Methods and compositions for inducing ferroptosis in vivo

Abstract

Methods and systems for the induction of ferroptosis in a tissue in a subject are provided. Various ferroptosis-inducing agents a described. Various methods of administration are described for optimal ferroptosis induction and killing of target cells.

What is claimed is: 
     
         1 . A method of inducing iron-dependent cell death in a tissue in a subject, the method comprising:
 contacting a tissue in vivo with an effective amount of an iron-dependent cell death agent for a duration of time of at least 4 hours,   wherein the tissue comprises one or more of:   (a) a plurality of cells comprising a concentration of selenium greater than a selenium concentration in a corresponding normal tissue;   (b) a plurality of cells comprising a concentration of iron greater than an iron concentration in a corresponding normal tissue;   (c) a plurality of cells comprising a PUFA concentration greater than a PUFA concentration in a corresponding normal tissue;   (d) a plurality of cells expressing one or more markers indicative of a mesenchymal state; and/or   (e) a plurality of cells comprising a peroxidizability index (PI) greater than a PI in a corresponding normal tissue,   wherein the effective amount of the iron-dependent cell death agent is a concentration of at least about 0.1 μM up to 500 μM in the tissue for the duration of time.   
     
     
         2 . The method of  claim 1 , wherein the ferroptosis-inducing agent is selected from the group consisting of: (1S,3R)-RSL3, ML-162, ML-210, JKE-1674, JKE-1716, erastin, jacaric acid, buthionine sulfoximine (BSO), trigonelline, glutamate, sulfasalazine, auranofin, brusatol, sorafenib, sorafenib-d3, sorafenib tosylate, trigonelline, FIN56, FINO 2 , CIL56, dihydroisotanshinone I, GPX4-IN-3, analogs, or derivatives thereof. 
     
     
         3 . The method of  claim 1 , wherein the iron-dependent cell death agent contacts the tissue at a localized site for about 6 hours, about 12 hour, about 24 hours, about 48 hours, or for about 72 hours. 
     
     
         4 . The method of  claim 1 , wherein the tissue is a tumor or a pre-cancerous lesion. 
     
     
         5 . The method of  claim 4 , wherein the tumor is a carcinoma, a melanoma, or a sarcoma. 
     
     
         6 . The method of  claim 1 , wherein the subject has cancer, wherein the cancer is breast cancer, brain cancer, pancreatic cancer, prostate cancer, skin cancer, bladder cancer, lung cancer, liver cancer, ovarian cancer, renal cancer, endometrial cancer, colorectal cancer, gastric cancer, skin cancer, head and neck cancer, or thyroid cancer. 
     
     
         7 . The method of  claim 4 , wherein the iron-dependent cell death agent reduces tumor size or tumor volume by at least 5%. 
     
     
         8 . The method of  claim 1 , wherein the iron-dependent cell death agent is administered with one additional agent. 
     
     
         9 . The method of  claim 8 , wherein the additional agent is a cell death-inducing agent or a dietary supplement. 
     
     
         10 . A method of inducing targeted cell death in a mammalian tissue in vivo, the method comprising:
 (a) contacting a mammalian tissue with a priming agent;   (b) contacting the mammalian tissue in vivo with an effective amount of a ferroptosis-inducing agent for a duration of time of at least 4 hours, when a plurality of cells within the mammalian tissue are responsive to the priming agent as determined by detecting in the mammalian tissue:
 (i) a plurality of cells comprising a concentration of selenium greater than a selenium concentration in the mammalian tissue prior to contacting with the priming agent; 
 (ii) a plurality of cells comprising a concentration of iron greater than an iron concentration in the mammalian tissue prior to contacting with the priming agent; 
 (iii) a plurality of cells comprising a PUFA concentration greater than a PUFA concentration in the mammalian tissue prior to contacting with the priming agent; 
 (iv) a plurality of cells expressing one or more markers indicative of a mesenchymal state; 
 (v) a plurality of cells comprising a peroxidizability index (PI) greater than a PI in the mammalian tissue prior to contacting with the priming agent; and/or 
 (vi) hyperproliferation of cells in the mammalian tissue, 
   wherein the ferroptosis-inducing agent induces targeted cell death in the mammalian tissue in vivo.   
     
     
         11 . The method of  claim 10 , wherein step (a) is performed, in vivo, in vitro, or ex vivo. 
     
     
         12 . The method of  claim 10 , further comprising a step of obtaining a biopsy of the mammalian tissue for histological analysis. 
     
     
         13 . The method of  claim 10 , further comprising a step of detecting a plurality of cells within the mammalian tissue as responsive to the priming agent. 
     
     
         14 . The method of  claim 10 , wherein the priming agent is liproxstatin-1, ferrostatin-1, deferoxamine (DFO), iron, vitamin E, a polyunsaturated fatty acid, or selenium. 
     
     
         15 . The method of  claim 10 , further comprising administering a cell death-inducing agent. 
     
     
         16 . The method of  claim 10 , wherein the ferroptosis-inducing agent is selected from the group consisting of: (1S,3R)-RSL3, ML-162, ML-210, JKE-1674, JKE-1716, erastin, jacaric acid, buthionine sulfoximine (BSO), trigonelline, glutamate, sulfasalazine, auranofin, brusatol, sorafenib, sorafenib-d3, sorafenib tosylate, trigonelline, FIN56, FINO 2 , CIL56, dihydroisotanshinone I, GPX4-IN-3, analogs, or derivatives thereof. 
     
     
         17 . The method of  claim 1 , wherein the tissue comprises (b) a plurality of cells comprising a concentration of iron greater than an iron concentration in a corresponding cell. 
     
     
         18 . The method of  claim 1 , wherein the tissue comprises (c) a plurality of cells comprising a PUFA concentration greater than a PUFA concentration in a corresponding normal tissue. 
     
     
         19 . The method of  claim 1 , wherein the tissue comprises (e) a plurality of cells comprising a peroxidizability index (PI) greater than a PI in a corresponding normal tissue. 
     
     
         20 . The method of  claim 1 , wherein the tissue comprises (a) a plurality of cells comprising a concentration of selenium greater than a selenium concentration in a corresponding normal tissue.