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Clinical Cancer Research 14, 1167, February 15, 2008. doi: 10.1158/1078-0432.CCR-07-4007
© 2008 American Association for Cancer Research
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Cancer Therapy: Preclinical

Suppression of Peutz-Jeghers Polyposis by Targeting Mammalian Target of Rapamycin Signaling

Chongjuan Wei1, Christopher I. Amos1, Nianxiang Zhang2, Xiaopei Wang1, Asif Rashid3, Cheryl L. Walker4, Richard R. Behringer5 and Marsha L. Frazier1

Authors' Affiliations: Departments of 1 Epidemiology, 2 Cancer Genetics, 3 Pathology, 4 Carcinogenesis, and 5 Molecular Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Marsha L. Frazier, Unit 1365, Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, 1155 Pressler Boulevard, Houston, TX 77030. Phone: 713-792-3393; Fax: 713-563-0999; E-mail: mlfrazier{at}mdanderson.org.


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: Peutz-Jeghers syndrome (PJS) is a unique disorder characterized by the development of hamartomas in the gastrointestinal tract as well as increased risks for variety of malignancies. Germ-line mutations of LKB1 cause PJS. We have generated Lkb1+/– mice, which model human PJS. Rapamycin and its analogues are promising preventive and therapeutic agents that specifically inhibit signaling from mammalian target of rapamycin (mTOR). Hyperactivation of mTOR signaling has been associated with PJS. The objective of the study is to investigate the efficacy of mTOR inhibition in suppressing Peutz-Jeghers polyposis in Lkb1+/– mice.

Experimental Design: We initiated a trial of rapamycin in Lkb1+/– mice at 9 months of age (after the onset of polyposis) at the dose of 2 mg/kg/d for a 2-month period. We assessed the efficacy of rapamycin by measuring polyp sizes and tumor burden. To examine the effect of rapamycin on mTOR signaling, phosphorylation levels of S6 were evaluated by immunostaining.

Results: We observed a significant decrease in mean tumor burden (Student's t test, P = 0.023) as well as total tumor burden in rapamycin-treated group compared with control group. Comparison of the polyp size observed in both rapamycin-treated and control groups showed that rapamycin efficiently decreased the tumor burden of large polyps (>8 mm). This inhibition of rapamycin was associated with a decrease in phosphorylated S6 levels in the polyps.

Conclusions: Rapamycin effectively suppresses Peutz-Jeghers polyposis in a mouse model, suggesting that rapamycin or its analogues may represent a new targeted therapy for the treatment of PJS.

Peutz-Jeghers syndrome (PJS) is an autosomal dominant disorder, characterized by mucocutaneous hyperpigmentation and multiple gastrointestinal hamartomatous polyps (1). Patients with PJS also have a dramatically increased incidence of various types of malignances (2, 3). These hamartomas, although benign, may lead to significant complications such as bowel obstruction, necessitating multiple surgical resections of clinically significant polyps (4). There is no treatment for this disease aside from surgical resection and follow-up endoscopies (5). Until recently, no chemopreventive agents had been suggested to decrease tumor burden in individuals with PJS. However, a recent pilot study (6) suggested that cyclooxygenase-2 inhibitor (celecoxib) could be beneficial in the chemoprevention of PJS polyposis. Cyclooxygenase-2 is not currently known to be directly influenced by LKB1, but it is up-regulated in some polyps and most cancers from patients with PJS (7–11).

Approximately 70% of clinically defined PJS families harbor pathologic germ-line point mutations or larger deletions of LKB1 (12–14). LKB1 is a serine-threonine kinase. Numerous molecular and biochemical studies have indicated that LKB1 functions as a tumor suppressor that regulates multiple biological processes and signaling pathways (15–17). Although homozygous Lkb1 knockout mice die at midgestation (18), several mouse model studies (7, 19–22), including our own (19), have reported that heterozygous Lkb1 knockout mice develop severe gastrointestinal polyposis, thus modeling the polyposis of PJS. The polyps seen in these Lkb1+/– mice are due to LKB1 haploinsufficiency (7, 19–22).

LKB1 has been reported as the major upstream kinase of AMPK (23–26). Through phosphorylation of AMPK, which in turn phosphorylates and activates TSC2, LKB1 negatively regulates mammalian target of rapamycin (mTOR) signaling (27). mTOR, a serine/threonine kinase, monitors intracellular nutrients and energy availability and promotes cell growth and proliferation (28). The dysregulation of the mTOR signaling pathway has been reported in multiple types of tumors. S6 kinase and eukaryotic translation initiation factor 4E–binding protein 1 are two well-characterized downstream targets of mTOR. On phosphorylation by mTOR, S6 kinase phosphorylates ribosomal S6 protein in response to growth factors. Elevated levels of phospho-S6 (pS6) kinase and pS6 are detected in the polyps from Lkb1+/– mice (27), suggesting that hyperactivation of mTOR signaling accounts for the development of the PJS-characteristic hamartomatous lesions. These observations suggested that mTOR inhibitors such as rapamycin and its analogues could be useful for the treatment of polyps arising from patients with PJS. In addition, in a small trial of tuberous sclerosis patients with astrocytomas, treatment with rapamycin induced regression of the tumors (29).

Therefore, in this study, we investigated whether inhibition of mTOR signaling will suppress the development and/or progression of Peutz-Jeghers polyposis in Lkb1+/– mice. We have determined the efficacy of rapamycin in reducing Peutz-Jeghers polyposis in Lkb1+/– mice.


   Materials and Methods
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 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Animals. Heterozygous Lkb1 knockout mice have been generated and described previously (17). All mice are on a C57BL/6J congenic background. Mice were housed under conventional specific pathogen-free conditions at the Department of Veterinary Medicine and Surgery, The University of Texas M. D. Anderson Cancer Center. All experiments described in this article were conducted according to an approved Institutional Animal Care and Use Committee protocol. To carry out the trial, we selected 36 healthy animals at 9 months of age and randomly assigned them to treatment and control groups. For each group, heterozygous Lkb1 mice were housed three to five mice per cage according to their sex.

Drug administration. Rapamycin (Wyeth Pharmaceuticals) was diluted in a solution containing 0.2% sodium-carboxymethylcellulose and 0.25% polysorbate-80 in distilled water and stored at 4°C protected from light. Thirty-six 9-month-old heterozygous Lkb1 mice were divided into two groups and injected i.p. with rapamycin at the dose of 2 mg/kg/d or the vehicle (the solution used to dilute the rapamycin) 5 days per week for 2 months.

Scoring of polyps. After 2 months of treatment, all mice were euthanized. The gastrointestinal tracts of the mice were dissected, fixed, coded, and scored blindly by two independent individuals (C.W. and X.W.). The diameter of the polyps was measured using a digital micrometer and the tumor volume was calculated using the formula V = {pi}/6 x a3, where a is the diameter. The sum of the areas of all polyps from individual mouse was used to determine the tumor burden for each mouse.

Immunostaining for pS6. Mouse tissues were dissected, fixed with 10% formalin solution, embedded in paraffin, and cut into 4- to 5-µm sections. Slides were deparaffinized and endogenous peroxidase activity was blocked by incubation in 3% H2O2 for 10 min at room temperature. Sections were then placed in 10 mmol/L citrate buffer (pH 6.0) and microwaved for 15 min for antigen retrieval. The anti–pS6 antibodies (Cell Signaling Technology) were applied at 1:50 dilution and incubated for 1 h at room temperature. Immunodetection was done with an LSAB 2 system (DAKO). Hematoxylin was used as a counterstain. Immunostaining for pS6 expression was scored by two blinded observers (C.W. and A.R.) and graded on a scale from 1 to 3 (1, weak staining; 2, moderate staining; and 3, strong staining). There were no major discrepancies between the two observers.

Statistical analysis. The statistical significance of the differences in tumor burden of polyps for rapamycin-treated mice and control mice was determined with Student's t test. Fisher's exact test was used to compare the frequency distribution of tumor sizes in treated and control groups and of immunostaining scores in treated and control groups. Spearman correlations were used to assess the correlation among tumor numbers in different size categories in different treatment groups, as well as the correlation among immunostaining scores in different treatment groups. We used Stata version 9 for all analysis. Data are presented as means ± SE.


   Results
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 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Rapamycin strongly suppresses polyposis in Lkb1+/– mice. To investigate whether the inhibition of mTOR activity was an effective means of suppressing polyposis, rapamycin was used to treat of Lkb1+/– mice at the dose of 2 mg/kg/d. This dose was derived form literature where rapamycin was effective as an immunosuppressant in mice (30, 31). As described in our previous study (19), polyposis is first observed in Lkb1+/– mice at 6 months of age. We initiated rapamycin treatment of Lkb1+/– mice at 9 months of age to examine the potential suppressive effects of rapamycin. After a 2-month period, the Lkb1+/– mice (n = 18) in the treatment group and the Lkb1+/– littermate in the control group (n = 18) were sacrificed. The numbers of polyps in different size categories (diameter in millimeters) were compared and the results are summarized in Table 1 . There was a statistically significant difference in polyp distribution between control and rapamycin-treated groups (Fisher's exact test, P = 0.017). Spearman correlation test (P = 0.028) revealed the presence of a trend in polyp distribution in treated versus control groups. Controls had fewer polyps in the smaller size category (none in <2 mm) and more polyps in the larger size category (18.4% in >8 mm), whereas treated animals had more polyps in the smaller size category (7% in <2 mm) and fewer polyps in the larger size category (1.9% in >8 mm). It is noteworthy that there were four small polyps (<2 mm) detected in the treated group whereas no polyps <2 mm were detected in the control group, suggesting that the presence of these small polyps in the rapamycin-treated mice was caused by shrinkage of the larger polyps. Furthermore, the number of polyps in the category of >8 mm was significantly decreased from 7 in the control group to 1 in the rapamycin-treated group (Table 1). A closer comparison of the size distribution of polyps (calculated as a polyp ratio of control/treated) showed that the ratio increased as the polyp size increased, suggesting a progressive reduction of larger polyps following rapamycin treatment (Fig. 1A ).


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  		Table 1. Number of polyps and tumor burden detected in control and rapamycin-treated mice

 

Figure 1
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  		Fig. 1. Rapamycin treatment reduces tumor burden in Lkb1+/– mice. A, comparison of polyp size distribution between control and rapamycin-treated mice, shown as a control/treated ratio for the indicated size categories (diameter in millimeters). No polyps of the smallest size category (<2 mm) were found in control group, compared with four in the treated group. In addition, only one polyp in the largest size category (>8 mm) was found in the treated group, compared with seven in the control group. B, mean tumor burden in control and rapamycin-treated mice. A significant decrease (Student's t test, P = 0.023) was noted in the mean tumor burden in the treated (n = 18; 804 ±131 mm3) versus control mice (n = 18; 1,708 ± 346 mm3; Student's t test, P = 0.023).

 
Next, we compared the tumor burden of polyps detected in control and rapamycin-treated mice in each different size category and overall (Table 1). There was a 47% decrease in total tumor burden in the rapamycin-treated mice (Table 1). Correspondingly, the mean tumor burden was significantly decreased from 1,708 ± 346 mm3 (control mice, n = 18) to 804 ± 131 mm3 (rapamycin-treated mice, n = 18; Student's t test, P = 0.023; Fig. 1B). Taken together, these data suggest that rapamycin treatment would prevent the polyps from forming an obstructive mass.

Effect of rapamycin treatment on mTOR signaling in Lkb1+/–mice. To test whether the tumor-suppressing effect of rapamycin was associated with inhibition of mTOR signaling, the polyps from control and rapamycin-treated Lkb1+/– mice were collected, paraffin embedded, and further analyzed. H&E staining revealed no significant changes in the morphology of the polyps (Fig. 2A and B ). We evaluated mTOR signaling in these polyps by immunostaining. Currently, existing antibodies for mTOR are not useful for immunohistochemistry because they do not produce clean results. Elevated pS6 is a useful marker for detecting increased mTOR kinase activity; therefore, we examined pS6 in polyps of Lkb1+/– mice. pS6 positivity was observed in polyps from both untreated Lkb1+/– mice (Fig. 2C) and Lkb1+/– mice treated with rapamycin (Fig. 2D), indicating that activation of mTOR signaling was associated with polyp development. However, the level of pS6 expression was different in control versus treated animals. We quantified pS6 immunostaining by scoring polyps on a scale from 1 to 3, with 3 being the most intense staining (summarized in Fig. 3A ). There was a significant difference in pS6 immunostaining between the control and rapamycin-treated groups (Fisher's exact test, P = 0.011). Spearman correlation test (P = 0.0019) revealed the presence of a trend in pS6 levels in these two different groups. We found that more of the polyps in the control group showed higher levels of pS6 staining, whereas more of the polyps from the rapamycin-treated group had lower levels of pS6 staining. As shown in Fig. 3B, the average pS6 levels in the polyps from rapamycin-treated Lkb1+/– mice (n = 11; 1.45 ± 0.16) were clearly reduced compared with those from the untreated control group (n = 17; 2.29 ± 0.17; Student's t test, P = 0.0019). This statistically significant reduction in pS6 levels with rapamycin treatment is consistent with a direct effect on the mTOR signaling pathway.


Figure 2
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  		Fig. 2. Rapamycin treatment reduces the phosphorylation level in S6 of Lkb1+/– polyps. A and B, representative H&E staining of the polyps from control (A) and rapamycin-treated (B) mice; original magnification, x40. C and D, representative anti-pS6 immunostaining of polyp sections from control (C) and rapamycin-treated (D) mice; original magnification, x200.

 

Figure 3
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  		Fig. 3. Summary of pS6 immunostaining of Lkb1+/– polyps. A, summary of pS6 level in polyps from control and rapamycin-treated mice. B, average staining score of control and rapamycin-treated mice determined from pS6 immunostaining. The average staining score is significantly reduced from 2.29 ± 0.17 (control; n = 17) to 1.45 ± 0.16 (rapamycin treated; n = 11, Student's t test, P = 0.0019).

 

   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
The present study evaluates the efficacy of rapamycin treatment to reduce Peutz-Jeghers polyposis in a mouse model. Our results revealed that the tumor burden of Lkb1+/– mice was significantly reduced after rapamycin treatment, suggesting that rapamycin is an effective candidate for the treatment of PJS.

The development of hamartomatous polyps constitutes the most significant clinical component of PJS. These hamartomas, although benign, lead to significant complications such as bowel obstruction, rectal prolapse, or severe gastrointestinal bleeding, necessitating multiple emergency laporotomies and bowel resections in PJS patients (4). The morbidity of the polyposis has been reviewed in a 78-year follow-up study of the original PJS family (32). In this family, 22 people were diagnosed as affected. Sixteen of them have been through at least one laparotomy, resulting in a total of 33 laparotomies due to bowel obstruction.

Considering the clinical situation of PJS in which the disease is typically noted through bowel obstruction due to the large polyps, we initiated a rapamycin treatment in a mouse model of PJS after the onset of polyposis (9 months of age). The objective of this study design was to mimic the clinical situation of PJS where patients have a significant tumor burden but often do not know that they have PJS until symptoms develop. Our data show that a 2-month rapamycin treatment led to a significant reduction in large polyps and tumor burden. Immunostaining for pS6 revealed that pS6 immunoreactivity was elevated in the control group, which is in agreement with a previous study (27), whereas the levels of pS6 dramatically decreased after the treatment. S6 phosphorylation levels serve as a good marker for mTOR kinase activity. Thus, our results suggest that polyposis regression via rapamycin is associated with down-regulation of mTOR signaling. These findings support the utilization of mTOR inhibitors as an option for PJS treatment.

In a recent pilot study, Udd et al. (6) tested a selective cyclooxygenase-2 inhibitor (celecoxib) in a PJS mouse model and in patients with PJS and observed a distinct reduction in polyp burden, suggesting that celecoxib could be beneficial in the chemoprevention of PJS polyposis. Cyclooxygenase-2 is not currently known to be directly influenced by LKB1, whereas mTOR is known to be down-regulated by LKB1 signaling to AMPK, which phosphorylates and activates TSC2, the gatekeeper for mTOR signaling. Rapamycin and its analogues, CCI-779 and RAD001, are being evaluated in clinical trials for the treatment of several types of cancer (33–36). Our data suggest that rapamycin or its analogues may represent a new targeted therapy for the treatment of PJS.

In conclusion, we have shown that targeted therapy with a mTOR inhibitor dramatically suppressed the hamartomatous polyposis in the Lkb1+/– Peutz-Jeghers mouse model. Our findings have important implications for future clinical trials in patients with PJS. It would be of interest to conduct a rapamycin treatment study before polyp formation in this PJS mouse model to determine if this drug is able to prevent the formation of polyps and prevent bowl obstruction at the point of tumor initiation.


   Footnotes
 
Grant support: NIH grant R03 CA89843 (M. Frazier), NIH Cancer Center Support Grant CA16672 (J. Mendelsohn), NIH grant R03 CA123603 (C. Wei), and Janis David Gordon Memorial Fellowship from the Cancer Prevention Division at M. D. Anderson Center (C. Wei).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 8/23/07; accepted 10/11/07.


   References
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 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

  1. Jeghers H, McKusick VA, Katz KH. Generalized intestinal polyposis and melanin spots of the oral mucosa, lips and digits; a syndrome of diagnostic significance. N Engl J Med 1949;241:1031–6.[Medline]
  2. Giardiello FM, Welsh SB, Hamilton SR, et al. Increased risk of cancer in the Peutz-Jeghers syndrome. N Engl J Med 1987;316:1511–4.[Abstract]
  3. Spigelman AD, Murday V, Phillips RK. Cancer and the Peutz-Jeghers syndrome. Gut 1989;30:1588–90.[Abstract/Free Full Text]
  4. Buck JL, Harned RK, Lichtenstein JE, Sobin LH. Peutz-Jeghers syndrome. Radiographics 1992;12:365–78.[Abstract]
  5. McGrath DR, Spigelman AD. Preventive measures in Peutz-Jeghers syndrome. Fam Cancer 2001;1:121–5.[Medline]
  6. Udd L, Katajisto P, Rossi DJ, et al. Suppression of Peutz-Jeghers polyposis by inhibition of cyclooxygenase-2. Gastroenterology 2004;127:1030–7.
  7. Rossi DJ, Ylikorkala A, Korsisaari N, et al. Induction of cyclooxygenase-2 in a mouse model of Peutz-Jeghers polyposis. Proc Natl Acad Sci U S A 2002;99:12327–32.[Abstract/Free Full Text]
  8. McGarrity TJ, Peiffer LP, Amos CI, Frazier ML, Ward MG, Howett MK. Overexpression of cyclooxygenase 2 in hamartomatous polyps of Peutz-Jeghers syndrome. Am J Gastroenterol 2003;98:671–8.[CrossRef][Medline]
  9. Wei C, Amos CI, Rashid A, et al. Correlation of staining for LKB1 and COX-2 in hamartomatous polyps and carcinomas from patients with Peutz-Jeghers syndrome. J Histochem Cytochem 2003;51:1665–72.[Abstract/Free Full Text]
  10. Takeda H, Miyoshi H, Tamai Y, Oshima M, Taketo MM. Simultaneous expression of COX-2 and mPGES-1 in mouse gastrointestinal hamartomas. Br J Cancer 2004;90:701–4.[CrossRef][Medline]
  11. de Leng WW, Westerman AM, Weterman MA, et al. Cyclooxygenase 2 expression and molecular alterations in Peutz-Jeghers hamartomas and carcinomas. Clin Cancer Res 2003;9:3065–72.[Abstract/Free Full Text]
  12. Amos CI, Keitheri-Cheteri MB, Sabripour M, et al. Genotype-phenotype correlations in Peutz-Jeghers syndrome. J Med Genet 2004;41:327–33.[Abstract/Free Full Text]
  13. Aretz S, Stienen D, Uhlhaas S, et al. High proportion of large genomic STK11 deletions in Peutz-Jeghers syndrome. Hum Mutat 2005;26:513–9.[CrossRef][Medline]
  14. Schumacher V, Vogel T, Leube B, et al. STK11 genotyping and cancer risk in Peutz-Jeghers syndrome. J Med Genet 2005;42:428–35.[Free Full Text]
  15. Katajisto P, Vallenius T, Vaahtomeri K, et al. The LKB1 tumor suppressor kinase in human disease. Biochim Biophys Acta 2007;1775:63–75.[Medline]
  16. Alessi DR, Sakamoto K, Bayascas JR. LKB1-dependent signaling pathways. Annu Rev Biochem 2006;75:137–63.[CrossRef][Medline]
  17. Hardie DG. New roles for the LKB1->AMPK pathway. Curr Opin Cell Biol 2005;17:167–73.[CrossRef][Medline]
  18. Ylikorkala A, Rossi DJ, Korsisaari N, et al. Vascular abnormalities and deregulation of VEGF in Lkb1-deficient mice. Science 2001;293:1323–6.[Abstract/Free Full Text]
  19. Wei C, Amos CI, Stephens LC, et al. Mutation of Lkb1 and p53 genes exert a cooperative effect on tumorigenesis. Cancer Res 2005;65:11297–303.[Abstract/Free Full Text]
  20. Bardeesy N, Sinha M, Hezel AF, et al. Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation. Nature 2002;419:162–7.[CrossRef][Medline]
  21. Jishage K, Nezu J, Kawase Y, et al. Role of Lkb1, the causative gene of Peutz-Jegher's syndrome, in embryogenesis and polyposis. Proc Natl Acad Sci U S A 2002;99:8903–8.[Abstract/Free Full Text]
  22. Miyoshi H, Nakau M, Ishikawa TO, Seldin MF, Oshima M, Taketo MM. Gastrointestinal hamartomatous polyposis in Lkb1 heterozygous knockout mice. Cancer Res 2002;62:2261–6.[Abstract/Free Full Text]
  23. Hawley SA, Boudeau J, Reid JL, et al. Complexes between the LKB1 tumor suppressor, STRAD{alpha}/β and MO25{alpha}/β are upstream kinases in the AMP-activated protein kinase cascade. J Biol 2003;2:28.[CrossRef][Medline]
  24. Lizcano JM, Goransson O, Toth R, et al. LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J 2004;23:833–43.[CrossRef][Medline]
  25. Shaw RJ, Kosmatka M, Bardeesy N, et al. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci U S A 2004;101:3329–35.[Abstract/Free Full Text]
  26. Woods A, Johnstone SR, Dickerson K, et al. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr Biol 2003;13:2004–8.[CrossRef][Medline]
  27. Shaw RJ, Bardeesy N, Manning BD, et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 2004;6:91–9.[CrossRef][Medline]
  28. Raught B, Gingras AC, Sonenberg N. The target of rapamycin (TOR) proteins. Proc Natl Acad Sci U S A 2001;98:7037–44.[Abstract/Free Full Text]
  29. Franz DN, Leonard J, Tudor C, et al. Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol 2006;59:490–8.[CrossRef][Medline]
  30. Blazar BR, Taylor PA, Snover DC, Sehgal SN, Vallera DA. Murine recipients of fully mismatched donor marrow are protected from lethal graft-versus-host disease by the in vivo administration of rapamycin but develop an autoimmune-like syndrome. J Immunol 1993;151:5726–41.[Abstract]
  31. Chen H, Qi S, Xu D, Wu J, Daloze P. The immunosuppressive effect of rapamycin on mouse small bowel transplantation. Transplantation 1996;61:523–6.[CrossRef][Medline]
  32. Westerman AM, Entius MM, de Baar E, et al. Peutz-Jeghers syndrome: 78-year follow-up of the original family. Lancet 1999;353:1211–5.[CrossRef][Medline]
  33. Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev Cancer 2004;4:335–48.[CrossRef][Medline]
  34. Guertin DA, Sabatini DM. An expanding role for mTOR in cancer. Trends Mol Med 2005;11:353–61.[CrossRef][Medline]
  35. Rowinsky EK. Targeting the molecular target of rapamycin (mTOR). Curr Opin Oncol 2004;16:564–75.[CrossRef][Medline]
  36. Vignot S, Faivre S, Aguirre D, Raymond E. mTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol 2005;16:525–37.[Abstract/Free Full Text]




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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online