SAN FRANCISCO-The investigational
farnesyl transferase inhibitor
(FTI), R115777 (tipifarmib,
Zarnestra) causes robust clinical responses
in some patients with
myelodysplastic syndrome (MDS),
but these responses are not correlated
with the drug's ability to inhibit
farnesyl transferase, according to a
study presented at the 93rd Annual
Meeting of the American Association
for Cancer Research (abstract 4959).
The hypothesis-driven clinical trial
was a collaboration between M.D.
Anderson Cancer Center, where the
patients were accrued, and the H. Lee
Moffitt Cancer Center and Research
Institute, Tampa, where the biochemical
correlative work was carried out.
"In every patient, the molecular
target was hit, but only 30% responded,"
said researcher Said M.
Sebti, PhD, professor of oncology,
biochemistry and molecular biology,
Moffitt Cancer Center. "Our
study tells us that inhibition of
farnesyl transferation is critical for
response, but, by itself, it does not
correlate with response." Dr. Sebti
is also director of Moffitt's Drug
In the study, 6 of 20 evaluable
myelodysplastic syndrome patients
achieved a hematologic partial or
complete response to R115777, said
lead researcher Razelle Kurzrock,
MD, professor of medicine, M.D.
Anderson Cancer Center. Some of
the responses have been quite durable,
lasting up to 15 months. Responses
were seen at all dose levels,
and did not correspond with the
ability of the drug to hit its molecular
target and inhibit farnesyl transferase.
The study suggests that the six
patients who responded must have
a molecular signature-a blueprint-
that requires farnesyl transferase
for tumor survival. "That's
why we see responses in these patients,"
Dr. Sebti said.
Eligible patients had received less
than two prior therapies and had
adequate renal and hepatic function.
Myelodysplastic syndrome patients
of all subtypes were included in the
The patients received R115777
orally twice a day for 3 weeks of a 4-
week cycle. Dosing started at 300
mg twice daily and increased up to
900 mg/d until patients showed toxicity
or no longer benefited from
therapy. Three patients responded
at 600 mg/d, two at 800 mg/d, and
one at 900 mg/d. "There was more
than 80% farnesyl transferase inhibition
with every patient," Dr. Sebti
said. The enzyme did not come back
to basal level even 1 week after stopping
Six of the patients, but only two
of the responders, had Ras mutations,
indicating that these mutations
did not correlate with response,
Dr. Kurzrock said. In
myelodysplastic syndrome, 30% to
40% of patients have a Ras mutation,
making it an interesting disease
for studying FTIs.
The main serious side effect was
grade 3-4 myelosuppression. "Other
toxicities at grade 3-4 were observed,
but they were less frequent,"
Dr. Sebti said.
Dr. Kurzrock noted that although
the 30% response rate is modest, "the
responses occur at doses that have
minimal toxicity, even in elderly patients."
The patients in the study
ranged in age from 50 to 83 years
old (median, 66).
As predicted, R115777 was a selective
inhibitor of farnesyl transferase
and not geranylgeranyl transferase
(GGTase). "We have seen this
in animal models, but it is nice to
see it in patients," Dr. Sebti said.
The researchers also looked at the
effect of the drug on oncogenic signaling
pathways. R115777 inhibited
the prenylation of the exclusively
farnesylated protein HDJ-2 in all
patients, but this did not correlate
with a clinical response. "With this
drug, there seems to be some effects
on oncogenic signaling pathways,
but they do not correlate with response,"
Dr. Sebti said.
Since one of the downstream effects
of Ras is the induction of
cytokine synthesis, the researchers
also measured serum levels of TNF
(tumor necrosis factor)-alpha. Responding
patients had a 42% drop
in TNF-alpha, while nonresponders
experienced an 11% increase.
The study reveals that farnesyl
transferase targets "are just housekeeping
proteins," Dr. Sebti said.
"What we need now is the blueprint
for the tumors that depend on
farnesyl transferase," he said.
In a future study, the researchers
will examine the molecular profiles of
all patients who respond to the drug,
Dr. Sebti said. "We are looking for
profiles that could lead us to predict
which type of myelodysplastic syndrome
patients will respond."