Osteopontin targeted therapy for primary CNS lymphoma

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41CA210669-01A1
Agency Tracking Number: R41CA210669
Amount: $283,986.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: 102
Solicitation Number: PA16-303
Timeline
Solicitation Year: 2016
Award Year: 2017
Award Start Date (Proposal Award Date): 2017-08-28
Award End Date (Contract End Date): 2019-07-31
Small Business Information
2711 CENTERVILLE RD STE 400, Wilmington, DE, 19808-1645
DUNS: 968675244
HUBZone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 JOHN COPLAND
 (904) 953-6120
 copland.john@mayo.edu
Business Contact
 LORI HAZLEHURST
Phone: (813) 335-7401
Email: lori.hazlehurst@gmail.com
Research Institution
 MAYO CLINIC JACKSONVILLE
 4500 SAN PABLO RD
JACKSONVILLE, FL, 32224-1865
 Domestic nonprofit research organization
Abstract
Abstract Primary central nervous system lymphoma PCNSL is an aggressive brain tumor with a dire unmet therapeutic need It has an overall incidence of per person years and is regarded as an orphan disease with potential for fast track approval Our group made a discovery via gene expression analysis that osteopontin OPN is the most upregulated gene in PCNSL compared to its non CNS counterpart By immunohistochemistry analysis OPN is expressed heavily by all the lymphoma cells in of PCNSL cases Functional genomic studies identified OPN as an important pro tumorigenic driver with multifaceted role in CNS lymphoma including intracerebral tumor growth invasion and dissemination via a unique mechanistic activation of NF B signaling High OPN expression in PCNSL patients has a strong correlation with poor progression free and overall survival To target OPN we have developed a novel compound Chloro ethyl agelastatin A CEAA with excellent CNS penetration which demonstrates robust therapeutic activity against CNS lymphoma in a cell line derived murine model We have secured a patent for composition of matter of agelastatin A analogues and their therapeutic use in primary and secondary brain tumors such as primary and secondary CNS lymphoma glioblastoma multiforme and metastatic breast cancer of the brain We are proposing to further develop CEAA for PCNSL with two specific aims In Aim Copland Hazlehurst Modulation Therapeutics Inc the dose limiting toxicity DLT of CEAA will be determined in rats In Aim the Tun Laboratory will evaluate the therapeutic activity of CEAA against PCNSL in two novel patient derived xenograft PDX mouse models with high OPN expression in comparison to two control groups standard of care control with high dose Methotrexate and no treatment vehicle control The dose and frequency will be varied as guided by results from Aim to inform the Phase I clinical trial design The generated dataset will provide the necessary data to i initiate a pre IND meeting with the FDA ii design of the GLP studies required for the IND application and iii design of the phase I clinical trial CEAA represents a first in class agent which targets a specific molecular abnormality in PCNSL We believe that due to high penetrance to the brain and robust in vivo activity of CEAA that further pre clinical development of CEAA for the treatment of PCNSL is warranted As OPN is ubiquitously over expressed in many aggressive cancers including other brain tumors we anticipate that the study results will have ramifications and applications for many other cancers Project Narrative We propose to develop Chloro ethyl agelastatin A CEAA as an orphan drug for primary brain lymphoma based on our strong preliminary data CEAA has high brain penetration and targets osteopontin which plays an essential multi faceted role in brain lymphoma

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

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