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Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and the second most common form of acute leukemia in children. Despite this, very little improvement in survival rates has been achieved over the past few decades. This is partially due to the heterogeneity of AML and the need for more targeted therapeutics than the traditional cytotoxic chemotherapies that have been a mainstay in therapy for the past 50 years. In the past 20 years, research has been diversifying the approach to treating AML by investigating molecular pathways uniquely relevant to AML cell proliferation and survival. Here we review the development of novel therapeutics in targeting apoptosis, receptor tyrosine kinase (RTK) signaling, hedgehog (HH) pathway, mitochondrial function, DNA repair, and c-Myc signaling. There has been an impressive effort into better understanding the diversity of AML cell characteristics and here we highlight important preclinical studies that have supported therapeutic development and continue to promote new ways to target AML cells. In addition, we describe clinical investigations that have led to FDA approval of new targeted AML therapies and ongoing clinical trials of novel therapies targeting AML survival pathways. We also describe the complexity of targeting leukemia stem cells (LSCs) as an approach to addressing relapse and remission in AML and targetable pathways that are unique to LSC survival. This comprehensive review details what we currently understand about the signaling pathways that support AML cell survival and the exceptional ways in which we disrupt them.

Acute myeloid leukemia (AML) remains a challenging disease to treat and urgently requires new therapies to improve its treatment outcome. In this study, we investigated the molecular mechanisms underlying the cooperative antileukemic activities of panobinostat and cytarabine or daunorubicin (DNR) in AML cell lines and diagnostic blast samples in vitro and in vivo. Panobinostat suppressed expression of BRCA1, CHK1, and RAD51 in AML cells in a dose-dependent manner. Further, panobinostat significantly increased cytarabine- or DNR-induced DNA double-strand breaks and apoptosis, and abrogated S and/or G2/M cell cycle checkpoints. Analogous results were obtained by shRNA knockdown of BRCA1, CHK1, or RAD51. Cotreatment of NOD-SCID-IL2Rγ(null) mice bearing AML xenografts with panobinostat and cytarabine significantly increased survival compared to either cytarabine or panobinostat treatment alone. Additional studies revealed that panobinostat suppressed the expression of BRCA1, CHK1, and RAD51 through downregulation of E2F1 transcription factor. Our results establish a novel mechanism underlying the cooperative antileukemic activities of these drug combinations in which panobinostat suppresses expression of BRCA1, CHK1, and RAD51 to enhance cytarabine and daunorubicin sensitivities in AML cells.

Pancreatic cancer is a highly malignant disease with an extremely poor prognosis. Histone deacetylase inhibitors (HDACIs) have shown promising antitumor activities against preclinical models of pancreatic cancer, either alone or in combination with chemotherapeutic agents. In this study, we sought to identify clinically relevant histone deacetylases (HDACs) to guide the selection of HDAC inhibitors (HDACIs) tailored to the treatment of pancreatic cancer. HDAC expression in seven pancreatic cancer cell lines and normal human pancreatic ductal epithelial cells was determined by Western blotting. Antitumor interactions between class I- and class II-selective HDACIs were determined by MTT assays and standard isobologram/CompuSyn software analyses. The effects of HDACIs on cell death, apoptosis and cell cycle progression, and histone H4, alpha-tubulin, p21, and γH2AX levels were determined by colony formation assays, flow cytometry analysis, and Western blotting, respectively. The majority of classes I and II HDACs were detected in the pancreatic cancer cell lines, albeit at variable levels. Treatments with MGCD0103 (a class I-selective HDACI) resulted in dose-dependent growth arrest, cell death/apoptosis, and cell cycle arrest in G2/M phase, accompanied by induction of p21 and DNA double-strand breaks (DSBs). In contrast, MC1568 (a class IIa-selective HDACI) or Tubastatin A (a HDAC6-selective inhibitor) showed minimal effects. When combined simultaneously, MC1568 significantly enhanced MGCD0103-induced growth arrest, cell death/apoptosis, and G2/M cell cycle arrest, while Tubastatin A only synergistically enhanced MGCD0103-induced growth arrest. Although MC1568 or Tubastatin A alone had no obvious effects on DNA DSBs and p21 expression, their combination with MGCD0103 resulted in cooperative induction of p21 in the cells. Our results suggest that classes I and II HDACs are potential therapeutic targets for treating pancreatic cancer. Accordingly, treating pancreatic cancer with pan-HDACIs may be more beneficial than class- or isoform-selective inhibitors.

Background Venetoclax + azacitidine is a frontline treatment for older adult acute myeloid leukemia (AML) patients and a salvage therapy for relapsed/refractory patients who have been treated with intensive chemotherapy. While this is an important treatment option, many patients fail to achieve complete remission and of those that do, majority relapse. Leukemia stem cells (LSCs) are believed to be responsible for AML relapse and can be targeted through oxidative phosphorylation reduction. We previously reported that ONC213 disrupts oxidative phosphorylation and decreases Mcl-1 protein, which play a key role in venetoclax resistance. Here we investigated the antileukemic activity and underlying molecular mechanism of the combination of ONC213 + venetoclax against AML cells. Methods Flow cytometry was used to determine drug-induced apoptosis. Protein level changes were determined by western blot. An AML cell line-derived xenograft mouse model was used to determine the effects of ONC213 + venetoclax on survival. A patient-derived xenograft (PDX) mouse model was used to determine drug effects on CD45+/CD34+/CD38-/CD123 + cells. Colony formation assays were used to assess drug effects on AML progenitor cells. Mcl-1 and Bax/Bak knockdown and Mcl-1 overexpression were used to confirm their role in the mechanism of action. The effect of ONC213 + venetoclax on mitochondrial respiration was determined using a Seahorse bioanalyzer. Results ONC213 + venetoclax synergistically kills AML cells, including those resistant to venetoclax alone as well as venetoclax + azacitidine. The combination significantly reduced colony formation capacity of primary AML progenitors compared to the control and either treatment alone. Further, the combination prolonged survival in an AML cell line-derived xenograft model and significantly decreased LSCs in an AML PDX model. Conclusions ONC213 can resensitize VEN + AZA-resistant AML cells to venetoclax therapy and target LSCs ex vivo and in vivo.

Venetoclax, an FDA-approved Bcl-2 selective inhibitor for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia (AML), is tolerated well in elderly patients with AML and has good overall response rates; however, resistance remains a concern. In this study, we show that targeting CDK9 with voruciclib in combination with venetoclax results in synergistic antileukemic activity against AML cell lines and primary patient samples. CDK9 inhibition enhances venetoclax activity through downregulation of Mcl-1 and c-Myc. However, downregulation of Mcl-1 is transient, which necessitates an intermittent treatment schedule to allow for repeated downregulation of Mcl-1. Accordingly, an every other day schedule of the CDK9 inhibitor is effective in vitro and in vivo in enhancing the efficacy of venetoclax. Our preclinical data provide a rationale for an intermittent drug administration schedule for the clinical evaluation of the combination treatment for AML.

About 25% of patients with acute myeloid leukemia (AML) harbor FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations and their prognosis remains poor. Gilteritinib is a FLT3 inhibitor approved by the US FDA for use in adult FLT3-mutated relapsed or refractory AML patients. Monotherapy, while efficacious, shows short-lived responses, highlighting the need for combination therapies. Here we show that gilteritinib and CUDC-907, a dual inhibitor of PI3K and histone deacetylases, synergistically induce apoptosis in FLT3-ITD AML cell lines and primary patient samples and have striking in vivo efficacy. Upregulation of FLT3 and activation of ERK are mechanisms of resistance to gilteritinib, while activation of JAK2/STAT5 is a mechanism of resistance to CUDC-907. Gilteritinib and CUDC-907 reciprocally overcome these mechanisms of resistance. In addition, the combined treatment results in cooperative downregulation of cellular metabolites and persisting antileukemic effects. CUDC-907 plus gilteritinib shows synergistic antileukemic activity against FLT3-ITD AML in vitro and in vivo, demonstrating strong translational therapeutic potential.

Detailed diagnostic features of acute myeloid leukemia in Down syndrome are lacking, leading to potential misdiagnoses as standard acute myeloid leukemia occurring in patients with Down syndrome. To evaluate diagnostic features of acute myeloid leukemia and myelodysplastic syndrome in patients with Down syndrome. Diagnostic bone marrow samples from 163 patients enrolled in the Children's Oncology Group study AAML0431 were evaluated by using central morphologic review and institutional immunophenotyping. Results were compared to overall survival, event-free survival, mutation status, cytogenetics, and minimal residual disease results. Sixty myelodysplastic syndrome and 103 acute myeloid leukemia samples were reviewed. Both had distinctive features compared to those of patients without Down syndrome. They showed megakaryocytic and erythroid but little myeloid dysplasia, and marked megakaryocytic hyperplasia with unusual megakaryocyte morphology. In acute myeloid leukemia cases, megakaryoblastic differentiation of blasts was most common (54 of 103, 52%); other cases showed erythroblastic (11 of 103, 11%), mixed erythroid/megakaryoblastic (20 of 103, 19%), or no differentiation (10 of 103, 10%). Myelodysplastic syndrome and acute myeloid leukemia cases had similar event-free survival and overall survival. Leukemic subgroups showed interesting, but not statistically significant, trends for survival and minimal residual disease. Cases with institutional diagnoses of French American British M1-5 morphology showed typical features of Down syndrome disease, with survival approaching that of other cases. Myelodysplastic syndrome and acute myeloid leukemia in Down syndrome display features that allow discrimination from standard cases of disease. These distinctions are important for treatment decisions, and for understanding disease pathogenesis. We propose specific diagnostic criteria for Down syndrome-related subtypes of acute myeloid leukemia and myelodysplastic syndrome.

High-risk neuroblastoma remains a therapeutic challenge with a long-term survival rate of less than 40%. Therefore, new agents are urgently needed to overcome chemotherapy resistance so as to improve the treatment outcome of this deadly disease. Histone deacetylase (HDAC) inhibitors (HDACIs) represent a novel class of anticancer drugs. Recent studies demonstrated that HDACIs can down-regulate the CHK1 pathway by which cancer cells can develop resistance to conventional chemotherapy drugs. This prompted our hypothesis that combining HDACIs with DNA damaging chemotherapeutic drugs for treating neuroblastoma would result in enhanced anti-tumor activities of these drugs. Treatment of high-risk neuroblastoma cell lines with a novel pan-HDACI, panobinostat (LBH589), resulted in dose-dependent growth arrest and apoptosis in 4 high-risk neuroblastoma cell lines. Further, the combination of panobinostat with cisplatin, doxorubicin, or etoposide resulted in highly synergistic antitumor interactions in the high-risk neuroblastoma cell lines, independent of the sequence of drug administration. This was accompanied by cooperative induction of apoptosis. Furthermore, panobinostat treatment resulted in substantial down-regulation of CHK1 and its downstream pathway and abrogation of the G2 cell cycle checkpoint. Synergistic antitumor interactions were also observed when the DNA damaging agents were combined with a CHK1-specific inhibitor, LY2603618. Contrary to panobinostat treatment, LY2603618 treatments neither resulted in abrogation of the G2 cell cycle checkpoint nor enhanced cisplatin, doxorubicin, or etoposide-induced apoptosis in the high-risk neuroblastoma cells. Surprisingly, LY2603618 treatments caused substantial down-regulation of total CDK1. Despite this discrepancy between panobinostat and LY2603618, our results indicate that suppression of the CHK1 pathway by panobinostat is at least partially responsible for the synergistic antitumor interactions between panobinostat and the DNA damaging agents in high-risk neuroblastoma cells. The results of this study provide a rationale for clinical evaluation of the combination of panobinostat and cisplatin, doxorubicin, or etoposide for treating children with high-risk neuroblastoma.

Chromosomal analysis demonstrated 46,XX,der(21)t(8;21)(q22;q22)ins(5;21)(q12q21;q22) [20], and fluorescence in situ hybridization (FISH) analysis demonstrated RUNX1–RUNX1T1/t(8;21) variant gene fusion in 98.5% of cells and gain of chromosome 15q24 in 7% of cells. A repeat PET scan performed after the induction I cycle demonstrated improved appearance of the breast masses with decreasing FDG tracer uptake overall, focal area of soft tissue thickening in the left chest wall was no longer evident and improved subcarinal adenopathy (Figure 1). There is no consensus about the optimal treatment of MS. High-dose chemotherapy, radiation, surgical resection, and allogeneic stem cell transplantation are all modalities that can be incorporated into the therapy of MS [ 1, 27].

FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (FLT3-ITD) mutations occur in about 25% of all acute myeloid leukemia (AML) patients and confer a poor prognosis. FLT3 inhibitors have been developed to treat patients with FLT3-mutated AML and have shown promise, though the acquisition of resistance occurs, highlighting the need for combination therapies to prolong the response to FLT3 inhibitors. In this study, we investigated the selective Mcl-1 inhibitor AZD5991 in combination with the FLT3 inhibitors gilteritinib and MRX-2843. The combinations synergistically induce apoptosis in AML cell lines and primary patient samples. The FLT3 inhibitors downregulate c-Myc transcripts through the suppression of the MEK/ERK and JAK2/STAT5 pathways, resulting in the decrease in c-Myc protein. This suppression of c-Myc plays an important role in the antileukemic activity of AZD5991. Interestingly, the suppression of c-Myc enhances AZD5991-inudced cytochrome c release and the subsequent induction of apoptosis. AZD5991 enhances the antileukemic activity of the FLT3 inhibitors gilteritinib and MRX-2843 against FLT3-mutated AML in vitro, warranting further development.