Biomarkers for treatment of neoplastic disorders using androgen-targeted therapies

#Cancer represents a significant burden on human health, accounting for an estimated 13% of all deaths each year. In particular, several common cancers and diseases are associated with androgen hormone signaling, such as, for example, prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, and polycystic ovary disease. For example, prostate cancer (PCa) is the second most common cancer in men. The majority of prostate cancer deaths are due to the development of metastatic disease that is unresponsive to conventional androgen deprivation therapy. Androgen deprivation therapy has been the standard of care in subjects with prostate cancer since the 1940s. Despite androgen deprivation, most subjects ultimately experience disease progression. For many years this later phase of the disease was called “hormone insensitive prostate cancer” or “androgen independent prostate cancer.” It has since become clear that the prostate cancer that emerges after androgen deprivation therapy remains dependent upon androgen. The prostate cancer cells that have survived have gained the ability to import low levels of circulating androgens (expressed from adrenal glands), become much more sensitive to these low levels of testosterone, and actually synthesize testosterone within the prostate cancer cell itself. This stage of prostate cancer is now termed “castration resistant prostate cancer” or CRPC.

#Identification of patients that are likely to respond or identification of those patients that are responding to therapy for prostate cancer is a goal for medical management of this disease. While current clinical guidelines are focused on symptoms, blood levels of prostate specific antigen (PSA), and imaging studies, other biological markers may be useful for clinical decision making. There remains a need for biomarkers of the disease and their relationship to identification of efficacy or toxicity of a therapeutic compound, and biomarkers which could provide information regarding identification of patients most likely to respond to therapeutic agents, or to identify patients receiving therapeutic agents who are not responding (either through primary or acquired resistance mechanisms), or to predict those patients that may develop undesirable side effects.

#The biomarkers identified below may be used, for example, to evaluate treatment options at various points in the course of treatment of a patient. For example, the biomarkers are used in the evaluation of treatment options at various cancer treatment transition points by analysis of one ore more biomarkers or a biomarker panel to identify and optimize therapeutic choices. Biomarkers may also be used to predict unresponsiveness or poor responsiveness to existing anti-cancer therapy and responsiveness to galeterone in the same patient. In one embodiment, biomarker detection is performed and correlated with galeterone efficacy in the treatment of prostate cancer.

#The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

#FIG. 1 depicts androgen receptor (AR) and alternative splice variants thereof.

#FIG. 2 shows that galeterone downregulates full-length and splice variant AR and reduces cell proliferation in a CWR22rv1 cell line.

#A “subject” as used herein refers to a patient or subject in a clinical trial and more broadly a biological entity containing expressed genetic materials. Tissues (including biopsied materials), cells and their progeny from a subject obtained in vivo or cultured in vitro are also encompassed.

#By “sample” is meant a fluid, solid, or tissue removed from a subject and includes whole blood, serum, plasma, tissue, semen, cell, biopsy, mucous, feces, bone, teeth, nasal or throat or cheek swab, urine, skin, tears, organ biopsy (liver, kidney, colon, lung, pancreas), tumor biopsy, or tumor tissue, circulating tumor cells, exosomes from the primary tumor or metastatic tissue. The sample may also include a portion of the collected fluid, solid, or tissue from a subject, for example a circulating tumor cell, or an analyte. By “processed sample” is meant the fluid, solid, or tissue from the subject is treated, handled, or managed via laboratory techniques to enrich for an analyte. By “processed whole blood sample” is meant that the whole blood sample is processed through in vitro laboratory techniques to analyze a component of the whole blood sample including cells, DNA, RNA, proteins, peptides, or an analyte as described below; for example, cells found in a whole blood sample may be enriched, washed, and analyzed separately; more specifically, circulating tumor cells may be enriched from a whole blood sample and analyzed for a biomarker or biomarkers, and these biomarkers may include a mutated form of androgen receptor. Another example is to enrich a whole blood sample for DNA (for example circulating DNA or tumor cell DNA) that can be analyzed for a biomarker or biomarkers and these biomarkers may include a mutated form of androgen receptor.

#By “analyte” is meant a substance or a constituent of a sample to be analyzed. Exemplary analytes include one or more species of one or more of the following: a protein, a peptide, a polypeptide, an amino acid, a nucleic acid, an oligonucleotide, mRNA, RNA, microRNA, long non-coding RNA, DNA, circulating DNA, cDNA, an antibody, a carbohydrate, a polysaccharide, glucose, a lipid, a gas (e.g., oxygen or carbon dioxide), an electrolyte (e.g., sodium, potassium, chloride, bicarbonate, BUN, magnesium, phosphate, calcium, ammonia, lactate, zinc, citrate), a lipoprotein, cholesterol, a fatty acid, a glycoprotein, a proteoglycan, a lipopolysaccharide, a cell surface marker (e.g., CD3, CD4, CD8, IL2R, or CD35), a tumor marker (BCL-2, ERK5), prostate specific antigen (PSA), a cytoplasmic marker, a therapeutic agent, a metabolite of a therapeutic agent, a cell (e.g., a whole cell, a tumor cell, a circulating tumor cell, a stem cell, a white blood cell, a T cell (e.g., displaying CD3, CD4, CD8, IL2R, CD35, or other surface markers), or another cell identified with one or more specific markers). As used herein, the term “small molecule” refers to a drug, medication, medicament, or other chemically synthesized compound that is contemplated for human therapeutic use. As used herein, the term “biologic” refers to a substance derived from a biological source, not synthesized and that is contemplated for human therapeutic use. A biomarker is a biological substance that can be used as an indicator of a particular disease state or particular physiological state of an organism, generally a biomarker is a protein or other native compound measured in bodily fluid whose concentration reflects the presence or severity or staging of a disease state or dysfunction, can be used to monitor therapeutic progress of treatment of a disease or disorder or dysfunction, or can be used as a surrogate measure of clinical outcome or progression. As used herein, the term “metabolic biomarker” refers to a substance, molecule, or compound that is synthesized or biologically derived that is used to determine the status of a patient or subject's liver or kidney function. As used herein, the term “genotyping” refers to the ability to determine genetic differences in specific genes that may or may not affect the phenotype of the specific gene. As used herein, the term “phenotype” refers to the resultant biological expression, (metabolic or physiological) of the protein set by the genotype. As used herein, the term “gene expression profiling” refers to the ability to determine the rate or amount of the production of a gene product or the activity of gene transcription in a specific tissue, in a temporal or spatial manner. As used herein, the term “proteomic analysis” refers to a protein pattern or array to identify key differences in proteins or peptides in normal and diseased tissues. Additional exemplary analytes are described herein. The term analyte further includes components of a sample that are a direct product of a biochemical means of amplification of the initial target analyte, such as the product of a nucleic acid amplification reaction.