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Small molecule Inhibitors of steroid receptor coactivator to treat breast cancer

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41CA217561-01A1
Agency Tracking Number: R41CA217561
Amount: $223,781.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: 102
Solicitation Number: PA16-303
Timeline
Solicitation Year: 2016
Award Year: 2018
Award Start Date (Proposal Award Date): 2018-09-01
Award End Date (Contract End Date): 2019-08-31
Small Business Information
2 GREENWAY PLAZA
Houston, TX 77006
United States
DUNS: 081158312
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 DAVID LONARD
 (713) 591-6281
 lonard@hotmail.com
Business Contact
 ANDREW WOOTEN
Phone: (713) 798-2116
Email: andrew.wooten@bcm.edu
Research Institution
 BAYLOR COLLEGE OF MEDICINE
 
1 BAYLOR PLAZA
HOUSTON, TX 77030-3411
United States

 Nonprofit College or University
Abstract

ABSTRACTSteroid Receptor CoactivatorSRCis a key breast cancer oncogene that is frequently
overexpressed or amplified in estrogen receptorERand human epidermal growth factor receptorHERpositive breast cancersElevated expression of SRCalso has been associated with resistance to tamoxifen
therapy and with poor disease outcome in HERpositive breast cancersNumerous studies have shown that
experimental targeting of SRCcan limit breast cancer cell growth and restore the anti estrogenic actions of
tamoxifenSRChas been well characterized and murine proof of concept studies suggest inhibition of this
target will lead to an entirely new class of drugs for a wide range of SRC overexpressing tumorsSRCs are a promising target since they function as coactivators not only for nuclear receptors like ERbut also as key coactivators for `growth promotingandapostranscription factors such as such as E FTwistNfkappaB and othersThese transcription factors are lucrative targets for difficult to treat tumors such as triple
negative breast cancerTNBCand hormone refractory breast cancerMost targeted therapeutic drugs
available are designed to inhibit only one pathwayHoweverdrug resistance often occurs when tumors shift to
alternative growth pathwaysrendering the original targeted pathway non essential for tumor growthInhibiting
SRChas implications on multiple relevant cancer signaling pathways simultaneouslyand accordingly it is an
ideal target for difficult to treat cancersWe have identified proprietary small molecules that selectively and potently inhibit SRCprotein levelsWe have demonstrated that these inhibitors prevent TNBC tumor growth in vivo and effectively kill cancer stem
cellsIn our preliminary studieswe elucidated the metabolic mechanisms of these inhibitors and developed
proprietary derivatives with improved drug like properties resulting in our current lead molecule SIDuring this PhaseSTTRinspired by our encouraging preliminary study showing that TNBC cell lines with
subtypes involving growth factor signaling pathways are more sensitive to SRCinhibition induced toxicitywe
will determine the ICvalues of SIin all the TNBC cell lines in the ATCC Breast Cancer Cell PanelATCCKand correlate the ICvalues with the TNBC subtypesWe will also measure the SRClevels in
these TNBC cell lines using Western blot with and without SItreatmentWe will compare whether a high
protein level of SRCin TNBC cell lines is correlated with SIsensitivity and evaluate the ability of SIto
block TNBC tumor growth in vivoIn a subset of SIsensitive TNBC cellswe will also determine the
changes of cell migration and invasion abilities upon SItreatmentWe will then extensively characterize SIfor the shelf stabilityin vitro and in vivo ADMET profilesproteomics based target identificationtranscriptome wide RNA sequencing and PKPD relationshipDuring Phase II SIwill be evaluated in patient
derived xenograft breast cancer models representing TNBC tumors and conduct extensive IND enabling
evaluations of SIandapos s biodistributionpharmacokinetics and toxicity Project NarrativeThere is an urgent need to identify new targets and to develop new therapeutics to inhibit metastasis
and in combination with standard of care to improve triple negative breast cancer managementOur novel
class of proprietary Steroid Receptor CoactivatorSRCinhibitor small molecules has been shown to limit
Triple Negative Breast CancerTNBCcell growth in vitro and in vivoSRChas been well characterized and
murine proof of concept studies suggest inhibition of this target will lead to an entirely new class of drugs for a
wide range of SRC overexpressing tumors including TNBC

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

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