COGNIZANCE BIOMARKERS, LLC — Department of Health and Human Services STTR Phase I: 107

Description

DESCRIPTION provided by applicant There are a growing number of human diseases that have been linked to abnormally enhanced activation of the mammalian target of rapamycin mTOR signaling cascade a central pathway governing eukaryotic protein synthesis These include neurodevelopmental disorders associated with epilepsy autism and intellectual disability as well as cancer obesity and diabetes Recent FDA approval for select mTOR inhibitors mTORi such as everolimus for the autosomal dominant neurodevelopmental disorder tuberous sclerosis complex TSC has provided a clinical platform to test the efficacy of mTORi everolimus in a multisystem disorder affecting the brain kidney lung and skin Everolimus has also been approved for use in breast cancer and renal cancer In this application we will develop a simple blood assay to define mTOR signaling in lymphocytes from TSC patients treated with mTORi as a strategy to improve the clinical efficacy of mTORi treatment Currently the assessment of mTORi effectiveness is predicated on serum mTORi levels and a normative range There is no metric to actually assess the degree to which any mTORi dose or blood level impacts mTOR signaling the central mechanism of action of mTORi Thus we will assess the phosphorylation of mTOR substrates p S kinase ribosomal S protein E BP and Akt in lymphocytes from TSC patients prior to the onset of mTORi treatment and then after weeks of treatment using a MesoScale Discovery Sector multiplex ELISA system Lower levels of phosphorylation serve as a metric for higher mTOR inhibition and lower mTOR signaling all indirect measures of mTORi efficacy We will correlate these data with serum drug levels and clinical effect on reduction in size of brain and renal lesions in TSC In the PI laboratory we will assess changes in leukocyte protein synthesis as a functional assay of mTORi and correlate these changes with levels of substrate phosphorylation Blood samples will be drawn at the Temple University TSC Clinic during routine outpatient visits Protein lysates from these samples will be assayed at Temple University School of Medicine in Dr Crinoandapos s laboratory and at Cognizance Biomarkers LLC CB an SBIR funded startup company The long term plan will be to commercialize this assay as a readily available and affordable screening therapeutic blood test for patients being treated with mTORi Based on the rapid evolution of disorders being associated with aberrant mTOR signaling we anticipate that our test will have very wide applicability in a broad range of disorders and clinical settings PUBLIC HEALTH RELEVANCE A number of diverse human disorders have been linked to the mammalian target of rapamycin mTOR signaling cascade Pharmacological mTOR inhibitors mTORi such as everolimus are gaining more widespread clinical use but there are no clinical assays other than serum drug levels to assess the degree of mTOR inhibition in patients treated with mTORi We propose to develop a simple blood test to quantify mTOR signaling in peripheral blood leukocytes that will provide a novel clinical assay to define the efficacy of mTORi in vivo