Tuesday, February 21, 2006

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

DailyUpdates 21th February: Regular visitors to this forum would have already realized that we don't post entries every day. Even though we try do so it is simply not possible with the work load imposed by our DailyUpdates service from which content on the forum is derived. Please feel free to register to our DailyUpdates service to keep up to date which breaking news & journal articles from the drug development sector (through today's edition if you wish).

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.

Peptide aptamers are synthetic recognition molecules whose design was inspired by the structure of antibodies. They consist of a variable peptide loop attached at both ends to a protein scaffold (see inset after Aptanomics). This double structural constraint greatly increases the binding affinity of the peptide aptamer to levels comparable to an antibody's (nanomolar range). One advantage of aptamers is that they can be designed to target a peptide domain in the context of a specific protein. The highlighted Oncogene study screened 250,000 peptide aptamers and identified one, Apt48, that binds to BCL-6 POZ but not POZ domains of related proteins.

Further study demonstrated that Apt48 relieved the repression of BCL-6 target genes and restored the ability of IL-2 and IL-5 to block the proliferation of BCL-6 overexpressing cells. Perhaps most dramatic was the observation that Apt48 was able to reduce the proliferation of BCL-6 overexpressing lymphoma cells by 40%.

The highlighted study suggests that aptamers targeted against BCL-6 offer a highly attractive approach to lymphoma and other malignancies associated with BCL-6 overexpression. Further in vivo studies that demonstrate the efficacy of systemically administered aptamers or even cell therapy approaches that promote expression of Apt48 are eagerly awaited.

Although the study highlights the potential of Apt48 in the treatment of lymphomas, Bos et al, 2003 and Logarajah et al, 2003 have both suggested that BCL-6 plays a role in high grade breast cancer. Likewise in 2004 Holzmann et al, reported that BCL-6 was overexpressed in pancreatic cancer extending the potential indications of Apt48.

While the present study suggests that Apt48 may have therapeutic potential it also forms the basis of an HTS assay being developed by the authors for the identification of small molecule inhibitors of the Bcl-6 POZ domain. Molecules would be identified on the basis of their ability to compete with Apt48 for binding to the Bcl-6 POZ domain.

This work represents a licensing opportunity and interested parties should contact Dr Simon Wagner at simon.wagner@imperial.ac.uk


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