Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the U.S. Based on numerous epidemiological studies and recent prospective clinical trials, the use of daily aspirin is associated with a significant reduction in CRC incidence, deaths and metastatic spread. However, the chronic use of this drug is limited due to the side-effects of gastrointestinal bleeding/ulceration in susceptible subjects. The main goal of this revised STTR Phase II proposal, developed by the PI, Lenard M. Lichtenberger, PhD, (Professor of Integrative Biology & Pharmacology, The University of Texas Health Science Center at Houston) and the small business, PLx Pharma Inc, based upon our encouraging results in Phase I, is to use cell culture studies and rodent colorectal cancer models to evaluate the chemopreventive activity of a recently approved novel aspirin drug, PL2200 (a phosphatidylcholine (PC)-associated aspirin; NDA issued to PLx Pharma in 01/ 2013), that has been documented in clinical trials to be safer to the GI mucosa than traditional aspirin. We will initially evaluate PL2200 (vs unmodified aspirin) alone on proliferation and apoptosis of mouse and human isogenic CRC cell culture lines. Studies to be performed in collaboration with Dr. Vinod Vijayan from Baylor College of Medicine (BCM), an expert on platelet function, will study the role of platelets in promoting growth, invasive activity and Epithelial-Mesenchymal Transition (EMT) in colon cancer cells and how these platelet-induced pro- carcinogenic changes are inhibited by Aspirin-PC via irreversible COX-1 inhibition. To gain insight into the mechanism of action of Aspirin-PC/PL2200 we will compare the COX-1 and COX-2 inhibitory activity of the test formulations on platelet aggregation/ thromboxane generation and PGE2 concentration of CRC tissue/lower gut epithelium, respectively. This will be followed by evaluating our test drugs ability to affect the dysplastic growth of colonic mucosa of APCMin/+ mice and APC-deficient rats challenged with dextran sodium sulfate (DSS) to induce colonic adenomas and genetic engineered mouse (GEM) models of CRC - to be performed in the laboratory of our collaborators, Drs Kopetz and Menter, at MD Anderson Cancer Center. The GI toxicity of the test-drugs will routinely be monitored in the above animal models. We will also study the role of PIK3CA mutation (which occurs in ~20% of CRC patients and enhances the patient's sensitivity to aspirin) on the chemopreventive efficacy of Aspirin-PC, using the isogenic CRC cell lines where the gene mutation is selectively expressed. Based upon these pre-clinical studies, PLx Pharma Inc will perform a pilot manufacturing run of low-dose (81mg) PL2200 and 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 PL2200 (81 mg/day) on ?at-risk? CRC patients and develop an IND package.

Public Health Relevance

Public Heath Relevance: This STTR Phase II proposal builds upon our encouraging preliminary data, most of which is derived from our STTR Phase I grant, on the chemopreventive activity of our novel lipid-associated aspirin product (PL2200 Aspirin), which was recently approved by the FDA. PL2200 causes reduced irritancy to the GI tract, under acute conditions, in comparison to plain aspirin. These earlier studies indicate that PL2200 may also possess profound chemopreventive activity for colorectal cancer (CRC) and also reduce metastatic spread of cancer. It is our objective to expand on these encouraging findings in the proposed Phase II studies using both in vitro and in vivo model systems. If successful, the proposed pre-clinical studies will lead the way to future clinical trials of low dose PL2200 on ?at-risk? CRC patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Business Technology Transfer (STTR) Grants - Phase II (R42)
Project #
5R42CA171408-03
Application #
9468354
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Rahbar, Amir M
Project Start
2013-05-03
Project End
2019-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Plx Opco, Inc.
Department
Type
DUNS #
140243572
City
Houston
State
TX
Country
United States
Zip Code
77054
Lichtenberger, Lenard M; Fang, Dexing; Bick, Roger J et al. (2017) Unlocking Aspirin's Chemopreventive Activity: Role of Irreversibly Inhibiting Platelet Cyclooxygenase-1. Cancer Prev Res (Phila) 10:142-152