Review
Biochemistry & Molecular Biology
Hannah E. Neiger, Emily L. Siegler, Yihui Shi
Summary: BRCA1 and BRCA2 are tumor suppressor genes crucial in DNA repair mechanisms. Synthetic lethality, caused by simultaneous perturbations of two genes, can help identify new therapeutic options for BRCA1/2 mutations. PARP inhibitor Olaparib has shown success as the first synthetic lethality-based therapy for BRCA1/2 breast and ovarian cancer, but drug resistance poses a challenge for targeted cancer therapy.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Cell Biology
Glinton Hanover, Frederick S. Vizeacoumar, Sara L. Banerjee, Raveena Nair, Renuka Dahiya, Ana I. Osornio-Hernandez, Alain Morejon Morales, Tanya Freywald, Juha P. Himanen, Behzad M. Toosi, Nicolas Bisson, Franco J. Vizeacoumar, Andrew Freywald
Summary: Eph receptors and ephrin ligands are considered promising targets for cancer treatment. However, their context-dependent functionalities hinder the targeting approach. To overcome this, we investigate the molecular landscapes of Ephs and ephrins and construct a cancer-related network of genetic interactions (GIs) to aid therapeutic manipulation. Our study highlights the involvement of EPHB6 in EGFR signaling and suggests the potential benefit of targeting EPHB6 in EGFR-dependent tumors.
Article
Pharmacology & Pharmacy
Hua-Li Wang, Xue Ma, Xin-Yuan Guan, Chen Song, Guo-Bo Li, Ya-Mei Yu, Ling-Ling Yang
Summary: This study found that a highly selective SIRT2 inhibitor, I, combined with sorafenib showed significant synergistic reduction in cell viability of MCF-7 cells. The combination treatment suppressed cell proliferation, migration, arrested cell cycle at G0/G1 phase, and induced apoptosis in MCF-7 cells. In vivo experiments also showed that the combination treatment had stronger tumor growth inhibition compared to single treatments with I or sorafenib alone.
PHARMACOLOGICAL RESEARCH
(2022)
Article
Chemistry, Medicinal
Tomohiro Asai, Masafumi Yokota, Hideki Isomura, Hiroyuki Koide, Naoyuki Sakurai, Ayaka Okamoto, Hidenori Ando, Takehisa Dewa, Naoto Oku
Summary: This study explores the synthetic lethal interaction between PTEN loss and PARP1 gene silencing in human triple-negative breast cancer cells. The delivery of siPARP1 using polycation liposomes resulted in cytotoxicity in PTEN-null MDA-MB-468 cells, but not in PTEN-positive MDA-MB-231 cells or normal cells. Simultaneous knockdown of PARP1 and PTEN inhibited cell growth in MDA-MB-231 cells. Furthermore, PARP1 knockdown led to increased DNA breaks and apoptosis in MDA-MB-468 cells compared to MDA-MB-231 cells. These findings suggest that synthetic lethality via PARP1 gene silencing holds promise for the treatment of PTEN-null breast cancer.
JOURNAL OF PHARMACEUTICAL SCIENCES
(2023)
Article
Oncology
Leonie Ratz, Chiara Brambillasca, Leandra Bartke, Maxim A. Huetzen, Jonas Goergens, Orsolya Leidecker, Ron D. Jachimowicz, Marieke van de Ven, Natalie Proost, Bjorn Siteur, Renske de Korte-Grimmerink, Peter Bouwman, Emilia M. Pulver, Roebi de Bruijn, Joerg Isensee, Tim Hucho, Gaurav Pandey, Maarten van Lohuizen, Peter Mallmann, Hans Christian Reinhardt, Jos Jonkers, Julian Puppe
Summary: This study identified the combined inhibition of EZH2 and ATM as a novel synthetic lethality-based therapy for the treatment of BRCA1-mutant breast cancer.
BREAST CANCER RESEARCH
(2022)
Article
Oncology
Manuela Zangrossi, Patrizia Romani, Probir Chakravarty, Colin D. H. Ratcliffe, Steven Hooper, Martina Dori, Mattia Forcato, Silvio Bicciato, Sirio Dupont, Erik Sahai, Marco Montagner
Summary: Many estrogen receptor-positive breast cancer patients experience relapses at the metastatic site even up to 20 years after primary tumor removal, a phenomenon known as metastatic dormancy. The molecule EphB6 has been identified as supporting the survival of disseminated dormant cancer cells, while the TFEB-lysosomal axis plays a crucial role in sustaining the survival of dormant cancer cells.
Article
Biochemistry & Molecular Biology
Hailin Zou, Juan Luo, Yibo Guo, Tongyu Tong, Yuchen Liu, Yun Chen, Yunjun Xiao, Liping Ye, Chengming Zhu, Liang Deng, Bo Wang, Yihang Pan, Peng Li
Summary: The study reveals that SRC regulates cancer stemness and metastasis in triple-negative breast cancer (TNBC) through a YAP1 tyrosine phosphorylation-dependent YAP1-KLF5 oncogenic module. Activation of SRC increases cancer stemness, tumor cell growth, and metastasis, while inhibition of SRC kinase reduces them. The interaction between YAP1 and KLF5, induced by SRC-mediated YAP1 tyrosine phosphorylation, promotes TEAD-mediated transcriptional program independently of canonical Hippo kinases, leading to enhanced cancer stemness and metastasis.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2023)
Article
Medicine, Research & Experimental
Chen Yang, Yuchen Guo, Ruolan Qian, Yiwen Huang, Linmeng Zhang, Jun Wang, Xiaowen Huang, Zhicheng Liu, Wenxin Qin, Cun Wang, Huimin Chen, Xuhui Ma, Dayong Zhang
Summary: Through the analysis of synthetic lethality interactions, potential therapeutic targets in liver cancer were identified, suggesting a novel personalized treatment approach. This may offer more effective treatment options for patients with liver cancer.
Article
Chemistry, Multidisciplinary
Hung-Wei Cheng, Chih-Sheng Chiang, Hsin-Yao Ho, Syun-Hong Chou, Yen-Ho Lai, Woei-Cherng Shyu, San-Yuan Chen
Summary: Precision cancer nanomedicine based on natural therapeutic materials has been developed to tackle serious side effects from chemotherapies. A novel nanomedicine, CuQDA/IO@HA, composed of hyaluronic acid (HA) / copper ion (Cu(II))-chelated dextran-aldehyde (DA)-quercetin (Q) with dual targeting for synthetic lethal therapy, has shown promising results in specifically targeting and inducing cytotoxicity in BRCA-mutant cancer cells.
JOURNAL OF CONTROLLED RELEASE
(2021)
Article
Biochemistry & Molecular Biology
Shams Twafra, Chana G. Sokolik, Tal Sneh, Kolluru D. Srikanth, Tomer Meirson, Alessandro Genna, Jordan H. Chill, Hava Gil-Henn
Summary: The dissemination of cancer cells is a major cause of death in cancer patients, but there is currently no treatment to eradicate metastatic cancer. This study developed a peptide inhibitor that can block the formation and function of invadopodia, reducing the ability of tumor cells to spread and invade. These findings have important implications for the prevention of highly metastatic primary breast tumors and secondary tumors that have already spread to other parts of the body.
Review
Pharmacology & Pharmacy
Kailin Li, Jieqiong You, Qian Wu, Wen Meng, Qiaojun He, Bo Yang, Chengliang Zhu, Ji Cao
Summary: Synthetic lethality is an effective antitumor strategy that has attracted great attention, with CDKs potentially serving as synthetic lethal factors when combined with certain oncogenes. This provides numerous antitumor treatment options and highlights the prospect of CDK inhibitors as antitumor compounds.
ACTA PHARMACEUTICA SINICA B
(2021)
Review
Oncology
Ananna Bhadra Arna, Hardikkumar Patel, Ravi Shankar Singh, Frederick S. Vizeacoumar, Anthony Kusalik, Andrew Freywald, Franco J. Vizeacoumar, Yuliang Wu
Summary: DEAD/H-box helicases play important roles in various aspects of RNA metabolism and their dysregulation is associated with cancer. Synthetic lethality (SL) and synthetic dosage lethality (SDL) approaches, which exploit genetic interactions among cancer-related genes, have shown promise in cancer research. This review analyzes the gene expression of DEAD/H-box helicases in different cancer types and discusses the potential therapeutic applications of their SL/SDL interactions. The latest developments in clinical applications and challenges in targeting DEAD/H-box helicases for drug discovery are also discussed.
FRONTIERS IN ONCOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Timothy G. Strozen, Jessica C. Sharpe, Evelyn D. Harris, Maruti Uppalapati, Behzad M. Toosi
Summary: EphB6, as a pseudokinase, plays a crucial role in expanding the signal repertoire generated by signal transduction systems by modulating the signal output of Eph receptor clusters. Despite the unclear molecular mechanisms of EphB6 function, it remains an active component of Eph receptor signaling by recruiting adaptor proteins to the Eph receptor cluster.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Oncology
Colm J. Ryan, Ishan Mehta, Narod Kebabci, David J. Adams
Summary: Synthetic lethal interactions, especially between paralogs, can be exploited for cancer targeted therapeutics development and existing small-molecule drugs may also target multiple paralogs simultaneously. The identification of these interactions is crucial for drug development.
Article
Oncology
Craig Davison, Roisin Morelli, Catherine Knowlson, Melanie McKechnie, Robbie Carson, Xanthi Stachtea, Kylie A. McLaughlin, Vivien E. Prise, Kienan Savage, Richard H. Wilson, Karl A. Mulligan, Peter M. Wilson, Robert D. Ladner, Melissa J. LaBonte
Summary: dUTPase has been identified as a critical factor in maintaining stability of tumor DNA, inhibition of dUTPase can increase sensitivity of TNBC cells to chemotherapy drugs, leading to cell death and reduced proliferation.
Article
Oncology
Sayem Miah, Edward Bagu, Raghuveera Goel, Yetunde Ogunbolude, Chenlu Dai, Alison Ward, Frederick S. Vizeacoumar, Gerald Davies, Franco J. Vizeacoumar, Deborah Anderson, Kiven Erique Lukong
Review
Biochemistry & Molecular Biology
Chelsea E. Cunningham, Mackenzie J. MacAuley, Garima Yadav, Frederick S. Vizeacoumar, Andrew Freywald, Franco J. Vizeacoumar
PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY
(2019)
Review
Oncology
Chelsea E. Cunningham, Mackenzie J. MacAuley, Frederick S. Vizeacoumar, Omar Abuhussein, Andrew Freywald, Franco J. Vizeacoumar
Article
Biochemistry & Molecular Biology
Lai Wong, Frederick S. Vizeacoumar, Franco J. Vizeacoumar, Linda Chelico
Summary: The study characterizes APOBEC1 and its potential role in cancer, suggesting that RPA may act as a defense against off-target deamination for certain APOBEC enzymes. The data supports a model where the competition between APOBEC and RPA can better predict genomic damage compared to mRNA expression levels and mutation signature analysis in tumors.
NUCLEIC ACIDS RESEARCH
(2021)
Review
Oncology
Kalpana K. Bhanumathy, Amrutha Balagopal, Frederick S. Vizeacoumar, Franco J. Vizeacoumar, Andrew Freywald, Vincenzo Giambra
Summary: Protein phosphorylation is a key regulatory mechanism controlling cellular responses, catalysed by members of the protein kinase superfamily. Tyrosine kinases have been extensively studied for their roles in human malignancies, leading to the development of targeted therapies. Various tyrosine kinases, both receptor and nonreceptor types, play critical roles in the pathogenesis and drug resistance of leukemia, highlighting their potential as therapeutic targets.
Article
Multidisciplinary Sciences
Frederick S. Vizeacoumar, Hongyu Guo, Lynn Dwernychuk, Adnan Zaidi, Andrew Freywald, Fang-Xiang Wu, Franco J. Vizeacoumar, Shahid Ahmed
Summary: This study identified leading differentially expressed genes in GE cancers that can potentially serve as biomarkers. By constructing a co-expression network and performing complex network analysis, the importance of these genes as biomarkers was confirmed.
SCIENTIFIC REPORTS
(2021)
Article
Infectious Diseases
Simon X. M. Dong, Frederick S. Vizeacoumar, Kalpana K. Bhanumathy, Nezeka Alli, Cristina Gonzalez-Lopez, Niranjala Gajanayaka, Ramon Caballero, Hamza Ali, Andrew Freywald, Edana Cassol, Jonathan B. Angel, Franco J. Vizeacoumar, Ashok Kumar
Summary: This study identified novel gene targets that induce apoptosis in HIV-infected macrophages, highlighting the potential of these targets for eliminating HIV-infected macrophages and reservoirs. The results suggest that targeting respiratory chain complex II and IV genes may selectively induce apoptosis of HIV-infected macrophages through enhanced ROS production, providing a potential strategy for HIV cure.
BMC INFECTIOUS DISEASES
(2021)
Article
Multidisciplinary Sciences
Shawn C. Chafe, Frederick S. Vizeacoumar, Geetha Venkateswaran, Oksana Nemirovsky, Shannon Awrey, Wells S. Brown, Paul C. McDonald, Fabrizio Carta, Andrew Metcalfe, Joanna M. Karasinska, Ling Huang, Senthil K. Muthuswamy, David F. Schaeffer, Daniel J. Renouf, Claudiu T. Supuran, Franco J. Vizeacoumar, Shoukat Dedhar
Summary: The study identified a redox homeostasis network involving the iron-sulfur cluster enzyme NFS1 in the survival mechanisms governed by the tumor hypoxia-induced pH regulator CAIX. Targeting CAIX while depleting NFS1 or blocking cyst(e)ine availability enhanced ferroptosis and inhibited tumor growth significantly. Altering intracellular pH and iron homeostasis through inhibiting CAIX activity may lead to the development of innovative therapeutic strategies for solid tumors to overcome hypoxia- and acidosis-mediated tumor progression and therapeutic resistance.
Article
Biochemistry & Molecular Biology
Zahra Sepehri, Archana Banerjee, Frederick S. Vizeacoumar, Andrew Freywald, Franco J. Vizeacoumar, Vernon W. Dolinsky, James R. Davie
Summary: HNF1A-AS1 is a long non-coding RNA expressed in multiple types of cancer and associated with poor clinical prognosis and oncogenic properties. This study reveals the epigenetic features of HNF1A gene locus in colorectal cancer cells and suggests that HNF1A-AS1 may contribute to oncogenic properties by interacting with specific proteins and forming RNA-DNA triplexes.
Article
Cell Biology
Shubham Dwivedi, Maricris Bautista, Sanskriti Shrestha, Hussain Elhasasna, Tanaya Chaphekar, Frederick S. Vizeacoumar, Anand Krishnan
Summary: Peripheral nerves may promote the progression of neuroendocrine prostate cancer, and high concentrations of the sympathetic neurotransmitter norepinephrine can induce neuroendocrine differentiation in prostate cancer cells, which can be effectively inhibited by medication.
CELL DEATH DISCOVERY
(2021)
Article
Cell Biology
Hussain Elhasasna, Raymond Khan, Kalpana K. Bhanumathy, Frederick S. Vizeacoumar, Prachi Walke, Maricris Bautista, Dinesh K. Dahiya, Vincent Maranda, Hardikkumar Patel, Amrutha Balagopal, Nezeka Alli, Anand Krishnan, Andrew Freywald, Franco J. Vizeacoumar
Summary: Neuroendocrine prostate cancer (NEPC) is a highly aggressive form of prostate tumors and often occurs as an adaptive response to androgen deprivation therapy. Overexpression of MYCN oncogene and loss of TP53 and RB1 activities are associated with NEPC. Fludarabine phosphate has been identified as a drug that can selectively inhibit the proliferation of N-MYC overexpressing NEPC cells by inducing reactive oxygen species (ROS).
Article
Oncology
Terra G. Arnason, Valerie MacDonald-Dickinson, Matthew Casey Gaunt, Gerald F. Davies, Liubov Lobanova, Brett Trost, Zoe E. Gillespie, Matthew Waldner, Paige Baldwin, Devon Borrowman, Hailey Marwood, Frederick S. Vizeacoumar, Franco J. Vizeacoumar, Christopher H. Eskiw, Anthony Kusalik, Troy A. A. Harkness
Summary: The insulin sensitizer, metformin, reduces drug resistance markers in canines with lymphoma and activates the Anaphase Promoting Complex (APC), suggesting its potential as a treatment for multiple drug resistant cancers. Cell lines selected for resistance to chemotherapeutic drugs showed that APC activation restored chemosensitivity and improved survival. These findings provide insights into the mechanisms of multiple drug resistance and suggest a potential therapeutic strategy for overcoming drug resistance in cancer.
Article
Oncology
Amr El Zawily, Frederick S. Vizeacoumar, Renuka Dahiya, Sara L. Banerjee, Kalpana K. Bhanumathy, Hussain Elhasasna, Glinton Hanover, Jessica C. Sharpe, Malkon G. Sanchez, Paul Greidanus, R. Greg Stacey, Kyung-Mee Moon, Ilya Alexandrov, Juha P. Himanen, Dimitar B. Nikolov, Humphrey Fonge, Aaron P. White, Leonard J. Foster, Bingcheng Wang, Behzad M. Toosi, Nicolas Bisson, Tajib A. Mirzabekov, Franco J. Vizeacoumar, Andrew Freywald
Summary: This study presents and validates a multipronged unbiased strategy for predicting optimal co-targets for bispecific therapeutics. EGFR and EPHA2 tyrosine kinase receptors are identified as the best fit co-targets for multiple tumor types. Furthermore, a new bispecific anti-EGFR/EPHA2 antibody is developed and shown to effectively suppress tumor growth compared to existing therapeutic antibodies.
CLINICAL CANCER RESEARCH
(2023)
Article
Cell Biology
Glinton Hanover, Frederick S. Vizeacoumar, Sara L. Banerjee, Raveena Nair, Renuka Dahiya, Ana I. Osornio-Hernandez, Alain Morejon Morales, Tanya Freywald, Juha P. Himanen, Behzad M. Toosi, Nicolas Bisson, Franco J. Vizeacoumar, Andrew Freywald
Summary: Eph receptors and ephrin ligands are considered promising targets for cancer treatment. However, their context-dependent functionalities hinder the targeting approach. To overcome this, we investigate the molecular landscapes of Ephs and ephrins and construct a cancer-related network of genetic interactions (GIs) to aid therapeutic manipulation. Our study highlights the involvement of EPHB6 in EGFR signaling and suggests the potential benefit of targeting EPHB6 in EGFR-dependent tumors.
Review
Oncology
Sreejit Parameswaran, Deeksha Kundapur, Frederick S. Vizeacoumar, Andrew Freywald, Maruti Uppalapati, Franco J. Vizeacoumar