Malignant cancers are the second leading cause of death in the USA with colorectal cancer being the second most fatal cancer. The elderly population is particularly at risk for colorectal cancer as its incidence increases with age. Circulating platelets are known to change with age which may affect a variety of degenerative diseases including cancers. Platelets are implicated in the promotion of carcinogenesis and its metastatic spread, and their circulating numbers are reported to be elevated in a number of solid tumors including colorectal cancer. Platelet aggregation with circulating cancer cells appears to protect the cancer cells and promote their metastasis. Recent studies of large populations of patients on low dose antiplatelet therapy (low dose aspirin) for cardiovascular risk reduction, have reported that aspirin confers significant protection against cancer formation, metastases and death. Thus, it is possible that the known chemopreventive activity of aspirin may be related to its antiplatelet action. Our hypothesis is that modulation of platelet activity i important for prevention of colorectal cancer and suppression of metastatic growth. One limitation to the widespread use of aspirin for chemoprevention is its side effect to induce acute gastrointestinal (GI) bleeding that may become life threatening if untreated. This is particularly problem for the elderly, as advanced age is a risk factor for NSAID-induced GI ulceration/bleeding. A recently FDA-approved aspirin product that is GI- safer (Aspirin-PC/PL2200) developed by the PI's laboratory may offer a means to provide significant chemoprevention with reduced GI side effects. We propose to investigate: 1) the in vitro cross-talk between platelets from young and elderly subjects and cancer cells, and their responsiveness to antiplatelet drugs, including various aspirin formulations, notably Aspirin-PC, and other agents;and 2) an in vivo colon cancer [models of both pre-cancer initiation] and metastatic growth in young and old animals for sensitivity to antiplatelet drugs. These studies will contribute to knowledge about the role of platelets in chemoprevention of colorectal cancer in the elderly, and may offer a timely and safe approach to reduce the metastatic spread of cancer in the elderly.
Colorectal cancer is the second leading cause of cancer-related deaths in the U.S. and its incidence increases with age. There is sufficient scientific and clinical information available to support the use of antiplatelet drugs such as low-dose aspirin as chemopreventive agents in patients at risk for this disease, but the side effect of aspirin to caus bleeding and ulceration of the gastrointestinal (GI) tract, as well as unknown age-related effectiveness of some drugs, limit the recommendation for use of these agents. The drugs under study in this proposal include a new formulation of aspirin that is safer for the GI tract (aspirin PC) and other antiplatelet drugs that are readily available and may enhance the chemopreventive action of aspirin. These studies have the potential to save lives and healthcare dollars by testing relatively low cost drugs that can prevent a fatal disease (colorectal cancer) and also avoid life-threatening side effects (bleeding).
|Lichtenberger, Lenard M; Fang, Dexing; Bick, Roger J et al. (2016) Unlocking aspirin's chemopreventive activity: Role of irreversibly inhibiting platelet cyclooxygenase-1. Cancer Prev Res (Phila) :|