RICERCA ITALIANA     

CHEMOPREVENTION AND CHEMORESISTANCE IN HELICOBACTER PYLORI-ASSOCIATED GASTRIC CARCINOGENESIS

Università degli Studi di Napoli "Federico II"

Abstract

Despite its decreasing incidence, gastric cancer (GC) remains a major clinic challenge due to its frequency, poor prognosis and limited treatment options. At present, the identification of patients at risk of developing GC and the overcoming of drug chemoresistance are likely to be the most effective methods to decrease the incidence and mortality of this neoplasm. However, to be successful this strategy depends upon knowledge of etiologic factors and pathogenetic mechanisms underlying gastric carcinogenesis.
Mounting evidences suggest that Helicobacter pylori (Hp) infection is the main etiologic factor and of cyclooxygenase-2 (COX-2) is implicated in both the early and late phases of tumorigenesis, including acquisition of drug-resistance.
Once Hp colonizes gastric mucosa, it induces a complex inflammatory and immune reaction that, without appropriate therapy, may damage cellular DNA. One of the most frequent Hp-related molecular alteration is COX-2 upregulation. COX-2 is involved in tumorigenis through inhibition of apoptosis, host-immune response modulation, signal transduction regulation and neoangiogenesis promotion.
Many reports, including experimental and clinical data have shown that selective COX-2 or non selective nonsteroidal anti-inflammatory drugs (NSAIDs) may be useful in the prevention and treatment of gastrointestinal cancer in a characterized subset of patients.
This project aims at identifying biological markers useful to >>>

Principal Investigator

Gerardo NARDONE Università degli Studi di NAPOLI "Federico II"

Research Objectives

The main objective of this research project is to define the role of COX in molecular alterations involved in the early and late phases of Hp-related gastric carcinogenesis. The phenotypic and genotypic profile of patients with chronic gastritis at risk of GC and those with GC and poor prognosis will be defined. The availability of selective and non-selective COX-2 inhibitors will permit new pharmacokinetics and pharmacodynamics approaches in in-vivo and ex-vivo models.

These objectives will be developed throughout the following steps:

1. Identification of the signal transduction pathways by which Hp triggers COX-2 overexpression and exerts a pivotal role in the molecular pathogenesis of gastritis and of GC;

2. Definition of the possible role of COX inhibitors in modulating mucosal immune responses triggered by Hp infection;

3. Characterization of markers and molecular profile implicated in the early phase of cellular transformation starting from inflammatory process and progressing to cancer;

4. Definition of markers and molecular profile implicated in the late phase of cellular transformation such as multi drug resistance acquisition;

5. Assessment of the pharmacodynamic responses to selective (rofecoxib) and non selective (aspirin) in in vivo and ex-vivo studies analysing patients with chronic gastritis and GC in relation to host genetic susceptibility, Hp strain and molecular >>>

First Results

1. To clarify the signal transduction pathways activated by Hp and associated to COX-2 overexpression in relation to the specific virulence factors;
2. To define the role of COX-2 in driving Th1/Th2 polarisation in gastric mucosa;
3. To in vitro test the effect of pharmacologic inhibition of COX-2 on gastric immune response.1. To define COX-2 related genetic profiles;
2. to correlate molecular profiles with clinical pathological parameters;
3. to identify molecular marker useful to early diagnosis in gastritis patients at risk of GC and prognosis and response to therapy in GC patients;
4. to clarify the role of PPAR-gamma genetic polymorphisms on genetic susceptibility to GC.1. Characterization of the pharmacokinetic and pharmacodynamic variability of the responses to non-specific and specific COX inhibitors in chronic gastritis and in GC.
2. Correlation of observed variability with Hp strain, constitutional genetic factors of patients, and somatic alterations, genetic or epigenetic, in gastric mucosa and/or in GC.1. To verify experimentally the role of constitutional gene variants and/or somatic molecular alterations as a cause of pharmacodynamic variability to treatment with COX inhibitors in gastritis- and/or gastric cancer-affected patients.
2. To define gastritis- and/or gastric cancer-affected patients that might benefit from treatment with coxibs or with aspirin.

Timescale

24 months

National and international background

Despite decreasing incidence and mortality rates observed globally in the last 50 years, gastric cancer (GC) still ranks as a leading cause of cancer-related deaths in many parts of the world (1). After lung cancer, GC kills more people than any other malignant tumor (2). The American Cancer Society indicates about 800.000 new cases and more than 600.000 people died of GC in 2000 estimating that the 5 year-relative survival rate is less than 20% (3). In Italy, from 1994 to 1998, up to 50.000 people died for GC (4). Gastric cancer yet remains a major clinical challenge and a public health concern. At present, primary or secondary prevention are likely to be the most effective method of reducing the incidence and mortality from this disease. However, to be successful this strategy depends upon knowledge of etiologic factors and pathogenetic mechanisms underlying gastric carcinogenesis.
In recent years, it has became apparent that the most important single factor responsible for the development of GC is infection with Helicobacter pylori (Hp) and the cyclo-oxygenase-2 (COX-2) is implicated in early and late phase of gastric carcinogenesis, such as acquisition of drug-resistance (5-6).
The relationship between Hp and GC has been postulated to exist mainly on the basis of retrospective, case-control, and prospective epidemiological investigations and animal model studies (7-11). However, the most powerful evidence come from a recent prospective epidemiological >>>