Potent anti ‐myeloma activity of the TOPK inhibitor OTS514 in pre‐clinical models

In this report, we demonstrate potent anti‐myeloma effects of the TOPK inhibitor OTS514 for the fir st time. OTS514 induces cell cycle arrest and apoptosis at nanomolar concentrations in a series of human myeloma cell lines (HMCL) and prevents outgrowth of a putative CD138+ stem cell population from MM patient ‐derived peripheral blood mononuclear cells. In bone marrow cells from MM patients, OTS514 treatment exhibited preferential killing of the malignant CD138+ plasma cells compared with the CD138− compartment. In an aggressive mouse xenograft model, OTS964 given orally at 100  mg/kg 5 days per week was well tolerated and reduced tumor size by 48%‐81% compared to control depending on the initial graft size. FOXO3 and its transcriptional targetsCDKN1A (p21) andCDKN1B (p27) were elevated and apoptosis was induced with OTS514 treatment of HMCLs. TOPK inhibition also induced loss of FOXM1 and disrupted AKT, p38 MAPK, and NF ‐κB signaling. The effects of OTS514 were independent of p53 mutation or deletion status. Combination treatment of HMCLs with OTS514 and lenalidomide produced synergistic effects, providing a rationale for the evaluation of TOPK inhibition in existing myeloma treatment regimens.
Source: Cancer Medicine - Category: Cancer & Oncology Authors: Tags: ORIGINAL ARTICLE Source Type: research

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This study evaluated year ‐to‐year changes in treatment choices in a cohort of patients aged 66 or older in the Surveillance, Epidemiology, and End Results (SEER)‐Medicare registry diagnosed with MM between 2007 and 2011. We found that while the usage of PIs among elderly MM patients increased significantly replacing I MiD‐based regimens (with or without alkylating agents but not with PI) between 2007 and 2011, this significant shift did not increase the proportion of treated patients. AbstractThe landscape of treatment for  multiple myeloma (MM) has significantly changed over the last decade due to&...
Source: Cancer Medicine - Category: Cancer & Oncology Authors: Tags: ORIGINAL RESEARCH Source Type: research
Multiple myeloma is a type of blood cancer. It accounts for approximately 2% of all cancers and is still considered incurable. For people with newly diagnosed multiple myeloma (NDMM), who are unsuitable for a procedure where damaged blood cells are replaced with healthy ones (stem-cell transplant), treatment is usually a multiple drug combination of bortezomib, lenalidomide, or thalidomide, plus melphalan and prednisolone (MP) or dexamethasone (D). Multiple drug combinations are approved for initial anti-myeloma therapy, however, access to these medicines is restricted in many countries worldwide.The Cochrane Review used n...
Source: Cochrane News and Events - Category: Information Technology Authors: Source Type: news
AbstractNovel anti-myeloma drugs have significantly improved the overall survival (OS) of patients with multiple myeloma (MM). However, not all MM patients treated with these drugs show survival benefits, and biologic and genetic prognostic factors are insufficient to predict the response to treatment. Decreasing treatment-related complications is important to improve the efficacy of treatment in patients with MM. The Controlling Nutritional Status (CONUT) score is a screening method for poor nutritional status, which is associated with poor prognosis in several cancers because it increases the rate of treatment-related co...
Source: Annals of Hematology - Category: Hematology Source Type: research
In this study, around 20% of all patients with HBV reactivation developed HBV reactivation after 2 years from the initiation of therapy, unlike malignant lymphoma. This might be due to the fact that almost all of the patients received chemotherapy for a long duration. Therefore, a new strategy for the prevention of HBV reactivation in MM patients is required.
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
This article discusses the historic context of HDM-ASCT, the modern role of HDM-ASCT given the availability of highly sensitive MRD testing, and the likely future of quadruplet treatment. In summary, patients who attain deep responses using IMiD- and PI-based regimens may not require early HDM-ASCT. A delayed approach to this treatment is acceptable, and might be preferred by patients. PMID: 31730582 [PubMed - in process]
Source: Clinical Advances in Hematology and Oncology - Category: Cancer & Oncology Tags: Clin Adv Hematol Oncol Source Type: research
ConclusionsThese data demonstrate that a transplantation protocol involving only selective tumor-reactive donor T cell families is an effective immunotherapy and results in long-term survival in a mouse model of human MM. The results highlight the need to develop similar ATCT strategies for MM patients that result in enhanced survival without symptoms of GvHD.
Source: Journal for Immunotherapy of Cancer - Category: Cancer & Oncology Source Type: research
We describe three clinical scenarios in which CAR T- cell immunotherapy interfered with HIV-1 testing including: (1) routine infectious disease screening prior to stem cell transplantation in a 16-year-old female with B-cell acute lymphoblastic leukemia, status post CAR T- cell treatment (2) routine infectious disease screening prior to 2nd CAR T- cell collection in a 65-year-old male with diffuse large B-cell lymphoma who failed initial CAR T- cell treatment and (3) routine infectious risk assessment following an occupational health exposure from a 58 -year-old male with multiple myeloma, status post CAR T- cell treatment...
Source: Clinical Lymphoma and Myeloma - Category: Cancer & Oncology Authors: Tags: J Clin Microbiol Source Type: research
Three researchers at the  Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have received awards totaling more than $18 million from the California Institute for Regenerative Medicine, the state’s stem cell agency. The recipients areDr. Sophie Deng, professor of ophthalmology at the UCLA Stein Eye Institute;  Yvonne Chen, a UCLA associate professor of microbiology, immunology and molecular genetics; andDr. Caroline Kuo, a UCLA assistant clinical professor of pediatrics. The awards were announced at a CIRM meeting today.Deng ’s four-year, $10.3 million award ...
Source: UCLA Newsroom: Health Sciences - Category: Universities & Medical Training Source Type: news
Contributor : Fenghuang ZhanSeries Type : Expression profiling by arrayOrganism : Homo sapiensAnalysis of sorted SP/LC population and a CD138+ main population cells. Results provide insight into which gene is involed in the drug resistance and tumor growth enriches for cancer stem-like cells.Keywords: multiple myeloma, cancer stem cell
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by array Homo sapiens Source Type: research
Abstract The progression of multiple myeloma (MM), a hematologic malignancy characterized by unregulated plasma cell growth, is associated with increasing innate and adaptive immune system dysfunction, notably in the T-cell repertoire. Although treatment advances in MM have led to deeper and more durable clinical responses, the disease remains incurable for most patients. Therapeutic strategies aimed at overcoming the immunosuppressive tumor microenvironment and activating the host immune system have recently shown promise in MM, particularly in the relapsed and/or refractory disease setting. As the efficacy of T-...
Source: Clinical Cancer Research - Category: Cancer & Oncology Authors: Tags: Clin Cancer Res Source Type: research
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