Methods for treating breast and other cancers by targeting argininosuccinate synthetase 1-deficiency

Abstract

Autophagy is the principal catabolic response to nutrient starvation. However, excessive autophagy can be cytotoxic or cytostatic, and contribute to cell death, but its mechanism of induction remains elusive. Here, it was demonstrated that prolonged arginine starvation by ADI-PEG20 induced an autophagy-dependent death of argininosuccinate synthetase 1 (ASS1)-deficient breast cancer cells. Consequently, arginine depleting agents such as ADI-PEG20 may be used in methods for killing one or more argininosuccinate synthetase 1 (ASS1)-deficient breast cancer cells. Further, abundance of ASS1 was either low or absent in more than 60% of 149 random breast cancer biosam pies, which could be exploited as candidates for arginine starvation therapy.

1 . A method for killing one or more argininosuccinate synthetase 1 (ASS1)-deficient breast cancer cells, prostate cancer cells, pancreas cancer cells, or urinary bladder cancer cells comprising contacting the one or more ASS1-deficient breast cancer cells, prostate cancer cells, pancreas cancer cells, or urinary bladder cancer cells with an effective amount of an arginine-depleting agent, wherein the arginine depleting agent is selected from the group consisting of arginase I, arginase II, a recombinant arginase I or II, a pegylated arginase I or II, arginine deiminase (ADI), a recombinant ADI (rADI), a pegylated ADI, or a recombinant pegylated ADI. 
     
     
         2 . The method of  claim 1 , wherein said arginine-depleting agent is ADI-PEG20. 
     
     
         3 . The method of  claim 1 , wherein the one or more ASS1-deficient breast cancer cells, prostate cancer cells, pancreas cancer cells, or urinary bladder cancer cells are part of a solid tumor. 
     
     
         4 . The method of  claim 3 , wherein contacting the one or more ASS1-deficient breast cancer cells, prostate cancer cells, pancreas cancer cells, or urinary bladder cancer cells causes regression of the solid tumor. 
     
     
         5 . The method of  claim 1 , wherein arginine-depleting agent is part of a pharmaceutical composition. 
     
     
         6 . A method for treating an arginine-auxotrophic breast cancer, prostate cancer, pancreas cancer, or urinary bladder cancer in a subject com prising
 administering a therapeutically effective amount of a pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises an arginine-depleting agent and a carrier, and wherein the arginine depleting agent is selected from the group consisting of arginase I, arginase II, a recombinant arginase I or II, a pegylated arginase I or II, arginine deiminase (ADI), a recombinant ADI (rADI), a pegylated ADI, or a recombinant pegylated ADI.   
     
     
         7 . The method of  claim 6 , wherein the subject is diagnosed with an arginine-auxotrophic breast cancer, prostate cancer, pancreas cancer, or urinary bladder cancer by detecting a low level of ASS1 expression in a tumor tissue sample obtained from the subject. 
     
     
         8 . The method of  claim 6 , wherein the arginine-depleting agent is ADI-PEG20. 
     
     
         9 . The method of  claim 6 , wherein the method further comprises administering a therapeutically effective amount of an additional anti-cancer treatment in combination with the pharmaceutical composition. 
     
     
         10 . The method of  claim 9 , wherein the additional anti-cancer treatment is doxorubicin. 
     
     
         11 . The method of  claim 9 , wherein the additional anti-cancer treatment is a doxorubicin analog. 
     
     
         12 . The method of  claim 11 , wherein the doxorubicin analog is selected from N-(5,5-Diacetoxypent-1-yl)doxorubicin (1 b), 4′-epidoxorubicin (epi-Dx), 4′-deoxy-doxorubicin (deoxy-Dx), 4′-O′methyldoxorubicin (O-Me-Dx), or N-(trifluoroacetyl) doxorubicin (FDOX). 
     
     
         13 . A method for optimizing treatment of breast cancer, prostate cancer, pancreas cancer, or urinary bladder cancer in a subject comprising
 detecting an expression level of ASS1 in a tumor tissue sample from the subject;   identifying the subject as a responsive subject when the expression level of ASS1 is at or below a low level of ASS1; and   administering a therapeutically effective amount of a pharmaceutical composition to the responsive subject, wherein the pharmaceutical composition comprises an arginine-depleting agent and a carrier, and wherein the arginine depleting agent is selected from the group consisting of arginase I, arginase II, a recombinant arginase I or II, a pegylated arginase I or II, arginine deiminase (ADI), a recombinant ADI (rADI), a pegylated ADI, or a recombinant pegylated ADI.   
     
     
         14 . The method of  claim 13 , wherein the arginine-depleting agent is ADI-PEG20. 
     
     
         15 . The method of  claim 13 , wherein the method further comprises administering a therapeutically effective amount of an additional anti-cancer treatment in combination with the pharmaceutical composition. 
     
     
         16 . The method of  claim 15 , wherein the additional anti-cancer treatment is doxorubicin. 
     
     
         17 . The method of  claim 15 , wherein the additional anti-cancer treatment is a doxorubicin analog. 
     
     
         18 . The method of  claim 17 , wherein the doxorubicin analog is selected from N-(5,5-Diacetoxypent-1-yl)doxorubicin (1b), 4′-epidoxorubicin (epi-Dx), 4′-deoxy-doxorubicin (deoxy-Dx), 4′-O′methyldoxorubicin (O-Me-Dx), or N-(trifluoroacetyl) doxorubicin (FDOX).