P53 biomarkers

Abstract

The present invention relates to the identification of p53 biomarker profiles that predict response in patients with hyperproliferative disease such as cancer to a therapy, and their use in methods of treating such patients with an anti-hyperproliferative disease gene therapy.

1 . A method of treating a subject having a tumor using p53 gene therapy, the method comprising:
 (a) determining whether tumor cells of said tumor comprise at least one wild-type p53 allele; and/or   (b) determining whether tumor cells of said tumor express p53 protein at a level that is higher than that expressed in normal p53-expressing non-tumor cells; and/or   (c) determining whether tumor cells of said tumor express a p53 protein that does not inhibit the function of wild-type p53;   wherein if said cells are found to   i) comprise at least one wild-type p53 allele, and/or   ii) express a level of p53 protein that is not higher than that expressed in normal p53-expressing non-tumor cells, and/or   iii) express an elevated level of p53 protein, defined as a level that is higher than that expressed in normal p53-expressing non-tumor cells, wherein said p53 protein does not inhibit the function of wild-type p53,   then treating the subject whose tumor is characterized by any one of i) through iii) with p53 gene therapy.   
     
     
         2 . A method of treating a subject having a tumor, the method comprising: determining whether cells of the tumor a) do not contain at least one wild-type p53 allele, and/or b) contain two mutant p53 alleles, and/or c) express a mutant p53 protein at levels higher than that expressed by normal p53-expressing normal cells and such mutant p53 inhibits the function of wild-type p53, wherein if the cells of the tumor satisfy any one of a) through c), then treating the subject with an anticancer therapy other than p53 therapy. 
     
     
         3 . The method of  claim 2 , wherein said other therapy is methotrexate. 
     
     
         4 . The method of  claim 1 , comprising the use of antibody detection of p53. 
     
     
         5 . The method of  claim 1 , comprising the use of immunohistochemistry detection of p53. 
     
     
         6 . The method of  claim 1 , comprises the use an ELISA, an immunoassay, a radioimmunoassay (RIA), an immunoradiometric assay, a fluoroimmunoassay, a chemiluminescent assay, a bioluminescent assay, a gel electrophoresis, a Western blot analysis or an in situ hybridization assay. 
     
     
         7 . The method of  claim 1 , wherein step (a) comprises amplification of a p53 transcript. 
     
     
         8 . The method of  claim 7 , wherein said amplification comprises PCR or RT-PCR. 
     
     
         9 . The method of  claim 1 , wherein step (a) comprises in situ hybridization, Northern blotting or nuclease protection. 
     
     
         10 . The method of  claim 1 , wherein step (b) comprises sequencing, gene arrays or gene chips. 
     
     
         11 . The method of  claim 10 , wherein genomic sequences are amplified in tumor cells of said tumor. 
     
     
         12 . The method of  claim 11 , wherein said tumor cells are paraffin-embedded. 
     
     
         13 . The method of  claim 2 , wherein said mutant p53 comprises DNA binding mutations. 
     
     
         15 . The method of  claim 1 , wherein the tumor is a benign tumor growth. 
     
     
         16 . The method of  claim 15 , wherein the benign tumor growth is benign prostatic hyperplasia, oral leukoplakia, a colon polyp, an esophageal pre-cancerous growth or a benign lesion. 
     
     
         17 . The method of  claim 1 , wherein the tumor is cancer. 
     
     
         18 . The method of  claim 17 , wherein the cancer is oral cancer, oropharyngeal cancer, nasopharyngeal cancer, respiratory cancer, urogenital cancer, gastrointestinal cancer, central or peripheral nervous system tissue cancer, an endocrine or neuroendocrine cancer or hematopoietic cancer, glioma, sarcoma, carcinoma, lymphoma, melanoma, fibroma, meningioma, brain cancer, oropharyngeal cancer, nasopharyngeal cancer, renal cancer, biliary cancer, pheochromocytoma, pancreatic islet cell cancer, Li-Fraumeni tumors, thyroid cancer, parathyroid cancer, pituitary tumors, adrenal gland tumors, osteogenic sarcoma tumors, multiple neuroendocrine type I and type II tumors, breast cancer, lung cancer, head and neck cancer, prostate cancer, esophageal cancer, tracheal cancer, liver cancer, bladder cancer, stomach cancer, pancreatic cancer, ovarian cancer, uterine cancer, cervical cancer, testicular cancer, colon cancer, rectal cancer or skin cancer. 
     
     
         19 . The method of  claim 18 , wherein the cancer is squamous cell carcinoma (SCCHN). 
     
     
         20 . The method of  claim 1 , further comprising a second anti-tumor therapy. 
     
     
         21 . The method of  claim 20 , wherein the second anti-tumor therapy is gene therapy. 
     
     
         22 . The method of  claim 20 , wherein the second anti-tumor therapy is chemotherapy. 
     
     
         23 . The method of  claim 20 , wherein the second anti-tumor therapy is radiotherapy. 
     
     
         24 . The method of  claim 20 , wherein the second anti-tumor therapy is cytokine therapy. 
     
     
         25 . The method of  claim 20 , wherein the second anti-tumor therapy is anti-angiogenic therapy. 
     
     
         26 . The method of  claim 1 , wherein the p53 gene therapy is delivered by a non-viral vector. 
     
     
         27 . The method of  claim 26 , wherein the non-viral vector is entrapped in a lipid vehicle. 
     
     
         28 . The method of  claim 27 , wherein the lipid vehicle is a liposome. 
     
     
         29 . The method of  claim 28 , wherein the vehicle is a nanoparticle. 
     
     
         30 . The method of  claim 1 , wherein the p53 gene therapy is delivered by a viral vector. 
     
     
         31 . The method of  claim 30 , wherein the viral vector is a retroviral vector, an adenoviral vector, an adeno-associated viral vector, a pox viral vector, a polyoma viral vector, a lentiviral vector, or a herpesviral vector. 
     
     
         32 . The method of  claim 1 , wherein said p53 gene therapy is loco-regional gene therapy. 
     
     
         33 . The method of  claim 32 , wherein the loco-regional gene therapy comprises localized gene therapy. 
     
     
         34 . The method of  claim 33 , wherein the localized gene therapy comprises direct injection of the tumor. 
     
     
         35 . The method of  claim 34 , wherein the localized gene therapy comprises injection of tumor vasculature. 
     
     
         36 . The method of  claim 32 , wherein the loco-regional gene therapy comprises regional gene therapy. 
     
     
         37 . The method of  claim 36 , wherein the regional gene therapy comprises administration into a tumor-associated lymph vessel or duct. 
     
     
         38 . The method of  claim 37 , wherein the administration comprises intraperitoneal, intrapleural, intravesicular, or intrathecal administration. 
     
     
         39 . The method of  claim 36 , wherein the regional gene therapy comprises administration into the vasculature system of a limb associated with the tumor. 
     
     
         40 . The method of  claim 1 , wherein favorable response to the therapy comprises reduction in tumor size or burden, blocking of tumor growth, reduction in tumor-associated pain, reduction in tumor associated pathology, reduction in tumor associated symptoms, tumor non-progression, increased disease free interval, increased time to progression, induction of remission, reduction of metastasis, or increased patient survival. 
     
     
         41 . The method of  claim 1 , further defined as comprising the steps of:
 (a) determining whether the tumor cells comprise two wild-type p53 alleles; and, if so, then   (b) administering a p53 gene therapy to the subject.   
     
     
         42 . The method of  claim 1 , further defined as comprising the steps of:
 (a) determining whether the tumor cells comprise at least one wild-type p53 allele and whether the tumor cells do not overexpress p53 protein; and, if so, then   (b) administering to the subject a p53 gene therapy.   
     
     
         43 . The method of  claim 1 , further defined as comprising the steps of:
 (a) determining whether the tumor cells do not contain a p53 mutant allele; and, if so, then (c) administering to the subject a p53 gene therapy.   
     
     
         44 . The method of  claim 1 , further defined as comprising the steps of:
 (a) determining whether the tumor cells do not overexpress a p53 mutant protein that inhibit the function of wild-type p53; and, if so, then   (b) administering to the subject a p53 gene therapy.   
     
     
         45 . The method of  claim 1 , further defined as comprising the steps of:
 (a) determining whether the tumor cells overexpress a p53 protein that does not inhibit the function of wild-type p53; and, if so, then   (b) administering to the subject a p53 gene therapy.   
     
     
         46 . The method of  claim 1 , further defined as comprising the steps of:
 (a) determining whether the tumor cells overexpress a mutant p53 protein and such mutant p53 inhibits the function of wild-type p53; and, if so, then   (b) administering to the subject a therapy other than p53 therapy.   
     
     
         47 . The method of  claim 1 , further defined as comprising the steps of:
 (a) determining whether the tumor cells do not contain at least one wild-type p53 allele; and, if so, then   (b) administering to the subject a therapy other than p53 therapy.   
     
     
         48 . The method of  claim 1 , further defined as comprising the steps of:
 (a) determining whether the tumor cells contain two mutant p53 allele; and, if so, then   (b) administering to the subject a therapy other than p53 therapy.   
     
     
         49 . The method of  claim 1 , further comprising obtaining from the patient a biological sample comprising tumor cells. 
     
     
         50 . A kit comprising:
 (a) a p53 antibody or probe for detecting an amount of p53 protein in a tumor sample;   (b) a plurality of probes for determining a p53 gene or transcript structure.