Compositions and methods for treating cancer and modulating stress granule formation

Abstract

The invention provides methods for treating or decreasing the likelihood of developing a stress-granule related disorder and/or cancer by administering one or more poly-ADP-ribose polymerase (PARP) inhibitors, one or more PARP activators, one or more poly-ADP-ribose glycosylase (PARG) activators, and/or one or more poly-ADP-ribose glycohydrolase ARH3 activators. The invention also provides corresponding methods of decreasing stress granule formation and/or proliferation in a cell or a population of cells. The invention further provides methods of increasing the number of stress granules and proliferation in a cell or a population of cells by administering one or more PARP activators, one or more PARP inhibitors, one or more PARG inhibitors, and/or one or more ARH3 inhibitors. The invention also provides methods for screening for agents for treating or decreasing the likelihood of developing a stress granule-related disorder or cancer, and methods for determining the propensity for developing a stress granule-related disorder or cancer, as well as compositions and kits containing one or more PARP inhibitors, one or more PARP activators, one or more PARG activators, and one or more ARH3 activators.

1 . A method of treating or decreasing the likelihood of developing cancer in a subject comprising administering to said subject a therapeutically effective amount of one or more poly-ADP-ribose polymerase (PARP) inhibitor(s). 
     
     
         2 . The method of  claim 1 , wherein said one or more PARP inhibitor(s) selectively decrease the expression and/or one or more activities of one or more PARP(s) selected from the group consisting of PARP1, PARP2, PARP5A, PARP5B, PARP7, PARP8, PARP14, and PARP16. 
     
     
         3 . The method of  claim 2 , wherein said decrease in expression is a decrease in the level of one or more nucleic acid(s) comprising a nucleic acid sequence having at least 95% sequence identity to PARP1 (SEQ ID NO: 1 or 2), PARP2 (SEQ ID NO: 3), PARP5A (SEQ ID NO: 8 or 9), PARP5B (SEQ ID NO: 10), PARP7 (SEQ ID NO: 12), PARP8 (SEQ ID NO: 13), PARP14 (SEQ ID NO: 21), or PARP16 (SEQ ID NO: 24), or in the level of one or more polypeptide(s) encoded by said one or more nucleic acid(s). 
     
     
         4 . The method of  claim 1 , wherein said cancer is selected from the group consisting of colon adenocarcinoma, esophagas adenocarcinoma, liver hepatocellular carcinoma, squamous cell carcinoma, pancreas adenocarcinoma, islet cell tumor, rectum adenocarcinoma, gastrointestinal stromal tumor, stomach adenocarcinoma, adrenal cortical carcinoma, follicular carcinoma, papillary carcinoma, breast cancer, ductal carcinoma, lobular carcinoma, intraductal carcinoma, mucinous carcinoma, phyllodes tumor, Ewing's sarcoma, ovarian adenocarcinoma, endometrium adenocarcinoma, granulose cell tumor, mucinous cystadenocarcinoma, cervix adenocarcinoma, vulva squamous cell carcinoma, basal cell carcinoma, prostate adenocarcinoma, giant cell tumor of bone, bone osteosarcoma, larynx carcinoma, lung adenocarcinoma, kidney carcinoma, urinary bladder carcinoma, Wilm's tumor, lymphoma, and non-Hodgkin's lymphoma.