Compounds and Methods Useful for Detection and Treatment of Cancer

Abstract

The present invention relates to compounds and methods useful for the detection and treatment of disorders associated with frameshift mutations in coding microsatellite regions. The compounds and methods are applicable in cancers, especially of DNA mismatch repair deficient (MMR) sporadic tumors and HNPCC associated tumors. The compounds are useful for detection of disorders and in therapy such as immuno-therapy. The diagnostic methods relate to diagnosis and prognostic assessment of disorders associated with frameshift polypeptides originating from frameshift mutations in coding microsatellite regions of genes based on the detection of immunological entities directed against said frameshift polypeptides in body fluids. With respect to the treatment of cancer, the invention pertains to methods which use immuno therapy with combinatorial mixtures of tumor specific frameshift peptides to elicit a cytotoxic T-cell response specifically directed against tumor cells for prevention and curative treatment of cancers and pre-cancers.

1 . A method comprising measuring the presence or absence or level of antibodies or antigen-recognizing cells directed against a frameshift polypeptide in a biological sample from a colorectal cancer patient, wherein the frameshift polypeptide is derived from a frameshift mutation in the A11 repeats in a coding microsatellite region of a gene selected from the group consisting of TAF1B, MACS, and HT001. 
     
     
         2 . The method of  claim 1 , wherein the frameshift polypeptide is derived from the A11 repeat of the TAF1B gene. 
     
     
         3 . The method of  claim 1 , wherein the frameshift polypeptide is derived from the A11 repeat of the HT001 gene. 
     
     
         4 . The method of  claim 1  wherein the frameshift polypeptide is derived from the A11 repeat of the MACS gene. 
     
     
         5 . The method of  claim 1 , which measures the presence or absence and/or level of the antibodies. 
     
     
         6 . The method of  claim 1 , which measures the presence or absence and/or level of the antigen-recognizing cells. 
     
     
         7 . The method of  claim 1 , wherein colorectal cancer patient is a patient in which the presence or absence and/or level of antibodies or antigen-recognizing cells against the one or more frameshift polypeptides has not previously been detected. 
     
     
         8 . The method of  claim 1 , wherein the presence or absence and/or level of a plurality of antibodies or antigen-recognizing cells is measured, each of the plurality directed against one of a set of frameshift polypeptides, the set of frameshift polypeptides comprising at least one of the frameshift polypeptides derived from the frameshift mutation in the A11 repeats in the coding microsatellite region of the gene selected from the group consisting of TAF1B, MACS, and HT001. 
     
     
         9 . The method of  claim 8 , wherein the set of frameshift polypeptides further comprises one or more frameshift polypeptides derived from a frameshift mutation in the A11 repeats in a coding microsatellite region of a gene selected from the group consisting of UVRAG, ELAVL3, TCF6L1, ABCF1, AIM2, and CH D2. 
     
     
         10 . The method of  claim 8 , wherein the set of frameshift polypeptides comprises at least 3 frameshift polypeptides. 
     
     
         11 . The method of  claim 8 , wherein the set of frameshift polypeptides comprises at least 4 frameshift polypeptides. 
     
     
         12 . The method of  claim 8 , wherein the set of frameshift polypeptides comprises at least 5 frameshift polypeptides. 
     
     
         13 . The method of  claim 8 , wherein the set of frameshift polypeptides comprises up to 30 frameshift polypeptides. 
     
     
         14 . The method of  claim 8 , wherein the set of frameshift polypeptides is selected from the group consisting of:
 Set 1, consisting of HT001, U79260, and MACS;   Set 2, consisting of HT001, TAF 1B, and MACS;   Set 3, consisting of HT001, TGFB2R, and MACS;   Set 4, consisting of HT001, U79260, and TGFB2R;   Set 5, consisting of HT001, U79260, and TAF1B;   Set 6, consisting of HT001, TGFB2R, and TAF1B;   Set 7, consisting of HT001, U79260, TGFB2R, and MACS;   Set 8, consisting of HT001, U79260, TGFB2R, and AC1;   Set 9, consisting of HT001, U79260, TGFB2R, and TAF1B;   Set 10, consisting of HT001, TGFB2R, MACS, and CASP5;   Set 11, consisting of HT001, U79260, MACS, and CASP5;   Set 12, consisting of HT001, U79260; MACS, and AC1;   Set 13, consisting of HT001, TGFB2R, TAF1B, and CASP5;   Set 14, consisting of HT001, U79260, MACS, and OGT;   Set 16, consisting of HT001, U79260, TGFB2R, MACS, and AC1;   Set 17, consisting of HT001, U79260, TGFB2R, TAF1B, and MACS;   Set 18, consisting of HT001, U79260, TGFB2R, TAF1B, and AC1;   Set 19, consisting of HT001, U79260, TGFB2R, MACS, and AIM2;   Set 20, consisting of HT001, U79260, TGFB2R, TAF1B, and AIM2;   Set 21, consisting of U79260, TGFB2R, TAF1B, AC1, and CASP5;   a set consisting of HT001, U79260, TGFB2R, AC1, and CASP5;   Set 22, consisting of U79260, TGFB2R, MACS, AC1, and CASP5;   Set 23, consisting of HT001, U79260, TAF1B, MACS, and AC1;   Set 24, consisting of HT001, U79260, TAF1B, MACS, and CASP5;   a set consisting of HT001, U79260, MACS, AC1, and OGT;   Set 25, consisting of HT00, U79260, MACS, MSH3, and OGT;   Set 26, consisting of HT001, U79260, TGFB2R, MACS, and OGT;   Set 27, consisting of HT001, TGFB2R, TAF1B, AC1, and CASP5; and   Set 28, consisting of HT001, U79260, TGFB2R, AC1, and AIM2.