The invention provides methods and compositions to detect expression of one or more biomarkers, including FGFR3, TP53, and/or EGFR, for treating, diagnosing, and providing a prognosis for cancer, e.g., bladder cancer. The invention also provides kits and articles of manufacture for use in the methods.

The present invention refers to p53 sequence and post translational modifications (PTMs) and to their use as biomarkers in the diagnosis of neurodegenerative disease and cognitive decline and/or in the prognosis of Alzheimer's disease at different stages and/or of neurodegenerative disease in a biological sample. The invention also provides for a 1) diagnostic method based on a highly accurate mass spectrometry analysis for the diagnosis of neurodegenerative disease, including Mild Cognitive Impairment (MCI), Alzheimer's disease (AD), fronto-temporal dementia (FTD), Lewi's Body (LB), and vascular dementia (VD) in a subject, by evaluating the PTMs to the said p53 linear sequence protein and possible cut of its full sequence specifically in human plasma of patients; and 2) prognosis of AD in CU and MCI patients.

Provided herein are methods of treating a patient having a cancer that exhibits (i) a hemizygous loss of the TP53 gene; (ii) a hemizygous loss of the POLR2A gene; and/or (iii) a decreased level of expression of a POLR2A gene product relative to a reference (i.e., control) expression level. The methods comprise administering a therapeutically effective amount of a POLR2A inhibitor (e.g., a nucleic acid that inhibits the expression of a POLR2A protein, an amatoxin, alpha-amanitin, or alpha-amanitin conjugated to a cell targeting moiety, such as an EpCAM antibody) to a patient having or determined to have (i) a hemizygous loss of the TP53 gene; (ii) a hemizygous loss of the POLR2A gene; and/or (iii) a decreased level of expression of a POLR2A gene product relative to a reference (i.e., control) level.

Disclosed are isolated or purified T cell receptors (TCRs) having antigenic specificity for human p53.sup.R175H or human p53.sup.Y220C. Related polypeptides and proteins, as well as related nucleic acids, recombinant expression vectors, host cells, populations of cells, and pharmaceutical compositions are also provided. Also disclosed are methods of detecting the presence of cancer in a mammal and methods of treating or preventing cancer in a mammal.

Heritable mutations in the BRCA1 and BRCA2 and other genes in the DNA double-strand break (DSB) repair pathway increase risk of breast, ovarian and other cancers. In response to DNA breaks, the proteins encoded by these genes bind to each other and are transported into the nucleus to form nuclear foci and initiate homologous recombination. Flow cytometry-based functional variant analyses (FVAs) were developed to determine whether variants in BRCA1 or other DSB repair genes disrupted the binding of BRCA1 to its protein partners, the phosphorylation of p53 or the transport of the BRCA1 complex to the nucleus in response to DNA damage. Each of these assays distinguished high-risk BRCA1 mutations from low-risk BRCA1 controls. Mutations in other DSB repair pathway genes produced molecular phenocopies with these assays. FVA assays may represent an adjunct to sequencing for categorizing VUS or may represent a stand-alone measure for assessing breast cancer risk.

The present invention is in the field of oncology, and more particularly of cancer stem cells. It relates to a method for producing cancer stem cells based on overexpression of Δ133ρ536 isoform, Δ133ρ53γ isoform, or both Δ133ρ536 and Δ133ρ53γ isoforms; a method for predicting the risk that treatment with a chemotherapeutic anti-cancer agent induces cancer stem cells in a subject suffering from cancer from a cancer sample of said subject, based on detection of an increase in Δ133ρ536 isoform, Δ133ρ53γ isoform, or both Δ133ρ536 and Δ133ρ53γ isoforms following chemotherapeutic anti-cancer treatment; to therapeutic uses of a combination of chemotherapeutic anti-cancer agent and an agent reducing Δ133p536 isoform, Δ133ρ53γ isoform, or both Δ133ρ536 and Δ133ρ53γ isoforms expression; and also to screening methods for anti-cancer stem cells agents.

An aspect of the invention provides a method of selectively necrosing cells, comprising: providing a plurality cells, including at least one cancer cell and at least one non-cancerous cell; and administering to the cells a compound, including an HDM-2 targeting component and a cytotoxic component attached to the HDM-2 targeting component, wherein said compound comprises a membrane-active form.

The invention provides methods and compositions to detect expression of one or more biornarkers, including FGFR3, TP53, and/or EGFR, for treating, diagnosing, and providing a prognosis for cancer, e.g., bladder cancer. The invention also provides kits and articles of manufacture for use in the methods.

Described herein are methods of treating cancer using one or more PRMT5 inhibitors, for example using one or more compounds of Formulae (1-5) or (A-F), pharmaceutically acceptable salts thereof, and/or pharmaceutical compositions thereof. Described herein are methods of treating cancer using one or more PRMT5 inhibitors, for example using one or more compounds of Formulae (1-5) or (A-F), pharmaceutically acceptable salts thereof, and/or pharmaceutical compositions thereof.

The invention provides methods and compositions to detect expression of one or more biomarkers, including FGFR3, TP53, and/or EGFR, for treating, diagnosing, and providing a prognosis for cancer, e.g., bladder cancer. The invention also provides kits and articles of manufacture for use in the methods.