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Feature

A novel therapeutic candidate for the treatment of lymphomas and other cancers

Posted on: 21 Feb 06
A novel therapeutic candidate for the treatment of lymphomas and other cancers

Summary

Today's edition of DailyUpdates features work conducted by Imperial College researchers who have identified an aptamer able to reduce the proliferation of lymphoma cells by 40%. This work represents a licensing opportunity. The aptamer is of potential therapeutic use and may be of interest to companies with an interest in biologic approach to oncology. The aptamers also forms the basis of a HTS assay that should help identify small molecule therapeutics for the treatment of hematological cancers

Today's edition of DailyUpdates features work conducted by Imperial College researchers who have identified an aptamer able to reduce the proliferation of lymphoma cells by 40%. This work represents a licensing opportunity. The aptamer is of potential therapeutic use and may be of interest to companies with an interest in biologic approach to oncology. The aptamers also forms the basis of a HTS assay that should help identify small molecule therapeutics for the treatment of hematological cancers as well as breast and maybe pancreatic cancer.


Lymphoma is the fifth most common cancer in the US and represents over forty subtypes of cancers arising within the lymphatic system. The most prevalent type is non-Hodgkin's lymphoma (NHL) which accounted for 88% of the 63,700 estimated new cases of lymphoma diagnosed in the US in 2005, making this the most common hematological cancer. The incidence of NHL has increased, nearly doubling over the past 30 years, faster than any other type of cancer.


NHL can result from malignancies of either T- or B-cells however most are of the latter. B-cell NHLs can be further sub-divided according to stage of differentiation of cells from which they are derived. Large cell B-cell lymphoma tumors are amongst the most common accounting for 30% of newly diagnosed cases and emerge from either germinal center B-cells or activated B-cells.


Disease can be divided into two groups based on prognostic factors of tumor growth; indolent and aggressive. Large cell B-cell lymphomas are the most common malignancies found in patients presenting with aggressive disease. In this group, doxorubicin (Adriamycin)-based combination chemotherapy is the primary clinical approach and produces long-term disease-free survival in 35% to 45% of patients. The CHOP (cyclophosphamide, Adriamycin, vincristine, prednisone) regimen was among the first combinations to produce complete response rates and long-term survival. More recently, the addition of Rituxan to the CHOP regimen has been shown to increase the likelihood of a complete-response by 20% without a significant rise in the risk of a serious adverse event and this is now the standard regimen for newly diagnosed patients with diffuse large B-cell lymphoma.


Although NHL is highly treatable, significant unmet needs exist. Addressing these needs will in part involve the better definition of the various NHL subtypes, particularly with respect to molecular etiology. This should allow more targeted approaches which will in turn lead to a reduced rate of relapse and hopefully extended survival.


Targeting BAFF/APRIL is one highly promising approach to NHL as well as multiple myeloma. This target was recently evaluated in our report BAFF & APRIL: Emerging Targets for autoimmune disease & Cancer Therapeutics - Proof of concept, indications and development activity. Here we focus on another promising molecular target, BCL-6.


BCL-6 is a transcription factor which is normally expressed at high levels in lymph node germinal centers. Germinal centers are found in splenic or lymph node follicle and is the site where activated B-cells mature into memory and plasma cells. This reaction is important for immune memory and for the production of antibodies to pathogen however germinal center B-cells are also thought to be involved in the pathogenesis of most types of human B-cell malignancies. Targeting BCL-6 may therefore be a rational approach to both types of condition.


The BCL-6 gene was originally cloned from chromosomal translocations in diffuse large-cell lymphoma, and is expressed in other lymphoproliferative disorders. Approximately 40% of diffuse large cell lymphomas and 5-10% of follicular lymphomas are associated with chromosomal translocations that deregulate expression of BCL6 by juxtaposing heterologous promoters to the BCL-6 coding domain.


BCL-6 is a repressor of transcription that limits B-cell differentiation and cell death. Repression is quite specific, a selectivity afforded by its POZ domain and mediated by the recruitment of histone deacetylases (see Histone deacetylase inhibitors-Moving from the bench to a promising companion for classic and targeted cancer therapies for an overview of histone deactylases).


Inhibiting BCL-6 may therefore offer a novel approach to the treatment of lymphomas and other hematological malignancies. Here, we highlight a recent study published by Chattopadhyay et al in the journal, Oncogene that identifies a peptide aptamer targeted towards BCL-6.


LeadDiscovery

Last updated on: 27/08/2010 11:40:18

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