PLx Opco Inc. — Department of Health and Human Services STTR Phase II: NCI

Description

ABSTRACT Colorectal cancerCRCis the third leading cause of cancer related deaths in the U SBased on numerous epidemiological studies and recent prospective clinical trialsthe use of daily aspirin is associated with a significant reduction in CRC incidencedeaths and metastatic spreadHoweverthe chronic use of this drug is limited due to the side effects of gastrointestinal bleeding ulceration in susceptible subjectsThe main goal of this revised STTR Phase II proposaldeveloped by the PILenard MLichtenbergerPhDProfessor of Integrative Biology andampPharmacologyThe University of Texas Health Science Center at Houstonand the small businessPLx Pharma Incbased upon our encouraging results in Phase Iis to use cell culture studies and rodent colorectal cancer models to evaluate the chemopreventive activity of a recently approved novel aspirin drugPLa phosphatidylcholinePCassociated aspirinNDA issued to PLx Pharma inthat has been documented in clinical trials to be safer to the GI mucosa than traditional aspirinWe will initially evaluate PLvs unmodified aspirinalone on proliferation and apoptosis of mouse and human isogenic CRC cell culture linesStudies to be performed in collaboration with DrVinod Vijayan from Baylor College of MedicineBCMan expert on platelet functionwill study the role of platelets in promoting growthinvasive activity and Epithelial Mesenchymal TransitionEMTin colon cancer cells and how these platelet induced procarcinogenic changes are inhibited by Aspirin PC via irreversible COXinhibitionTo gain insight into the mechanism of action of Aspirin PC PLwe will compare the COXand COXinhibitory activity of the test formulations on platelet aggregationthromboxane generation and PGEconcentration of CRC tissue lower gut epitheliumrespectivelyThis will be followed by evaluating our test drugs ability to affect the dysplastic growth of colonic mucosa of APCMinmice and APC deficient rats challenged with dextran sodium sulfateDSSto induce colonic adenomas and genetic engineered mouseGEMmodels of CRCto be performed in the laboratory of our collaboratorsDrs Kopetz and Menterat MD Anderson Cancer CenterThe GI toxicity of the test drugs will routinely be monitored in the above animal modelsWe will also study the role of PIK CA mutationwhich occurs inof CRC patients and enhances the patientandapos s sensitivity to aspirinon the chemopreventive efficacy of Aspirin PCusing the isogenic CRC cell lines where the gene mutation is selectively expressedBased upon these pre clinical studiesPLx Pharma Inc will perform a pilot manufacturing run of low dosemgPLand develop a strategy in consultation with the PI and our colleagues at MDACC to design a future clinical trial to evaluate the chronic use of low dose PLmg dayonat riskCRC patients and develop an IND package Public Heath RelevanceThis STTR Phase II proposal builds upon our encouraging preliminary datamost of which is derived from our STTR Phase I granton the chemopreventive activity of our novel lipid associated aspirin productPLAspirinwhich was recently approved by the FDAPLcauses reduced irritancy to the GI tractunder acute conditionsin comparison to plain aspirinThese earlier studies indicate that PLmay also possess profound chemopreventive activity for colorectal cancerCRCand also reduce metastatic spread of cancerIt is our objective to expand on these encouraging findings in the proposed Phase II studies using both in vitro and in vivo model systemsIf successfulthe proposed pre clinical studies will lead the way to future clinical trials of low dose PLonat riskCRC patients