Utilizing Synergistic Potential of Mitochondria-Targeting Drugs for Leukemia Therapy

Acute myeloid leukemia (AML) is an aggressive group of cancers with high mortality rates and significant relapse risks. Current treatments are insufficient, and new therapies are needed. Recent discoveries suggest that AML may be particularly sensitive to chemotherapeutics that target mitochondria. To further investigate this sensitivity, six compounds that target mitochondria [IACS-010759, rotenone, cytarabine, etoposide, ABT-199 (venetoclax), and carbonyl cyanide m-chlorophenylhydrazone] were each paired with six compounds with other activities, including tyrosine kinase inhibitors (midostaurin and dasatinib), glycolytic inhibitors (2-deoxy-D-glucose, 3-bromopyruvate, and lonidamine), and the microtubule destabilizer vinorelbine. The 36 resulting drug combinations were tested for synergistic cytotoxicity against MOLM-13 and OCI-AML2 AML cell lines. Four combinations (IACS-010759 with vinorelbine, rotenone with 2-deoxy-D-glucose, carbonyl cyanide m-chlorophenylhydrazone with dasatinib, and venetoclax with lonidamine) showed synergistic cytotoxicity in both AML cell lines and were selective for tumor cells, as survival of healthy PBMCs was dramatically higher. Among these drug pairs, IACS-010759/vinorelbine decreased ATP level and impaired mitochondrial respiration and coupling efficiency most profoundly. Some of these four treatments were also effective in K-562, KU812 (chronic myelogenous leukemia) and CCRF-CEM, MOLT-4 (acute lymphoblastic leukemia) cells, suggesting that t...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research

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T cell cancer neoantigens are created from peptides derived from cancer-specific aberrant proteins, such as mutated and fusion proteins, presented in complex with human leukocyte antigens on the cancer cell surface. Because expression of the aberrant target protein is exclusive to malignant cells, immunotherapy directed against neoantigens should avoid “on-target, off-tumor” toxicity. The efficacy of neoantigen vaccines in melanoma and glioblastoma and of adoptive transfer of neoantigen-specific T cells in epithelial tumors indicates that neoantigens are valid therapeutic targets. Improvements in sequencing tec...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
Conclusion: The cumulative incidence of malnutrition in Finnish pediatric cancer patients is comparable to that reported in other populations. The nutritional status of patients with acute myeloid leukemia, CNS tumors, or solid tumors should be monitored with extra care to facilitate early intervention in the case of impending malnutrition.What is known:•Both malnutrition and obesity are associated with reduced survival and increased drug toxicity in pediatric cancer patients.What is new:•Overall, 28 % of Finnish children receiving chemotherapy for cancer suffer from malnutrition during the first 42 months follow...
Source: European Journal of Pediatrics - Category: Pediatrics Source Type: research
Conclusions The discovery of JAK2V617F mutation in BCR-ABL1-negative MPNs by four different international cooperative groups in 2005 (2–5) led to significant insights on the pathogenesis of these disorders. In fact, this mutation results in a gain-of-function with activation of cytokine and growth factor receptors, and thus of the downstream JAK-STAT pathway (79, 95–98). The JAK2 point mutation in exon 12, present in a small percentage of patients with PV, is able to induce the MPN phenotype through the same pathogenic mechanism (6, 7). In 2006 the MPLW515L/K was reported in ET and PMF patients (44, 45) and d...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
This study proposed a pilot study of a new tool for a reliable and accurate stratification of patients with acute leukemia based on an integrative model of leukemia behavior, cell characterization, and clinical features, in addition, to an evaluation of intra-tumor and inter-tumor heterogeneity. Together our approach allows us to introduce an integrative quantitative approach to use zebrafish and tumor characterization as a prediction tool for the behavior of acute leukemia in young adults. Materials and Methods Animal Care and Handling Zebrafish wild-type (A/B and TAB5) adults were raised and maintained according to st...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
CONCLUSION: This analysis may provide a useful tool for the discrepant pathogenesis and drug design of different types of leukemia. PMID: 30599106 [PubMed - as supplied by publisher]
Source: Combinatorial Chemistry and High Throughput Screening - Category: Chemistry Authors: Tags: Comb Chem High Throughput Screen Source Type: research
Children and adolescents with leukemia are potentially at a high risk of developing vitamin D deficiency, due to limited physical activity and sunlight exposure, poor nutrition, chemotherapy, and its complications. The prevalence of vitamin D inadequacy in European pediatric cancer patients has been reported to be high. It is not known how many patients already have vitamin D deficiency at the time of diagnosis and whether vitamin D status at the time of diagnosis influences clinical outcome.We aimed to investigate vitamin D status in children with leukemia at the time of diagnosis and explore possible factors (age, type o...
Source: Blood - Category: Hematology Authors: Tags: 612. Acute Lymphoblastic Leukemia: Clinical Studies: Poster III Source Type: research
Background: Various pro-inflammatory and stress-related stimuli activate p38 mitogen-activated protein kinase (p38MAPK), triggering cascades of cell proliferation, differentiation, and apoptosis signaling. We have previously found that inflammatory cytokines promote growth and survival in primary cells from acute myeloid leukemia (AML) patients. The downstream mediator of inflammatory pathways is p38MAPK, and blocking this regulator with kinase inhibitors abrogates inflammation signaling in AML cells.Methods: We used a functional ex vivo screening assay to identify small-molecule targeted inhibitors and inhibitor combinati...
Source: Blood - Category: Hematology Authors: Tags: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Poster II Source Type: research
Conclusion: Both myeloid and lymphoid-derived primary leukemia cells show sensitivity to combined inhibition of BCL2 and BTK with the combination of venetoclax and ibrutinib, suggesting this drug pair may have broad therapeutic indications.DisclosuresTyner: Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Constellation: Research Funding; Janssen: Research Funding; AstraZeneca: Research Funding; Incyte: Research Funding; Array: Research Funding; Aptose: Research Funding. Danilov: TG Therapeutics: Consultan...
Source: Blood - Category: Hematology Authors: Tags: 802. Chemical Biology and Experimental Therapeutics: New Targeted Therapies and Drug Development Source Type: research
Exposure to ionizing radiation is a well-established risk of cancer development. Atomic bomb (A-bomb) survivors were exposed to A-bomb radiation, then developed acute myeloid leukemia (AML), acute lymphoblastic leukemia, and chronic myeloid leukemia with the highest incidence around five to ten years after the bombing. On the other hand, the risk of myelodysplastic syndromes (MDS) were significantly high among the survivors even after 40 to 60 years from the bombing (Iwanaga et al. J Clin Oncol 2011), indicating a long-lasting influence of A-bomb radiation on human hematopoiesis. In general, genetic mutations are found in ...
Source: Blood - Category: Hematology Authors: Tags: 636. Myelodysplastic Syndromes-Basic and Translational Studies: Poster III Source Type: research
IntroductionAdvances in clinical practice for allogeneic hematopoietic cell transplantation (HCT), a potentially curative treatment most frequently indicated for hematologic malignancies, have led to substantial improvements in prognosis. HCT survivors are at risk for a number of post-transplant complications, including the development of new malignancies. Although cutaneous melanoma risk is known to be increased after HCT, no previous study has comprehensively investigated risk factors in order to identify patients at highest risk for melanoma development. The purpose of this study was to identify risk factors for develop...
Source: Blood - Category: Hematology Authors: Tags: 723. Clinical Allogeneic and Autologous Transplantation: Late Complications and Approaches to Disease Recurrence: HSCT Late Effects and Disease Monitoring Source Type: research
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