A growing body of research highlights the role of histone deacetylases (HDAC) in regulating gene expression, particularly the expression of cancer-related genes.
HDAC inhibitors represent a new mechanistic class of anti-cancer therapeutics that target HDAC enzymes, and have been shown to: arrest growth of cancer cells (including drug resistant subtypes); induce apoptosis, or programmed cell death; promote differentiation; inhibit angiogenesis; and sensitise cancer cells to overcome drug resistance phenotype when used in combination with other anti-cancer agents.
HDAC inhibitors are believed to play a role in a wide range of solid tumours, such as breast, colon, lung and ovarian cancers, and haematological malignancies, such as lymphoma, leukaemia and myeloma.
Presenting at the American Society of Haematology (ASH) Annual Meeting in Atlanta, Georgia, the companies presented preliminary results on 16 patients, which showed that PXD101 is well tolerated following intravenous administration demonstrating potential anti-tumour activity against multiple myeloma, non-Hodgkin's lymphoma (NHL) and transformed chronic lymphocytic leukemia (CLL).
The Phase I clinical findings, plus results from preclinical studies evaluating PXD101 activity on a number of haematologic and multi-drug resistant cancer cell lines found the drug to be generally well-tolerated with the most common adverse events being fatigue, nausea and vomiting, consistent with what has been seen in a larger parallel Phase I study for patients with solid tumours.
Two patients with multiple myeloma developed an acute decrease in renal function concomitant with decrease in tumour burden, consistent with possible tumour lysis syndrome, an indication of potential clinical activity.
In addition, it was reported that one patient with NHL had stable disease for five cycles and one patient with transformed CLL had stable disease for nine cycles.
"These results formed the basis for our ongoing Phase II clinical trial, which is currently evaluating PXD101 for the treatment of advanced multiple myeloma. We anticipate that preliminary results from this Phase II study will be available by mid-2006," said Timothy Shannon, Executive Vice President of Research and Development and Chief Medical Officer at CuraGen.
In a second presentation, the University of Pittsburgh reported additional preclinical data on PXD101 in multiple myeloma.
The results showed that PXD101 monotherapy had antiproliferative activity on myeloma cells and inhibited osteoclast formation. Furthermore, synergistic activity was observed when PXD101 was combined with Velcade in antiproliferative and osteoclast formation in vitro assays, and this drug combination strongly inhibited myeloma tumour growth in an animal model.
These preclinical data support the evaluation of PXD101 as monotherapy and in combination with Velcade in clinical trials of patients with multiple myeloma.
The exponential growth in the level of research activity surrounding the histone deacetylases (HDACs) witnessed over the past decade has been driven by the ability of HDAC inhibitors to modulate transcriptional activity.
As a result, this therapeutic class is able to block angiogenesis and cell cycling, and promote apoptosis and differentiation. By targeting these key components of tumour proliferation, HDAC inhibitors have the potential to occupy a strong position in the fast-moving cytostatic market.
Two reasons why HDAC inhibitors could play such a key role in this $2 billion (€1.7 billion) market are they are able to improve the efficacy of existing cytostatics (such as the retinoids) and they are able to target the transcription of specific disease-causing genes, opening therapeutic opportunities to cancer therapy.