Available Technology

Synergy of ABT-737 with an Immunotoxin to Kill Cancer Cells

Programmed cell death (i.e., apoptosis) represents an attractive approach for treating cancer. However, anti-apoptotic proteins that are frequently active in cancer cells can allow the cells to survive induction of apoptosis. While inhibiting anti-apoptotic proteins has shown promise in combination with apoptosis-inducing treatments, current inhibitors only show incomplete effectiveness in promoting the induction of apoptosis.

ABT-737 is one such inhibitor; it can only inhibit the function of three of the four major anti-apoptosis proteins. The fourth member, known as a MCL1, is a short-lived protein that can still prevent apoptosis in the presence of ABT-737. Importantly, because MCL1 is a short-lived protein, it requires protein synthesis to maintain levels that are sufficient to continue blocking apoptosis.

This technology uses a combination approach in the treatment of cancer. The inventors considered that combining ABT-737 with a protein synthesis inhibitor might completely inhibit anti-apoptotic proteins, leading to efficient induction of apoptosis. Specifically, NIH inventors found that combining ABT-737 and immunotoxins did result in enhanced killing of cancer cells. Because immunotoxins function by inhibiting protein synthesis, the two agents in combination are able to inhibit all of the anti-apoptotic proteins simultaneously. Furthermore, immunotoxins can be specifically targeted to cancers cells, thereby increasing their effectiveness over a non-specific protein synthesis inhibitor. The results suggest that the combination could represent an effective approach to enhancing the induction of apoptosis as an anti-cancer therapy.

Patent Abstract: 

Programmed cell death (i.e., apoptosis) represents an attractive approach for treating cancer. However, anti-apoptotic proteins that are frequently active in cancer cells can allow the cells to survive induction of apoptosis. While inhibiting anti-apoptotic proteins has shown promise in combination with apoptosis-inducing treatments, current inhibitors only show incomplete effectiveness in promoting the induction of apoptosis.

ABT-737 is one such inhibitor; it can only inhibit the function of three of the four major anti-apoptosis proteins. The fourth member, known as a MCL1, is a short-lived protein that can still prevent apoptosis in the presence of ABT-737. Importantly, because MCL1 is a short-lived protein, it requires protein synthesis to maintain levels that are sufficient to continue blocking apoptosis.

This technology uses a combination approach in the treatment of cancer. The inventors considered that combining ABT-737 with a protein synthesis inhibitor might completely inhibit anti-apoptotic proteins, leading to efficient induction of apoptosis. Specifically, NIH inventors found that combining ABT-737 and immunotoxins did result in enhanced killing of cancer cells. Because immunotoxins function by inhibiting protein synthesis, the two agents in combination are able to inhibit all of the anti-apoptotic proteins simultaneously. Furthermore, immunotoxins can be specifically targeted to cancers cells, thereby increasing their effectiveness over a non-specific protein synthesis inhibitor. The results suggest that the combination could represent an effective approach to enhancing the induction of apoptosis as an anti-cancer therapy.

Benefits 
Overcomes the anti-apoptotic proteins frequently associated with inducing apoptosis, thereby leading to an effective therapeutic approach -Synergistic effect improves toxicity of both the apoptosis-inducing agents and immunotoxins -Selective inhibition of protein synthesis by immunotoxins increases effectiveness versus using non-specific inhibitors
Inventors: 

David Fitzgerald

Patent Number: 
61238,032 PCT Application No. PCTUS2010046382 U
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