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mTOR Substrate Phosphorylation: A New Bioassay for Therapeutics

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41NS093970-01
Agency Tracking Number: R41NS093970
Amount: $225,000.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: 107
Solicitation Number: PA14-072
Timeline
Solicitation Year: 2015
Award Year: 2015
Award Start Date (Proposal Award Date): 2015-09-15
Award End Date (Contract End Date): 2016-08-31
Small Business Information
3160 CHESTNUT ST, STE 200
Philadelphia, PA 19104-2853
United States
DUNS: 968476957
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 PETER CRINO
 (215) 707-3040
 peter.crino@temple.edu
Business Contact
 JOHN POLLARD
Phone: (215) 349-5166
Email: jpollard@mail.med.upenn.edu
Research Institution
 TEMPLE UNIV OF THE COMMONWEALTH
 
PHILADELPHIA, PA 19122-6003
United States

 Nonprofit College or University
Abstract

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

* Information listed above is at the time of submission. *

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