Emerging Therapeutic Targets in Diffuse Large B-Cell Lymphoma

Janakiram, Murali; Thirukonda, Venu K.; Sullivan, Matthew R.; Petrich, Adam M.

doi:10.1007/s11864-011-0178-9

Cited by 5 publications

(4 citation statements)

References 113 publications

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“…There are a significant percentage of patients with DLBCL who fail conventional therapy, and the number of ongoing clinical trials attest to the search for novel-targeted agents tailored towards specific molecules or pathways. 75 One example is the promising use of PIM2 inhibitors, which act on cytokine pathways (IL2, IL6) and the JAK-STAT pathway. 6 Finding the ‘Achilles heel’ of DLBCL will require case selection based on gene expression, cytokine and signal transduction pathways among others.…”

Section: Discussionmentioning

confidence: 99%

Aggressive B-cell lymphomas: how many categories do we need?

Said

2013

Modern Pathology

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Aggressive B-cell lymphomas are diverse group of neoplasms that arise at different stages of B-cell development and by various mechanisms of neoplastic transformation. The aggressive B-cell lymphomas include many types, subtypes and variants of diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), mantle cell lymphoma and its blastoid variant, and B lymphoblastic lymphoma. Differences in histology, cytogenetic and molecular abnormalities, as well as the relationship with the tumor microenvironment, help define characteristic signatures for these neoplasms, and in turn dictate potential therapeutic targets. Rather than survey the entire spectrum of aggressive B-cell lymphomas, this report aims to identify and characterize important clinically aggressive subtypes of DLBCL, and explore the relationship of DLBCL to BL and the gray zone between them (B-cell lymphoma unclassifiable with features intermediate between DLBCL and BL).

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Section: Discussionmentioning

confidence: 99%

Aggressive B-cell lymphomas: how many categories do we need?

Said

2013

Modern Pathology

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“…80 mTOR inhibitors are currently being studied as an alternative therapeutic approach in the treatment of myeloid malignancies, including MDS. 81…”

Section: Novel Therapiesmentioning

confidence: 99%

Current Current and novel therapeutic approaches in myelodysplastic syndromes

Estephan

Tiu

2014

JCSO

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Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic neoplasms with an annual incidence of 4.1 cases per 100,000 Americans. Patients with MDS suffer from chronic cytopenias that may lead to recurrent transfusions, infections, and increased risk for bleeding. They are also at risk for progression to acute myeloid leukemia. Allogeneic hematopoietic cell transplantation is the only potentially curative treatment for MDS, although 3 drugs have been approved by the US Food and Drug Administration for its treatment: lenalidomide, 5-azacitidine, and decitabine. These therapies can be effective in the relief of cytopenias, achievement of cytogenetic remissions, and reduction in bone marrow blasts. 5-azacitidine has also been shown to improve overall survival. However, there remain many unmet needs in the treatment of MDS. Breakthroughs in our understanding of the complex pathogenesis of MDS through epigenetic, genetic, immunologic, and other biological mechanisms have allowed us to develop new therapeutic strategies that can lead to improvements in outcomes in MDS. In this review, we aim to provide an overview of the evolution in classifcation and risk stratifcation in MDS and to illustrate how we can use this to guide us in tailoring therapeutic choices in this disease. Responses and outcomes related to com monly used MDS therapies will be discussed together with novel therapies that have evolved with the improved understanding of MDS pathophysiology.

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“…Unfortunately, NCT 00809185 which was meant to evaluate everolimus in MDS was terminated due to slow accrual. Despite this initial set back, with results of many studies yet to be presented, the role of mTOR inhibition could still hold promise in MDS [48]. …”

Section: Reviewmentioning

confidence: 99%

Signal transduction inhibitors in treatment of myelodysplastic syndromes

et al. 2013

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Myelodysplastic syndromes (MDS) are a group of hematologic disorders characterized by ineffective hematopoiesis that results in reduced blood counts. Although MDS can transform into leukemia, most of the morbidity experienced by these patients is due to chronically low blood counts. Conventional cytotoxic agents used to treat MDS have yielded some encouraging results but are characterized by many adverse effects in the predominantly elderly patient population. Targeted interventions aimed at reversing the bone marrow failure and increasing the peripheral blood counts would be advantageous in this cohort of patients. Studies have demonstrated over-activated signaling of myelo-suppressive cytokines such as TGF-β, TNF-α and Interferons in MDS hematopoietic stem cells. Targeting these signaling cascades could be potentially therapeutic in MDS. The p38 MAP kinase pathway, which is constitutively activated in MDS, is an example of cytokine stimulated kinase that promotes aberrant apoptosis of stem and progenitor cells in MDS. ARRY-614 and SCIO-469 are p38 MAPK inhibitors that have been used in clinical trials and have shown activity in a subset of MDS patients. TGF-β signaling has been therapeutically targeted by small molecule inhibitor of the TGF-β receptor kinase, LY-2157299, with encouraging preclinical results. Apart from TGF-β receptor kinase inhibition, members of TGF-β super family and BMP ligands have also been targeted by ligand trap compounds like Sotatercept (ACE-011) and ACE-536. The multikinase inhibitor, ON-01910.Na (Rigosertib) has demonstrated early signs of efficacy in reducing the percentage of leukemic blasts and is in advanced stages of clinical testing. Temsirolimus, Deforolimus and other mTOR inhibitors are being tested in clinical trials and have shown preclinical efficacy in CMML. EGF receptor inhibitors, Erlotinib and Gefitinib have shown efficacy in small trials that may be related to off target effects. Cell cycle regulator inhibitors such as Farnesyl transferase inhibitors (Tipifarnib, Lonafarnib) and MEK inhibitor (GSK1120212) have shown acceptable toxicity profiles in small studies and efforts are underway to select mutational subgroups of MDS and AML that may benefit from these inhibitors. Altogether, these studies show that targeting various signal transduction pathways that regulate hematopoiesis offers promising therapeutic potential in this disease. Future studies in combination with high resolution correlative studies will clarify the subgroup specific efficacies of these agents.

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Emerging Therapeutic Targets in Diffuse Large B-Cell Lymphoma

Cited by 5 publications

References 113 publications

Aggressive B-cell lymphomas: how many categories do we need?

Aggressive B-cell lymphomas: how many categories do we need?

Current Current and novel therapeutic approaches in myelodysplastic syndromes

Signal transduction inhibitors in treatment of myelodysplastic syndromes

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