Emerging evidence suggests that histone deacetylase inhibitors (HDACi) play a significant role in cancer treatment by allowing for the expression of a tumor suppressant gene. However, the inventors have discovered that HDACi also up-regulates the expression of Bcl2 protein, which leads to resistance to chemotherapy in almost every tumor model. Therefore, HDACi treatment has been limited in its ability to treat solid tumors. This technology aims at combining HDACi with Bcl2 inhibitors, to provide treatment for solid tumors.
• Cancer Therapeutics
Features, Benefits, and Advantages:
Histone deacetylase inhibitors (HDACi) such as Vorinostat (SAHA), Panabinostat and Trichostatin A epigenetically modify histones by deacetylation and decrease the access of transcription factors to the promoter region of the responsive genes. Emerging evidences suggest that HDACi play a major role in cancer treatment. For example, SAHA and depsipeptide were approved by the FDA for the treatment of refractory cutaneous T-cell lymphoma. However, HDACi have only modest activity against solid tumors such as pancreatic cancer. In the present invention, it was found that HDACi (SAHA, Panabinostat, Trichostatin A) drastically up regulate Bcl2 expression (>100 fold) in the pancreatic tumor cells. Bcl2 is an anti-apoptotic protein, overexpression of which lead to resistance to chemotherapy in almost every tumor model. It was also found that the transcription factors such as NF-kB, STAT3 and Sp1 play a significant role in the up regulation of Bcl2. Experimental evidence has shown that combining Bcl2, STAT3, NF-kB, Sp1 or CD44 inhibitors along with HDACi significantly suppress the growth of pancreatic tumor cells.
• Better treatment of solid malignancies
• More effective than HDACi alone for treatment of solid tumors
This technology has been reduced to practice.