ATR addiction in multiple myeloma: synthetic lethal approaches exploiting established therapies.

ATR addiction in multiple myeloma: synthetic lethal approaches exploiting established therapies. Haematologica. 2019 Nov 14;: Authors: Botrugno OA, Bianchessi S, Zambroni D, Frenquelli M, Belloni D, Bongiovanni L, Girlanda S, Di Terlizzi S, Ferrarini M, Ferrero E, Ponzoni M, Marcatti M, Tonon G Abstract Therapeutic strategies designed to tinker with cancer cell DNA damage response have led to the widespread use of PARP inhibitors for BRCA1/2-mutated cancers. In the haematological cancer multiple myeloma, we sought to identify analogous synthetic lethality mechanisms that could be leveraged upon established cancer treatments. The combination of ATR inhibition using the compound VX-970 with a drug eliciting interstrand cross-links, melphalan, was tested in in vitro, ex vivo, and most notably in vivo models. Cell proliferation, induction of apoptosis, tumor growth and animal survival were assessed. The combination of ATM inhibition with a drug triggering double strand breaks, doxorucibin, was also probed. We found that ATR inhibition is strongly synergistic with melphalan, even in resistant cells. The combination was dramatically effective in targeting myeloma primary patient cells and cell lines reducing cell proliferation and inducing apoptosis. The combination therapy significantly reduced tumor burden and prolonged survival in animal models. Conversely, ATM inhibition only marginally impacted on myeloma cell survival, even in combination with doxorucibi...
Source: Haematologica - Category: Hematology Authors: Tags: Haematologica Source Type: research

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Dependence on the 26S proteasome is an Achilles’ heel for triple-negative breast cancer (TNBC) and multiple myeloma (MM). The therapeutic proteasome inhibitor, bortezomib, successfully targets MM but often leads to drug-resistant disease relapse and fails in breast cancer. Here we show that a 26S proteasome-regulating kinase, DYRK2, is a therapeutic...
Source: Proceedings of the National Academy of Sciences - Category: Science Authors: Tags: Biological Sciences Source Type: research
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Source: Pallimed: A Hospice and Palliative Medicine Blog - Category: Palliative Care Tags: cancer opioids pain rosielle The profession Source Type: blogs
Therapeutic strategies designed to tinker with cancer cell DNA damage response have led to the widespread use of PARP inhibitors for BRCA1/2-mutated cancers. In the hematological cancer multiple myeloma, we sought to identify analogous synthetic lethality mechanisms that could be leveraged upon established cancer treatments. The combination of ATR inhibition with a drug eliciting interstrand cross-links, melphalan, was tested in in vitro, ex vivo, and most notably in vivo models. Cell proliferation, induction of apoptosis, tumor growth and animal survival were assessed.
Source: Clinical Lymphoma, Myeloma and Leukemia - Category: Hematology Authors: Source Type: research
Antonio Lucena-Cacace1, Masayuki Umeda1, Lola E. Navas2,3 and Amancio Carnero2,3* 1Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan 2CIBERONC, ISCIII, Madrid, Spain 3Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío (HUVR), CSIC, Universidad de Sevilla, Sevilla, Spain Glioma Cancer Stem-Like Cells (GSCs) are a small subset of CD133+ cells with self-renewal properties and capable of initiating new tumors contributing to Glioma progression, maintenance, hierarchy, and complexity. GSCs are highly res...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Yi He†, Wenyong Long† and Qing Liu* Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China Super-enhancers (SEs) refer to large clusters of enhancers that drive gene expressions. Recent data has provided novel insights in elucidating the roles of SEs in many diseases, including cancer. Many mechanisms involved in tumorigenesis and progression, ranging from internal gene mutation and rearrangement to external damage and inducement, have been demonstrated to be highly associated with SEs. Moreover, translocation, formation, deletion, or duplication of SEs themselves co...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
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Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
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Source: Cancer Medicine - Category: Cancer & Oncology Authors: Tags: Original Research Source Type: research
Proteasome, the essential giant protease, is the hub of the ubiquitin-proteasome pathway critical for maintaining intracellular proteostasis. Inhibitors of the proteasome cause overload of cells with non-degraded protein debris and activate proapoptotic signaling. The effects are especially dramatic in fast metabolizing cancer cells; hence the proteasome inhibitors are used as anti-cancer drugs. There are two FDA-approved drugs directly blocking the proteasome activity, bortezomib and carfilzomib, and several others are in trials. So far, the high effectiveness of these drugs is limited to multiple myeloma and other hemato...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Poster Session Abstracts Source Type: research
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