Lung Cancer.pdf

Prevention and Early Detection of Lung Cancer 273
These studies of various treatment approaches in patients with p53 mutations
may lead one day to the creation of chemoprevention strategies for
patients with similar molecular defects.
RAS
RAS genes are mutated in approximately 30% of lung adenocarcinomas,
and mutated RAS genes can be found in premalignant lesions in smokers.
Activation is due to a point mutation. Mutations in k-ras predict a poorer
prognosis in both early-stage and late-stage NSCLC. Eventually, the signal
cascade activates nuclear proto-oncogene products such as those generated
by the MYC genes.
Farnesyl transferase inhibitors (FTIs) are a novel class of compounds
that inhibit a critical enzymatic step in the constitutive expression of mutated
RAS genes. In preclinical studies utilizing HNSCC cell lines and
NSCLC cell lines, SCH66336, a novel tricyclic peptidomimetic compound
designed by Schering-Plough, appears to have extensive activity. Other
FTIs have been developed and are being tested in the clinical setting (e.g.,
R115777, Janssen Pharmaceutica, Inc.)
Preclinical data from Moasser and colleagues had indicated that the addition
of FTIs to either paclitaxel or epothilones was able to overcome acquired
resistance to these tubulin toxins in a variety of different cancer cell
lines (Moasser et al, 1998). We reported results of a phase I trial of
SCH66336 in combination with paclitaxel in adults with solid tumors
(Kim et al, 2001). Patients received paclitaxel at doses ranging from 135
mg/m2 to 175 mg/m2 in combination with oral SCH66336, which was
started 7 days prior to the paclitaxel, at doses ranging from 100 mg twice
daily to 150 mg twice daily. The maximum tolerated dose was found to be
175 mg/m2 of paclitaxel every 3 weeks with SCH66336 at 100 mg twice
daily. Of 24 patients, 21 were evaluable for assessment for response and
toxicity. Side effects were acceptable, with the dose-limiting side effects
being neutropenic fever and, occasionally, grade 3 diarrhea. Responses
were quite striking: 8 (38%) of 21 evaluable patients had a major confirmed
response, and only 5 of 21 patients had disease progression by
cycle 3 of combination therapy. Responses were seen in NSCLC, HNSCC,
and various salivary gland tumors, with 1 individual having stable disease
for a total of 24 cycles of therapy encompassing 19 months.
Given the promising results with FTIs in lung cancer treatment and
their mild toxicity profile, we are planning a multi-institutional, randomized,
double-blind, placebo-controlled chemoprevention trial utilizing the
FTI R115777 in patients at high risk for the development of lung cancer. To
be eligible for the trial, patients must have undergone definitive treatment
for a tobacco-related cancer, must have a smoking history of at least 30
pack-years, and must have evidence of sputum atypia. After a baseline
bronchoscopy, patients will take study medication for 6 months and will
then be observed for 6 months. We will evaluate bronchial histologic