Identification of cardiovascular disparities among Black and Hispanic survivors of adolescent and young adult (AYA) lymphoma

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Therapeutic targeting in pediatric acute myeloid leukemia with aberrant HOX/MEIS1 expression

Despite advances in the clinical management of childhood acute myeloid leukemia (AML) during the last decades, outcome remains fatal in approximately one third of patients. Primary chemoresistance, relapse and acute and long-term toxicities to conventional myelosuppressive therapies still constitute significant challenges and emphasize the unmet need for effective targeted therapies. Years of scientific efforts have translated into extensive insights on the heterogeneous spectrum of genetics and oncogenic signaling pathways of AML and identified a subset of patients characterized by upregulation of HOXA and HOXB homeobox genes and myeloid ecotropic virus insertion site 1 (MEIS1). Aberrant HOXA/MEIS1 expression is associated with genotypes such as rearrangements in Histone-lysine N-methyltransferase 2A (KMT2A-r), nucleoporin 98 (NUP98-r) and mutated nucleophosmin (NPM1c) that are found in approximately one third of children with AML. AML with upregulated HOXA/MEIS1 shares a number of molecular vulnerabilities amenable to recently developed molecules targeting the assembly of protein complexes or transcriptional regulators. The interaction between the nuclear scaffold protein menin and KMT2A has gained particular interest and constitutes a molecular dependency for maintenance of the HOXA/MEIS1 transcription program. Menin inhibitors disrupt the menin-KMT2A complex in preclinical models of KMT2A-r, NUP98-r and NPM1c acute leukemias and its occupancy at target genes leading to leukemic cell differentiation and apoptosis. Early-phase clinical trials are either ongoing or in development and preliminary data suggests tolerable toxicities and encouraging efficacy of menin inhibitors in adults with relapsed or refractory KMT2A-r and NPM1c AML. The Pediatric Acute Leukemia/European Pediatric Acute Leukemia (PedAL/EUPAL) project is focused to advance and coordinate informative clinical trials with new agents and constitute an ideal framework for testing of menin inhibitors in pediatric study populations. Menin inhibitors in combination with standard chemotherapy or other targeting agents may enhance anti-leukemic effects and constitute rational treatment strategies for select genotypes of childhood AML, and provide enhanced safety to avoid differentiation syndrome. In this review, we discuss the pathophysiological mechanisms in KMT2A-r, NUP98-r and NPM1c AML, emerging molecules targeting the HOXA/MEIS1 transcription program with menin inhibitors as the most prominent examples and future therapeutic implications of these agents in childhood AML.</p

Preclinical Efficacy of Endoglin-Targeting Antibody–Drug Conjugates for the Treatment of Ewing Sarcoma

[EN] Endoglin (ENG; CD105) is a coreceptor of the TGFb family that is highly expressed in proliferating endothelial cells. Often coopted by cancer cells, ENG can lead to neo-angiogenesis and vasculogenic mimicry in aggressive malignancies. It exists both as a transmembrane cell surface protein, where it primarily interacts with TGFb, and as a soluble matricellular protein (sENG) when cleaved by matrix metal-loproteinase 14 (MMP14). High ENG expression has been associated with poor prognosis in Ewing sarcoma, an aggressive bone cancer that primarily occurs in adolescents and young adults. However, the therapeutic value of ENG targeting has not been fully explored in this disease. Experimental Design: We characterized the expression pattern of transmembrane ENG, sENG, and MMP14 in preclinical and clinical samples. Subsequently, the antineoplastic potential of two novel ENG-targeting monoclonal antibody–drug conjugates (ADC), OMTX503 and OMTX703, which differed only by their drug payload (nigrin-b A chain and cytolysin, respectively), was assessed in cell lines and preclinical animal models of Ewing sarcoma. Results: Both ADCs suppressed cell proliferation in proportion to the endogenous levels of ENG observed in vitro. Moreover, the ADCs significantly delayed tumor growth in Ewing sarcoma cell line–derived xenografts and patient-derived xenografts in a dose-dependent manner. Conclusions: Taken together, these studies demonstrate potent preclinical activity of first-in-class anti-ENG ADCs as a nascent strategy to eradicate Ewing sarcoma

Abstract 5497: Targeting glioblastoma stem cells with withaferin A

Abstract Introduction. Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain cancer affecting 3 to 4 per 100,000 people annually in the United States. Despite aggressive therapy including surgical resection followed by both radiation and chemotherapy, overall survival remains dismal at approximately 14 months. Recent studies have determined that GBM's contain a small population of stem cells (GSCs), which promote tumor growth through unlimited self-renewal. Since GSCs are chemo- and radio-resistant and drive tumor regrowth following therapy, successful treatment depends on the elimination of these cells. Withaferin A (WA) is a bioactive compound derived from the plant Withonia somnifera which possesses anti-inflammatory and anti-cancer properties. Here we evaluated the effects of WA on patient derived GSCs. Methods. With IRB approval, GSC lines were generated. GSCs were propagated in neurosphere media and examined for the stem cell markers CD133, nestin, musashi and BMi1 by immunocytochemistry and western blot analysis. Effect of WA on cell viability was determined using MTS assay. The effect of WA on cell survival and stress pathways was evaluated by western blot analysis. Results. WA induced a significant decrease in cell viability at low micromolar concentrations. The IC50 for 3 patient derived GSC lines ranged between 0.96-1.78μM. WA induced ER stress and apoptosis in the GSCs as indicated by increased expression of ER stress markers grp78 and CHOP and increased levels of cleaved PARP. Furthermore, WA decreased survivin but increased phospho-ERK levels. However, inhibition of ERK activity with U0126 did not potentiate the effect of WA on cell death. Conclusion. Ashwagandha has been used safely for medicinal purposes for centuries and pharmacokinetic studies in mice indicate that micromolar plasma concentrations of WA are obtainable. Our studies indicate that very low concentrations of WA induce ER stress and cell death in GSC lines. Targeting GSC with WA may increase patient survival by hindering GSC mediated tumor regrowth following surgery. Our data demonstrates the efficacy of WA and supports additional studies toward the use of WA as an adjuvant GBM therapy. Citation Format: Baoyu Zhang, Branko Cuglievan, Nadia G. Myrthil, Steven Vanni, Ricardo J. Komotar, Regina M. Graham. Targeting glioblastoma stem cells with withaferin A. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5497. doi:10.1158/1538-7445.AM2014-5497</jats:p

NAMPT Inhibition Induces Neuroblastoma Cell Death and Blocks Tumor Growth

High-risk neuroblastoma (NB) portends very poor prognoses in children. Targeting tumor metabolism has emerged as a novel therapeutic strategy. High levels of nicotinamide-adenine-dinucleotide (NAD+) are required for rapid cell proliferation. Nicotinamide phosphoribosyl transferase (NAMPT) is the rate-limiting enzyme for NAD+ salvage and is overexpressed in several cancers. Here, we determine the potential of NAMPT as a therapeutic target for NB treatment. NAMPT inhibition cytotoxicity was determined by trypan blue exclusion and LDH assays. Neuroblastoma stem cell self-renewal was evaluated by neurosphere assay. Protein expression was evaluated via Western blot. The effect of targeting NAMPT in vivo was determined using an NB1691-xenografted mouse model. Robust NAMPT expression was demonstrated in multiple N-MYC amplified, high-risk neuroblastoma cell lines. NAMPT inhibition with STF-118804 (STF) decreased ATP, induced apoptosis, and reduced NB stem cell neurosphere formation. STF treatment down-regulated N-MYC levels and abrogated AKT activation. AKT and glycolytic pathway inhibitors in combination with NAMPT inhibition induced robust, greater-than-additive neuroblastoma cell death. Lastly, STF treatment blocked neuroblastoma tumor growth in mouse xenograft models. NAMPT is a valid therapeutic target as inhibition promoted neuroblastoma cell death in vitro and prevented tumor growth in vivo . Further investigation is warranted to establish this therapy’s role as an adjunctive modality

Classical Hodgkin Lymphoma: From Past to Future—A Comprehensive Review of Pathophysiology and Therapeutic Advances

Hodgkin lymphoma, a hematological malignancy of lymphoid origin that typically arises from germinal-center B cells, has an excellent overall prognosis. However, the treatment of patients who relapse or develop resistant disease still poses a substantial clinical and research challenge, even though current risk-adapted and response-based treatment techniques produce overall survival rates of over 95%. The appearance of late malignancies after the successful cure of primary or relapsed disease continues to be a major concern, mostly because of high survival rates. Particularly in pediatric HL patients, the chance of developing secondary leukemia is manifold compared to that in the general pediatric population, and the prognosis for patients with secondary leukemia is much worse than that for patients with other hematological malignancies. Therefore, it is crucial to develop clinically useful biomarkers to stratify patients according to their risk of late malignancies and determine which require intense treatment regimens to maintain the ideal balance between maximizing survival rates and avoiding late consequences. In this article, we review HL’s epidemiology, risk factors, staging, molecular and genetic biomarkers, and treatments for children and adults, as well as treatment-related adverse events and the late development of secondary malignancies in patients with the disease

Unmet Clinical Needs and Management Recommendations for Blastic Plasmacytoid Dendritic Cell Neoplasm: A Consensus-based Position Paper From an Ad Hoc International Expert Panel

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a hematological malignancy characterized by recurrent skin nodules, an aggressive clinical course with rapid involvement of hematological organs, and a poor prognosis with overall survival. The rarity of the disease results in a few large-scale studies, a lack of controlled clinical trials for its management, and a lack of evidence-based guidelines. Here, we present a review of unmet clinical needs on the management of BPDCN by a panel of eleven experts involved in the research and clinical practice of BPDCN. Recommendations and proposals were achieved by multiple-step formalized procedures to reach a consensus after a comprehensive analysis of the scientific literature. The panel analyzed the critical issues of diagnostic pathway, prognostic stratification, therapy for young and fit patients and elderly and unfit patients, indication for allotransplant and for autotransplant, indication for central nervous system prophylaxis, and management of pediatric BPDCN patients. For each of these issues, consensus opinions were provided and, when appropriate, proposals for advancement in clinical practice were addressed. The hope is that this comprehensive overview will serve to improve the practice of BPDCN and inform the design and implementation of new studies in the field