Development of fluorogenic substrates for the diagnosis of pancreatic cysts

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R43DK115341-01A1
Agency Tracking Number: R43DK115341
Amount: $235,341.00
Phase: Phase I
Program: SBIR
Solicitation Topic Code: 300
Solicitation Number: PA16-302
Timeline
Solicitation Year: 2016
Award Year: 2017
Award Start Date (Proposal Award Date): 2017-09-20
Award End Date (Contract End Date): 2019-09-19
Small Business Information
27 CABRILLO ST, APT E, San Francisco, CA, 94118-4081
DUNS: 078643292
HUBZone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 GISELLE KNUDSEN
 (415) 476-1196
 knudsen@cgl.ucsf.edu
Business Contact
 CHARLES CRAIK
Phone: (415) 476-8146
Email: charles.craik@ucsf.edu
Research Institution
N/A
Abstract
Abstract The dramatic increase in the number of patients being diagnosed with incidental pancreatic cysts through improved imaging represents a unique opportunity to detect and treat cystic precursor lesions before the onset of malignancy However pancreatic cysts also represent a major clinical challenge because current diagnostics do not adequately reflect the biology of cyst malignant transformation Misregulated pericellular proteolysis is a hallmark of invasive cancer Therefore we are exploiting the activities of proteases in cyst fluid to develop an enzyme based diagnostic test for the sensitive and specific identification of pre malignant pancreatic lesions Our goals are to develop a rapid and minimally invasive assay that improves patient stratification over current standard diagnostic markers and guides clinical decision making to avoid unnecessary surgical intervention The Alaunus Biosciences diagnostic pipeline takes advantage of a substrate profiling technology developed in the Craik Laboratory at UCSF referred to as Multiplex Substrate Profiling by Mass Spectrometry MSP MS The MSP MS assay uses a peptide library platform to monitor global protease substrate specificity and kinetic efficiency in complex biological samples in an unbiased manner Through applying this substrate profiling approach to small volumes of cyst fluid andlt L obtained by endoscopic ultrasound we have identified proteases that have highly increased activity in pre malignant cysts and developed a proof of principle fluorogenic substrate assay that achieves improved sensitivity and specificity compared to the current clinical standard CEA In Aim we propose to use our activity based profiling approach to identify additional distinguishing protease markers in an expanded patient cohort and already evident in our existing cyst fluid data In Aim substrate specificity profiles then will be used to rationally design and optimize specific fluorogenic peptide substrates that are cleaved by the target proteases discovered Lead candidate substrates will be benchmarked in a blinded validation cohort for their performance compared to CEA in distinguishing pre malignant from benign cysts If successful this proposal will lay the groundwork for an actionable diagnostic test that will enable early identification of pre malignant cysts and transform the clinical management of these challenging lesions Project Narrative Early diagnosis is the single most important tool to delay or avoid cancer related mortality Many people undergoing abdominal MRI or CT scans today are found to have cysts in their pancreas which in some cases can evolve into pancreatic cancer however it is currently very difficult to predict which cysts are true precursor lesions and which will remain asymptomatic We are developing a minimally invasive and highly sensitive diagnostic assay to identify cysts with a high likelihood of progressing into pancreatic cancer to facilitate early detection of malignancy as well as avoid unnecessary and costly surgeries for cases with benign cystic lesions

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

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