach for CML.
BRITISH JOURNAL OF HAEMATOLOGY
(2023)
Article
Oncology
Dachuan Zeng, Miao Gao, Renren Zheng, Run Qin, Wei He, Suotian Liu, Wei Wei, Zhenglan Huang
Summary: The study revealed that KW-2478 has anti-cancer properties in both imatinib-sensitive and imatinib-resistant CML cells by inhibiting the chaperone function of HSP90α, weakening the BCR/ABL and MAPK signaling pathways. In mouse models, KW-2478 effectively prolonged lifespan and alleviated disease symptoms.
EXPERIMENTAL HEMATOLOGY & ONCOLOGY
(2022)
Article
Chemistry, Physical
Abhijit Kantankar, Y. Jayaprakash Rao, G. Mallikarjun, Y. Hemasri, Raghava Reddy Kethiri
Summary: A new series of pyrimidine based chromone hybrids were synthesized and evaluated for their anti-cancer activity, showing potent effects against A549, HeLa, and K562 cancer cell lines while maintaining relative non-toxicity against normal cell lines. The selectivity of these compounds against K562 cell line was confirmed using molecular docking analysis.
JOURNAL OF MOLECULAR STRUCTURE
(2021)
Article
Biochemistry & Molecular Biology
Ashraf K. El-Damasy, Heewon Jin, Jung Woo Park, Hyun Ji Kim, Hanan Khojah, Seon Hee Seo, Ju-Hyeon Lee, Eun-Kyoung Bang, Gyochang Keum
Summary: This study identifies AK-HW-90 (2b) as a potent inhibitor against imatinib-resistant BCR-ABL mutants, especially T315I. AK-HW-90 exhibits superior anticancer activity compared to imatinib and shows strong cytotoxicity against multiple cancer cells, including leukemia cells.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Kiran Kumar Adepu, Sangita Kachhap, Dipendra Bhandari, Andriy Anishkin, Sree Chintapalli
Summary: This study investigated the interaction sites of acifran with G-protein-coupled receptor proteins, specifically GPR109A and GPR109B. Computational studies revealed that acifran binds differently to both receptors, with lower affinity to GPR109B. The weaker binding of acifran-GPR109B can be attributed to specific amino acid residues in the receptor's ECL1 and ECL2 regions. On the other hand, stability of the GPR109A-acifran complex relies on key residues in TMH3 and TMH6. Energy analysis showed that both GPR109A- and GPR109B-acifran complexes are energetically stable, with lower binding free energy values for the latter.
JOURNAL OF MOLECULAR MODELING
(2022)
Article
Medicine, Research & Experimental
Mansi Shah, Harish Kumar, Shaowei Qiu, Hui Li, Mason Harris, Jianbo He, Ajay Abraham, David K. Crossman, Andrew Paterson, Robert S. Welner, Ravi Bhatia
Summary: In chronic myeloid leukemia (CML), LT-HSCs expressing low c-KIT levels are primitive, quiescent, and drug-resistant leukemia-initiating cells, representing a critical target for eliminating disease persistence.
Article
Oncology
Zhen Liu, Wenlong Zheng, Yuan Liu, Binghe Zhou, Yuqing Zhang, Fan Wang
Summary: The study showed that HSPA8 is overexpressed in imatinib-resistant CML cells and its ablation can inhibit cell proliferation, induce autophagy, and enhance the anti-tumor activity of imatinib. These findings reveal the role of HSPA8 in IR-CML and suggest its potential as a target for treatment.
EXPERIMENTAL CELL RESEARCH
(2021)
Article
Chemistry, Physical
Hsu-Chun Tsai, Tai-Sung Lee, Abir Ganguly, Timothy J. Giese, Maximilian C. C. J. C. Ebert, Paul Labute, Kenneth M. Merz, Darrin M. York
Summary: We propose a framework for optimized alchemical transformation pathways in free energy simulations using nonlinear mixing and a new functional form for softcore potentials. The framework is implemented and tested in the GPU-accelerated AMBER software suite. The optimized pathways integrate important features such as smoothstep functions, power scaling of interactions, LJ pairwise form, and smoothing of the potential at the nonbonded cutoff boundary. The pathways demonstrate superior numerical stability and minimal variance of free energy estimates compared to traditional methods.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Chemistry, Physical
Tai-Sung Lee, Hsu-Chun Tsai, Abir Ganguly, Darrin M. York
Summary: We propose an alchemical enhanced sampling method called ACES, implemented in the GPU-accelerated AMBER free energy MD engine. The method creates an enhanced sampling state by reducing or eliminating certain potential energy terms and interactions, while maintaining terms that limit the need for extensive phase space sampling. This enhanced sampling state is connected to the real state through a Hamiltonian replica exchange framework, resulting in a counterdiffusion of states. The ACES method has been successfully applied to various test cases and demonstrated superior performance compared to traditional MD and alternative enhanced sampling methods.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Hematology
Justin M. Watts, Maria R. Baer, Jay Yang, Thomas Prebet, Sangmin Lee, Gary J. Schiller, Shira N. Dinner, Arnaud Pigneux, Pau Montesinos, Eunice S. Wang, Karen P. Seiter, Andrew H. Wei, Stephane De Botton, Montserrat Arnan, Will Donnellan, Anthony P. Schwarer, Christian Recher, Brian A. Jonas, P. Brent Ferrell Jr, Christophe Marzac, Patrick Kelly, Jennifer Sweeney, Sanjeev Forsyth, Sylvie M. Guichard, Julie Brevard, Patrick Henrick, Hesham Mohamed, Jorge E. Cortes
Summary: This study evaluated the safety, pharmacokinetics, pharmacodynamics, and clinical activity of Olutasidenib in patients with acute myeloid leukemia or myelodysplastic syndrome with mutant IDH1. The results showed that Olutasidenib, as monotherapy or in combination with azacitidine, was well tolerated and exhibited meaningful clinical activity. These findings provide a rationale for further evaluation of Olutasidenib in different populations of patients with myeloid malignancies.
LANCET HAEMATOLOGY
(2023)
Article
Oncology
Nikhil Shri Sahajpal, Ashis K. Mondal, Harmanpreet Singh, Ashutosh Vashisht, Sudha Ananth, Daniel Saul, Alex R. Hastie, Benjamin Hilton, Barbara R. DuPont, Natasha M. Savage, Vamsi Kota, Alka Chaubey, Jorge E. Cortes, Ravindra Kolhe
Summary: The current genetic testing of myeloid cancers lacks resolution and is limited to specific genomic regions/genes. This study used a combination of high-resolution cytogenetic technology and next-generation sequencing to obtain a comprehensive genomic profile of these tumors. The combinatorial approach identified new genetic alterations and clinically relevant alterations in previously negative cases.
Article
Hematology
Mycal Casey, Lorriane Odhiambo, Nidhi Aggarwal, Mahran Shoukier, K. M. Islam, Jorge Cortes
Summary: Despite advances in cancer outcomes, there are significant health disparities in the treatment of lymphomas. This study examined the representation of different demographic groups in randomized controlled trials (RCTs) for lymphoma and found significant underrepresentation of black, Hispanic, and female patients. Geographic distribution of trials also limited access for patients in certain areas. Correcting enrollment disparities is crucial to ensure that the results of these trials are applicable to all populations.
Article
Oncology
Fabio Efficace, Francesco Cottone, Betina Yanez, Vamsi Kota, Fausto Castagnetti, Giovanni Caocci, Massimiliano Bonifacio, Andrea Patriarca, Isabella Capodanno, Maria Cristina Miggiano, Mario Tiribelli, Massimo Breccia, Luigia Luciano, Valentina Giai, Alessandra Iurlo, Elisabetta Abruzzese, Carmen Fava, Shira Dinner, Jessica K. Altman, Gianantonio Rosti, Jorge Cortes, Marco Vignetti, David Cella
Summary: Patient-reported symptom monitoring from the beginning of therapy in patients with CML may be critical to improve adherence to therapy and early molecular response rates. The current findings suggest that systematic monitoring of patient-reported symptoms is associated with high adherence rates.
Article
Oncology
Koji Sasaki, Kiyomi Morita, Hagop Kantarjian, Guillermo Garcia-Manero, Elias Jabbour, Farhad Ravandi, Marina Konopleva, Gautam Borthakur, William Wierda, Naval Daver, Koichi Takahashi, Courtney Dinardo, Guillermo Montalban Bravo, Ghayas C. Issa, Sherry A. Pierce, Kelly A. Soltysiak, Martha S. Tingen, Jorge E. Cortes
Summary: This study investigated the impact of geographic disparities on cancer survival. The study found that factors such as age, income, race, and distance to cancer centers were predictive of survival. The results showed significant disparities in cancer care based on geographic locations.
CLINICAL LYMPHOMA MYELOMA & LEUKEMIA
(2023)
Article
Economics
Jorge E. Cortes, Delphine Rea, Michael J. Mauro, Diana Tran, Pearl Wang, Kejal Jadhav, Aurore Yocolly, Koji Sasaki
Summary: This study assessed and compared the health care resource utilization (HCRU) rates of asciminib and bosutinib among 3 L+ patients with chronic myeloid leukemia in chronic phase (CML-CP) in the ASCEMBL trial. The results showed that asciminib-treated patients had lower resource utilization compared to bosutinib-treated patients over the long-term.
JOURNAL OF MEDICAL ECONOMICS
(2023)
Review
Hematology
Marisol Miranda-Galvis, Kellen C. Tjioe, E. Andrew Balas, Gagan Agrawal, Jorge E. Cortes
Summary: This article evaluates the impact of social determinants of health on the outcomes of patients with hematologic malignancies. The study found that factors such as education level, health insurance coverage, income level, and marital status significantly affect patients' survival rates. However, there are contradictory reports regarding the effect of distance to treatment centers on treatment outcomes. Additionally, data on transportation, debt, diet, and other factors are lacking.
Review
Hematology
Mahesh Swaminathan, Jorge E. E. Cortes
Summary: Gemtuzumab-ozogamicin (GO) is an ADC approved for the treatment of CD33(+) AML. Despite initial recall due to lack of efficacy and hepatotoxicities, subsequent phase 3 studies showed significant survival benefits with lower and fractionated doses of GO in combination with standard chemotherapy. GO at a dose of 6 mg/m(2) was associated with higher grade > 3 hepatotoxicities and VOD compared to 3 mg/m(2). GO has been reapproved in 2017 and is currently being studied for its role in combination therapies and MRD elimination in CD33(+) AML patients.
THERAPEUTIC ADVANCES IN HEMATOLOGY
(2023)
Meeting Abstract
Oncology
Jane Apperley, Jorge Cortes, Elias Jabbour, Andreas Hochhaus, Timothy Hughes, Charles Chuah, Hugues de Lavallade, Michael Deininger, Jeffrey H. Lipton, Elza Lomaia, Lori Maness, Michael Mauro, James McCloskey, Beatriz Moiraghi, Carolina Pavlovsky, Christine Rojas, Philippe Rousselot, Tomasz Sacha, Moshe Talpaz, Anna Turkina, Maria Undurraga Sutton, Xiaowei Ren, Alexander Vorog, Gianantonio Rosti
CLINICAL LYMPHOMA MYELOMA & LEUKEMIA
(2023)
Meeting Abstract
Oncology
Ehab Atallah, Michael Mauro, Koji Sasaki, Moshe Levy, Paul Koller, Daisy Yang, Dramane Laine, John Sabo, Ennan Gu, Jorge Cortes
CLINICAL LYMPHOMA MYELOMA & LEUKEMIA
(2023)
Meeting Abstract
Oncology
Aram Bidikian, Sreyashi Basu, Zhong He, Himachandana Atluri, Jabra Zarka, Michael Andreeff, Koji Sasaki, Elias Jabbour, Jorge E. Cortes, Padmanee Sharma, Ghayas C. Issa
CLINICAL LYMPHOMA MYELOMA & LEUKEMIA
(2023)
Meeting Abstract
Oncology
Joannie Clements, Cristina Ruiz, Andrea Damon, Peter Schuld, Pauline Frank, Cristina Constantinescu, Jorge Cortes
CLINICAL LYMPHOMA MYELOMA & LEUKEMIA
(2023)
Meeting Abstract
Oncology
Jorge Cortes, Michael Deininger, Elza Lomaia, Beatriz Moiraghi, Maria Undurraga Sutton, Carolina Pavlovsky, Charles Chuah, Tomasz Sacha, Jeffrey H. Lipton, James McCloskey, Philippe Rousselot, Gianantonio Rosti, Hugues de Lavallade, Christine Rojas, Anna Turkina, Moshe Talpaz, Michael Mauro, Vickie Lu, Alexander Vorog, Jane Apperley
CLINICAL LYMPHOMA MYELOMA & LEUKEMIA
(2023)