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

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 \u3c 7 months, (part 2) weekly with rapamycin (16 mg/kg) at 7 months ≤ age \u3c 12 months, and (part 3) daily with rapamycin (8 mg/kg) at 12 months ≤ age \u3c 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

Topical rapamycin inhibits tuberous sclerosis tumor growth in a nude mouse model

<p>Abstract</p> <p>Background</p> <p>Skin manifestations of Tuberous Sclerosis Complex (TSC) cause significant morbidity. The molecular mechanism underlying TSC is understood and there is evidence that systemic treatment with rapamycin or other mTOR inhibitors may be a useful approach to targeted therapy for the kidney and brain manifestations. Here we investigate topical rapamycin in a mouse model for TSC-related tumors.</p> <p>Methods</p> <p>0.4% and 0.8% rapamycin ointments were applied to nude mice bearing subcutaneous, TSC-related tumors. Topical treatments were compared with injected rapamycin and topical vehicle. Rapamycin levels in blood and tumors were measured to assess systemic drug levels in all cohorts.</p> <p>Results</p> <p>Treatment with topical rapamycin improved survival and reduced tumor growth. Topical rapamycin treatment resulted in systemic drug levels within the known therapeutic range and was not as effective as injected rapamycin.</p> <p>Conclusion</p> <p>Topical rapamycin inhibits TSC-related tumor growth. These findings could lead to a novel treatment approach for facial angiofibromas and other TSC skin lesions.</p

Obstetric Balloon for Treatment of Foreshortened Vagina Using the McIndoe Technique

BACKGROUND: When conservative options such as the use of vaginal dilators fail, the McIndoe technique may be used in the surgical treatment of a foreshortened vagina. The McIndoe procedure, an approach commonly used for the treatment of vaginal agenesis, requires a mold over which a skin graft is sutured and placed inside the vagina. In most surgical descriptions, this mold is made from non-sterile foam, condoms, or gloves. Because makeshift molds can no longer be used in operating rooms owing to strict regulations, alternative methods must be employed. INSTRUMENT: The obstetric balloon is a good choice for use as a soft and adjustable vaginal mold for a modified McIndoe procedure because it is readily available as an approved device in hospitals that provide obstetric services. EXPERIENCE: This technique was successfully employed in a 54-year-old woman to treat foreshortened vagina. CONCLUSION: An obstetric balloon can be used effectively as a mold for vaginal reconstruction with the McIndoe technique

Rapamycin levels in tumor samples after treatment with topical or IP rapamycin

Rapamycin levels in tumor homogenates from indicated treatment groups were measured 24 hours (A, C) and 48 hours (B, D) after the final dose of rapamycin. Panels C and D are enlarged versions of the boxed-in data in panels A and B respectively.<p><b>Copyright information:</b></p><p>Taken from "Topical rapamycin inhibits tuberous sclerosis tumor growth in a nude mouse model"</p><p>http://www.biomedcentral.com/1471-5945/8/1</p><p>BMC Dermatology 2008;8():1-1.</p><p>Published online 28 Jan 2008</p><p>PMCID:PMC2266897.</p><p></p

Rapamycin whole blood levels after treatment with topical and IP rapamycin

A) Whole blood rapamycin levels from tumor bearing animals from indicated treatment groups. Rapamycin levels were measured 24 hours after the final dose of rapamycin. B) Whole blood rapamycin levels were measured in cohorts of control mice with no tumors. As indicated, levels were measured 24 hours after either one or three doses of topical rapamycin. In some groups, Elizabethan collars or bandages were used to prevent ingestion of rapamycin ointment. All animals had rapamycin levels >3 ng/ml. The slightly higher levels in the Elizabethan collar group suggests that ingestion is not a major issue. The lower levels in the bandage groups suggests that the bandage polymer can affect drug absorption. C) Whole blood rapamycin levels were also measured 48 hours after the final dose in tumor bearing animals. D) In three of the control, non-tumor bearing groups, rapamycin levels were measured at 48 hours following their final treatment to compare to tumor bearing animals.<p><b>Copyright information:</b></p><p>Taken from "Topical rapamycin inhibits tuberous sclerosis tumor growth in a nude mouse model"</p><p>http://www.biomedcentral.com/1471-5945/8/1</p><p>BMC Dermatology 2008;8():1-1.</p><p>Published online 28 Jan 2008</p><p>PMCID:PMC2266897.</p><p></p

Tuberous sclerosis preclinical studies: timing of treatment, combination of a rapamycin analog (CCI-779) and interferon-gamma, and comparison of rapamycin to CCI-779-6

<p><b>Copyright information:</b></p><p>Taken from "Tuberous sclerosis preclinical studies: timing of treatment, combination of a rapamycin analog (CCI-779) and interferon-gamma, and comparison of rapamycin to CCI-779"</p><p>http://www.biomedcentral.com/1471-2210/7/14</p><p>BMC Pharmacology 2007;7():14-14.</p><p>Published online 6 Nov 2007</p><p>PMCID:PMC2213639.</p><p></p>t was administered. Whole blood, brain, kidney, and tumor tissue were collected at necropsy. a) Blood, brain, and kidney rapamycin levels from cohorts treated with rapamycin or CCI-779 for four consecutive days and euthanized 2–4 hours after drug injection. b) Blood, brain, and kidney rapamycin levels from cohorts treated with rapamycin or CCI-779 for four consecutive days and euthanized 24 hours after drug injection. c) Tumor rapamycin levels from indicated cohorts treated with rapamycin or CCI-779 and euthanized 2–4 hours after drug injection. Rapa = rapamycin. This data is shown in table format with statistical analyses in Table 2

Tuberous sclerosis preclinical studies: timing of treatment, combination of a rapamycin analog (CCI-779) and interferon-gamma, and comparison of rapamycin to CCI-779-5

<p><b>Copyright information:</b></p><p>Taken from "Tuberous sclerosis preclinical studies: timing of treatment, combination of a rapamycin analog (CCI-779) and interferon-gamma, and comparison of rapamycin to CCI-779"</p><p>http://www.biomedcentral.com/1471-2210/7/14</p><p>BMC Pharmacology 2007;7():14-14.</p><p>Published online 6 Nov 2007</p><p>PMCID:PMC2213639.</p><p></p>apamycin and early CCI-779-treated cohorts. c) Data shown in table format

Tuberous sclerosis preclinical studies: timing of treatment, combination of a rapamycin analog (CCI-779) and interferon-gamma, and comparison of rapamycin to CCI-779-1

<p><b>Copyright information:</b></p><p>Taken from "Tuberous sclerosis preclinical studies: timing of treatment, combination of a rapamycin analog (CCI-779) and interferon-gamma, and comparison of rapamycin to CCI-779"</p><p>http://www.biomedcentral.com/1471-2210/7/14</p><p>BMC Pharmacology 2007;7():14-14.</p><p>Published online 6 Nov 2007</p><p>PMCID:PMC2213639.</p><p></p