Rapamycin weekly maintenance dosing and the
potential efficacy of combination sorafenib plus rapamycin but not
atorvastatin or doxycycline in tuberous sclerosis preclinical models

BMC Pharmacology 2009,
9:8doi:10.1186/1471-2210-9-83. [Open Acces]

Abstract

Background

Tuberous sclerosis complex (TSC) is an autosomal dominant tumor
suppressor syndrome, characterized by hamartomatous growths in the
brain, skin, kidneys, lungs, and heart, which lead to significant
morbidity. TSC is caused by mutations in the TSC1 or TSC2 genes,
whose products, hamartin and tuberin, form a tumor suppressor complex
that regulates the PI3K/Akt/mTOR pathway. Early clinical trials show
that TSC-related kidney tumors (angiomyolipomas) regress when treated
with the mammalian target of rapamycin (mTOR) inhibitor, rapamycin
(also known as sirolimus). Although side effects are tolerable,
responses are incomplete, and tumor regrowth is common when rapamycin
is stopped. Strategies for future clinical trials may include the
investigation of longer treatment duration and combination therapy of
other effective drug classes.

Results

Here, we examine the efficacy of a prolonged maintenance dose of rapamycin in Tsc2^+/- mice
with TSC-related kidney tumors. Cohorts were treated with rapamycin
alone or in combination with interferon-gamma (IFN-g). The schedule of
rapamycin included one month of daily doses before and after five
months of weekly doses. We observed a 94.5% reduction in kidney tumor
burden in Tsc2^+/- mice treated (part one) daily
with rapamycin (8 mg/kg) at 6 months ≤ age < 7 months, (part 2)
weekly with rapamycin (16 mg/kg) at 7 months ≤ age < 12 months, and
(part 3) daily with rapamycin (8 mg/kg) at 12 months ≤ age < 13
months; but we did not observe any improvement with combination IFN-g
plus rapamycin in this study. We also used a Tsc2^-/- subcutaneous
tumor model to evaluate other classes of drugs including sorafenib,
atorvastatin, and doxycycline. These drugs were tested as single agents
and in combination with rapamycin. Our results demonstrate that the
combination of rapamycin and sorafenib increased survival and may
decrease tumor volume as compared to rapamycin treatment alone while
sorafenib as a single agent was no different than control. Atorvastatin
and doxycycline, either as single agents or in combination with
rapamycin, did not improve outcomes as compared with controls.

Conclusion

Our results indicate that prolonged treatment with low doses of mTOR
inhibitors may result in more complete and durable TSC-related tumor
responses, and it would be reasonable to evaluate this strategy in a
clinical trial. Targeting the Raf/Mek/Erk and/or VEGF pathways in
combination with inhibiting the mTOR pathway may be another useful
strategy for the treatment of TSC-related tumors.