Combination Cancer Therapy Using an IL13-Targeted Toxin and an HDAC Inhibitor
Posted Jul 25 2011 8:00pm
Description of Invention: Typical cancer treatments such as chemotherapy, radiation therapy and surgical resection are non-specific processes that kill healthy cells as well as diseased cells, ultimately resulting in discomfort and undesirable side-effects for patients. In an effort to reduce the burden on cancer patients, a tremendous effort has been placed on developing ways to increase the specificity of cancer treatments. One way to increase specificity is to identify proteins which are present on the surface of cancer cells but absent on normal healthy cells, and use that protein as a target for delivering a therapeutic agent. Because the therapeutic agent only reaches the diseased cell, patients are less likely to experience non-specific side-effects, reducing their pain burden during treatment.
IL13-receptor-alpha-2 (IL13-R-alpha-2) is a cell surface protein that is selectively expressed on certain diseased cells, including cancer cells. IL13-R-alpha-2 binds to the cytokine IL13, suggesting that a therapeutic agent fused to IL13 can target and kill only those cancer cells which express IL13-R-alpha-2. Our inventors previously constructed fusion proteins comprising (1) IL13 and (2) an active fragment of the bacterial toxin Pseudomonas exotoxin A (PE). These IL13-PE fusion proteins demonstrated the ability to selectively kill cancer cells that overexpressed IL13-R-alpha-2, as well as other types of diseased cells (asthma, pulmonary fibrosis) which overexpressed IL13-R-alpha-2. This suggested that IL13-PE fusion proteins were excellent candidates for new therapeutic agents.
In an effort to increase the effectiveness of these IL13-PE fusion proteins, the inventors sought ways to increase the expression of IL13-R-alpha-2 on cancer cells, thereby increasing the rate at which the therapeutic agent could kill the diseased cell. Histone deacetylase (HDAC) inhibitors have been employed as anti-cancer agents for several years, and a number of HDAC inhibitors are currently in clinical trials. Although the exact mechanism by which HDAC inhibitors function is unclear, it is believed that the ability of these molecules to increase the expression of anti-cancer genes is behind their therapeutic effect.
This invention concerns a means of improving specific cancer therapy through the combination of (a) IL13-PE fusion proteins and (b) HDAC inhibitors. The inventors surprisingly found that the expression of IL13-R-alpha-2 increased in several types of pancreatic cancer cells in response to HDAC inhibitors, whereas normal, healthy cells did not experience such an increase in IL13-R-alpha-2 expression. The use of IL13-PE fusion proteins in combination with HDAC inhibitors improved specific killing of pancreatic cancer cells relative to the use of IL13-PE fusion proteins in the absence of the HDAC inhibitors. This suggested that the use of IL13-PE fusion proteins along with HDAC inhibitors was a strong candidate combinatorial therapeutic for the treatment of various cancers (e.g., pancreatic, glioblastoma multiforme) and other diseases characterized by overexpression of IL13-R-alpha-2 (e.g., asthma, pulmonary fibrosis).
Treatment of diseases associated with the increased expression of IL13-R-alpha-2.
Relevant diseases include pulmonary fibrosis, asthma and cancers such as pancreatic cancer, glioblastoma multiforme and other head and neck cancers.
HDAC inhibitors only increased IL13-R-alpha-2 expression in diseased cells, leaving normal healthy cells unaltered.
IL13-PE fusion proteins only kill cells that overexpress IL13-R-alpha-2, allowing specific targeting of treatment.
Targeted treatment decreases non-specific killing of healthy, essential cells, resulting in fewer side-effects and healthier patients.
Development Status: Preclinical stage of development.
For more information, see:
HHS Reference No. E-266-1994/0 — US Patents 5,614,191, 5,919,456 and 6,518,061
HHS Reference No. E-032-2000/0 — US Patent Publication US 20040136959 A1
HHS Reference No. E-296-2001/0 — US Patent 7,541,040
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