Repurposing AZD5438 and Dabrafenib for Cisplatin-Induced
Acute Kidney Injury
by Chithra K. Pushpan, Daniel F. Kresock, Matthew A. Ingersoll, Richard D. Lutze,
Darby L. Keirns, William J. Hunter, Khalid Bashir, Tal Teitz
Cisplatin is an effective chemotherapy agent for a wide variety of solid tumors, but its use is dose-limited by serious side effects including acute kidney injury (AKI) and hearing loss. There are no FDA-approved drugs to treat both side effects. Recently, two anti-cancer oral drugs, AZD5438 and dabrafenib, were identified as protective against cisplatin-induced hearing loss in mice. We hypothesize that similar cell stress and death pathways are activated in kidney and inner ear cells when exposed to cisplatin, and tested whether these drugs alleviate cisplatin-induced AKI…
Dabrafenib protects from cisplatin-induced hearing loss in a clinically relevant mouse model
by Matthew A. Ingersoll*, Richard D. Lutze*, Chithra K. Pushpan, Regina G. Kelmann, Huizhan Liu, Mark T. May, William J. Hunter, David Z.Z. He, and Tal Teitz
*Equal contribution
The widely used chemotherapy cisplatin causes permanent hearing loss in 40-60% of cancer patients. One drug, sodium thiosulfate, is approved by the FDA for use in pediatric patients with localized solid tumors for preventing cisplatin-induced hearing loss, but more drugs…
In Silico Transcriptome-based Screens Identify Epidermal Growth Factor Receptor Inhibitors as Therapeutics for Noise-induced Hearing Loss
by Sarath Vijayakumar, Joe A. DiGuiseppi, Jila Dabestani, William G. Ryan, Rene Vielman Quevedo, Yuju Li, Jack Diers, Shu Tu, Jonathan Fleegel, Cassidy Nguyen, Lauren M. Rhoda, Ali Sajid Imami, Abdul-Rizaq Ali Hamoud, Sándor Lovas, Robert McCullumsmith, Marisa Zallocchi, Jian Zuo
Noise-Induced Hearing Loss (NIHL) represents a widespread disease for which no therapeutics have been approved by the Food and Drug Administration (FDA). Addressing the conspicuous void of efficacious in vitro or animal models for high throughput pharmacological screening, we utilized an in silico transcriptome-oriented drug screening strategy, unveiling 22 biological pathways and 64 promising small molecule candidates for NIHL protection….
ERK1/2 Inhibition Alleviates Noise-Induced Hearing Loss While Tempering Down the Immune Response
by Richard D. Lutze, Matthew A. Ingersoll, Alena Thotam, Anjali Joseph, Joshua Fernandes, Tal Teitz
Noise-induced hearing loss (NIHL) is a major cause of hearing impairment, yet no FDA-approved drugs exist to prevent it. Targeting the mitogen activated protein kinase (MAPK) cellular pathway has emerged as a promising approach to attenuate NIHL. Tizaterkib is an orally bioavailable, highly specific ERK1/2 inhibitor…
KSR1 knockout mouse model demonstrates MAPK pathway’s key role in cisplatin- and noise-induced hearing loss
by Matthew A. Ingersoll, Richard D. Lutze, Regina G. Kelmann, Daniel F. Kresock, Jordan D. Marsh, Rene V. Quevedo, Jian Zuo, and Tal Teitz
Hearing loss is a major disability in everyday life and therapeutic interventions to protect hearing would benefit a large portion of the world population. Here we found that mice devoid of the protein kinase suppressor of RAS 1 (KSR1) in their tissues (germline KO mice) exhibit resistance to both cisplatin- and noise-induced permanent hearing loss…
AZD5438-PROTAC: A selective CDK2 degrader that protects against cisplatin- and noise-induced hearing loss
by Santanu Hati*, Marisa Zallocchi*, Robert Hazlitt, Yuju Li, Sarath Vijayakumar, Jaeki Min, Zoran Rankovic, Sándor Lovas, Jian Zuo
*Equal contribution
Cyclin-dependent kinase 2 (CDK2) is a potential therapeutic target for the treatment of hearing loss and cancer. Previously, we identified AZD5438 and AT7519-7 as potent inhibitors of CDK2, however, they also targeted additional kinases,…
In silico transcriptomics identifies FDA-approved drugs and biological pathways for protection against cisplatin-induced hearing loss
by Pezhman Salehi*, Marisa Zallocchi*, Sarath Vijayakumar, Madeleine Urbanek, Kimberlee P. Giffen, Yuju Li, Santanu Hati, Jian Zuo
*Equal contribution
Acquired hearing loss is a major health problem that affects 5-10% of the world population. However, there are no FDA-approved drugs for the treatment or prevention
of hearing loss. Employing the Connectivity Map (CMap) that contains >54,000 compounds, we performed an unbiased in silico screen using the transcriptomic profiles
of cisplatin-resistant and -sensitive cancer cell lines….
Characterization of quinoxaline derivatives for protection against iatrogenically induced hearing loss
by Marisa Zallocchi, Santanu Hati, Zhenhang Xu, William Hausman, Huizhan Liu, David Z He, Jian Zuo
Hair cell loss is the leading cause of hearing and balance disorders in humans. It can be caused by many factors, including noise, aging, and therapeutic agents. Previous studies have shown the therapeutic potential of quinoxaline against drug-induced ototoxicity. Here, we screened a library of 68 quinoxaline derivatives for protection against aminoglycoside-induced damage…
BRAF inhibition protects against hearing loss in mice
by Matthew A. Ingersoll, Emma A. Malloy, Lauryn E. Caster, Eva M. Holland, Zhenhang Xu, Marisa Zallocchi, Duane Currier, Huizhan Liu, David Z.Z. He, Jaeki Min, Taosheng Chen, Jian Zuo, Tal Teitz*
Hearing loss caused by noise, aging, antibiotics, and chemotherapy affects 10% of the world population, yet there are no Food and Drug Administration (FDA)-approved drugs to prevent it. Here, we screened 162 small-molecule …
Supplementary Materials for BRAF inhibition protects against hearing loss in mice
by Matthew A. Ingersoll, Emma A. Malloy, Lauryn E. Caster, Eva M. Holland, Zhenhang Xu, Marisa Zallocchi, Duane Currier, Huizhan Liu, David Z.Z. He, Jaeki Min, Taosheng Chen, Jian Zuo, Tal Teitz*
Figures S1 – S8 and Table S1
Aggressive Childhood Neuroblastomas do not express caspase-8
by Dr Tal Teitz and Dr Vincent Kidd
Neuroblastomas that overexpress N-Myc due to amplification of the MYCN oncogene are aggressive tumors that become very resistant to treatment by chemotherapy and irradiation. to identify tumor suppressor genes in this …
Development of Second-Generation CDK2 Inhibitors for the Prevention of Cisplatin-Induced Hearing Loss
by Robert A. Hazlitt Tal Teitz, Justine D. Bonga , Jie Fang , Shiyong Diao, Luigi Iconaru, Lei Yang , Asli N. Goktug , Duane G. Currier, Taosheng Chen, Zoran Rankovic, Jaeki Min, and Jian Zuo
There are currently no FDA-approved therapies to prevent the hearing loss associated with the usage of cisplatin in chemotherapeutic regimens. We recently demonstrated that the pharmacologic inhibition with kenpaullone…
CDK2 inhibitors as candidate therapeutics for cisplatin- and noise-induced hearing loss
by Tal Teitz, Jie Fang, Asli N. Goktug, Justine D. Bonga, Shiyong Diao, Robert A. Hazlitt, Luigi Iconaru, Marie Morfouace, Duane Currier, Yinmei Zhou, Robyn A. Umans, Michael R. Taylor, Cheng Cheng, Jaeki Min, Burgess Freeman,, Junmin Peng, Martine F. Roussel, Richard Kriwacki,R. Kiplin Guy,Taosheng Chen, and Jian Zuo
Hearing loss caused by aging, noise, cisplatin toxicity, or other insults affects 360 million people worldwide, but there are no Food and Drug Administration–approved drugs to prevent or treat it. We screened 4,385…
Common variants in ACYP2 influence susceptibility to
cisplatin-induced hearing lossas
by Heng Xu, Giles W Robinson, Jie Huang, Joshua Yew-Suang Lim, Hui Zhang, Johnnie K Bass, Alberto Broniscer, Murali Chintagumpala, Ute Bartels, Sri Gururangan, Tim Hassall, Michael Fisher, Richard Cohn, Tetsuji Yamashita, Tal Teitz, Jian Zuo, Arzu Onar-Thomas, Amar Gajjar, Clinton F Stewart & Jun J Yang
Taking a genome-wide association study approach, we identified inherited genetic variations in ACYP2 associated with cisplatin-related ototoxicity (rs1872328: P = 3.9 × 10−8, hazard ratio = 4.5) in 238 children with newly diagnosed brain tumors, with independent replication in 68 similarly treated children. The ACYP2 risk variant strongly predisposed these patients to precipitous hearing loss and was related to ototoxicity severity. These results point to new biology underlying the ototoxic effects of platinum agents….