Cisplatin is a cornerstone therapy for a number of cancers including testicular, bladder, ovarian and lung. It is also used to treat cancers in children. In all cases there is a high incidence of acute kidney injury (AKI) that can also lead to later stage kidney damage. This risk limits its use. We have found in pilot studies that renalase, or peptide fragments of renalase, offers the innovative potential to limit or treat this damage, thereby improving the safety and utility of cisplatin and potentially resulting in better outcomes. This proposal will prioritize the best clinical candidate for later stage development and proof of concept clinical trials in patients. Renalase, a secreted flavin adenine dinucleotide (FAD) dependent amine oxidase, is synthesized by the renal proximal tubule, secreted in blood, preferentially metabolizes epinephrine, continuously excreted in urine in the basal state. We have shown renalase deficiency (renalase KO vs Wild type [WT] mice) is associated with dramatically more severe cisplatin-mediated acute and chronic renal injury. Most importantly, administration of recombinant renalase ameliorates AKI in mice by reducing renal tubular necrosis, apoptosis and markers of inflammation. We have recently discovered that, independent of its enzymatic properties, renalase also activates a receptor-mediated, pro-survival signaling cascade, with activation of protein kinase B (AKT), down- regulation of c-Jun N-terminal Kinase (JNK) and increased expression of Bcl-2. We have identified the critical regions of the renalase protein that mediate interaction with its cognate receptor, and synthesized several renalase peptides that fully mimic the protective effect of recombinant renalase. We have developed highly reproducible models of cisplatin-mediated acute and chronic kidney injury, and sensitive methods (multi-photon microscopy) to measure the percentage of atubular glomeruli (not contributing to glomeruli filtration) and quantify the extent renal fibrosis in CKD. In the proposed studies we will determine which renalase molecules (recombinant renalase or renalase peptides) are most effective in treating cisplatin AKI in mice. We will use histopathology, biochemical, inflammatory and functional markers of AKI to prioritize the results. We will analyze and correlate drug levels of the proposed therapies in biological fluids of the animal models with the pharmacologic results to aid in the lead drug prioritization and provide initial evidence for optimum routes of administration.
Public Health Relevance Statement: Public Health Relevance: This is a Phase 1 STTR application to develop a new, safe and effective therapy to significantly decrease the kidney toxicity of the widely used chemotherapeutic drug cisplatin; there is no current therapy for cisplatin-mediated renal toxicity. The project combines the efforts of Dr. Gary Desir and colleagues who discovered renalase with the translational efforts of the of an experienced drug development team of Bessor Pharma. The therapy selected, either renalase or a peptide fragment of renalase, can be of tremendous benefit to the millions of patients who receive cisplatin treatment for cancer and must presently decide with their physician whether to stop or reduce an otherwise effective therapy because of drug induced renal injury, or continue therapy and risk permanent renal damage.
Project Terms: Acute; Acute Renal Failure with Renal Papillary Necrosis; Aftercare; amine oxidase; Animal Model; Animals; Apoptosis; base; BCL2 gene; Biochemical; Biological; Bladder; Blood; Cancer Patient; Cancer Survivor; cancer therapy; chemotherapeutic agent; Child; Chronic; Chronic Kidney Failure; Cisplatin; Clinical; Clinical Trials; comparative efficacy; Creatinine; cytotoxicity; Data; design; Development; Dose; Down-Regulation; drug development; effective therapy; Enzyme-Linked Immunosorbent Assay; Epinephrine; experience; Fibrosis; Filtration; Flavin-Adenine Dinucleotide; Future; Histopathology; Immunofluorescence Immunologic; improved; In Situ Nick-End Labeling; In Vitro; in vivo; Incidence; Infiltration; Inflammation; Inflammatory; inflammatory marker; Injury; innovation; intravenous administration; Kidney; Laboratories; Lead; light microscopy; Liquid substance; Lung; macrophage; Malignant Neoplasms; MAP Kinase Gene; MAPK14 gene; Measurement; Measures; Mediating; Methods; Microscopy; Mitogens; Modeling; multi-photon; Mus; nephrotoxicity; neutrophil; Outcome; Ovarian; Patients; Peptide Fragments; Peptides; Pharmaceutical Preparations; Phase; Phosphotransferases; Physicians; Pilot Projects; Plasma; prevent; Property; protective effect; Proteins; Proto-Oncogene Proteins c-akt; Proximal Kidney Tubules; public health relevance; Rattus; Reaction; receptor; Recombinants; Renal function; Risk; Route; Safety; Signal Transduction; Small Business Technology Transfer Research; Smooth Muscle Actin Staining Method; Staging; Staining method; Stains; stress-activated protein kinase 1; subcutaneous; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Toxic effect; tubular necrosis; tumor; Urine; Western Blotting; Wild Type Mouse
