Monitoring antitumor efficacy of rapamycin in Kaposi sarcoma.
BACKGROUND
The clinical challenge for the application of rapamycin and its derivatives as anticancer drugs is the ability to prospectively identify which tumors will be sensitive to mammalian target of rapamycin (mTOR) inhibition. The present study is designed to explore mTOR signaling in peripheral-blood mononuclear cells (PBMCs) from renal transplant recipients with Kaposi sarcoma and ascertain whether it would reflect deregulation of the AKT-mTOR pathway in skin cancer tissue and might help identify which patients would benefit from rapamycin treatment, as well as to monitor their clinical response.


METHODS
We measured basal and in vivo stimulated AKT and P70 S6 kinase (P70(S6K)) phosphorylation in PBMCs from 37 cyclosporine A-treated patients, 10 of whom had Kaposi sarcoma, before and 6 months after conversion to rapamycin therapy.


RESULTS
Patients with Kaposi sarcoma showed markedly increased basal P70(S6K) activation and depressed phosphorylation of AKT. Long-term treatment with rapamycin was associated with marked inhibition of basal and stimulated phosphorylation of both AKT and P70(S6K), in parallel with regression of the dermal neoplasm.


CONCLUSIONS
Overactivation of basal P70(S6K) in PBMCs from renal transplant recipients appears to be associated with the presence of Kaposi sarcoma dermal lesions; conversely, kinase inhibition is linked to regression of skin cancer lesions. Thus, monitoring P70(S6K) phosphorylation can help predict and monitor the biological effectiveness of rapamycin in renal transplant recipients with Kaposi sarcoma and possibly adjust the biologically active doses of the mTOR inhibitor.
Di Paolo
Salvatore
S
Department of Emergency and Organ Transplants, Division of Nephrology, Dialysis and Transplantation, University of Bari, Policlinico-Piazza Giulio Cesare, 11-70124 Bari, Italy. s.dipaolo@nephro.uniba.it
Teutonico
Annalisa
A
Ranieri
Elena
E
Gesualdo
Loreto
L
Schena
Paolo F
PF
D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D005260:Female; D006801:Humans; D016030:Kidney Transplantation / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000502:physiology; D018579:Patient Selection; D010766:Phosphorylation; D011237:Predictive Value of Tests; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000502:physiology; D012514:Sarcoma, Kaposi / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology; D020123:Sirolimus / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D058570:TOR Serine-Threonine Kinases; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D015415:Biomarkers; D011494:Protein Kinases; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus