PMID- 16730273
OWN - NLM
STAT- MEDLINE
DCOM- 20060706
LR  - 20181201
IS  - 0093-7754 (Print)
IS  - 0093-7754 (Linking)
VI  - 33
IP  - 2 Suppl 7
DP  - 2006 Apr
TI  - Future directions in the treatment of hormone-sensitive advanced breast cancer: 
      the RAD001 (Everolimus)-letrozole clinical program.
PG  - S18-25
AB  - Therapeutics that interfere with estrogen receptor function (antiestrogens, eg, 
      tamoxifen; aromatase inhibitors, eg, letrozole) have contributed to a dramatic 
      reduction in breast cancer mortality; however, not all estrogen-receptor-positive 
      breast cancers respond. The mammalian target-of-rapamycin (mTOR) is emerging as 
      an important target molecule in the treatment of breast cancer. Furthermore, 
      activation of growth-factor signaling pathways that involve mTOR may contribute 
      to both the failure of endocrine therapy as well as the development of 
      resistance. RAD001 (everolimus) is a potent, orally bioavailable inhibitor of the 
      mTOR pathway. Preclinical data show that RAD001 effectively inhibits the 
      proliferation and growth of a number of cancer cell lines in vitro and a range of 
      tumor types in experimental animal models of cancer. Moreover, RAD001 exhibits an 
      antiangiogenic activity, which may also contribute to its anticancer activity. 
      The aromatase inhibitor letrozole is a potent endocrine therapy for breast cancer 
      that acts to inhibit the aromatization of androgens, thereby reducing plasma and 
      tumor estrogen levels. Combining RAD001 with letrozole is a rational approach to 
      the treatment of advanced breast cancer, offering the potential for inhibition of 
      tumor cell growth/proliferation and angiogenesis while at the same time 
      potentially preventing the development of letrozole resistance. Preclinical data, 
      derived from aromatase-expressing, estrogen-receptor-positive breast tumor 
      models, suggest a synergistic interaction between RAD001 and letrozole that 
      results in more profound effects on proliferation and the induction of tumor cell 
      death. Importantly, early clinical data show no pharmacokinetic interaction or 
      increase in toxicity with combined treatment, as compared with treatment with 
      RAD001 alone, and there is evidence of antitumor activity. Enrollment into phase 
      II studies is presently underway.
FAU - Lane, Heidi A
AU  - Lane HA
AD  - Novartis Institutes For BioMedical Research, Oncology Basel, Novartis Pharma AG, 
      Switzerland.
FAU - Lebwohl, David
AU  - Lebwohl D
LA  - eng
PT  - Journal Article
PT  - Review
PL  - United States
TA  - Semin Oncol
JT  - Seminars in oncology
JID - 0420432
RN  - 0 (Aromatase Inhibitors)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Nitriles)
RN  - 0 (Receptors, Estrogen)
RN  - 0 (Triazoles)
RN  - 7LKK855W8I (Letrozole)
RN  - 9HW64Q8G6G (Everolimus)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Aromatase Inhibitors/*therapeutic use
MH  - Breast Neoplasms/*drug therapy/metabolism/pathology
MH  - Clinical Trials as Topic
MH  - Everolimus
MH  - Female
MH  - Forecasting
MH  - Humans
MH  - Immunosuppressive Agents/*therapeutic use
MH  - Letrozole
MH  - Neoplasms, Hormone-Dependent/*drug therapy/metabolism/pathology
MH  - Nitriles/*therapeutic use
MH  - Receptors, Estrogen/*metabolism
MH  - Sirolimus/*analogs & derivatives/therapeutic use
MH  - Triazoles/*therapeutic use
RF  - 60
EDAT- 2006/05/30 09:00
MHDA- 2006/07/11 09:00
CRDT- 2006/05/30 09:00
PHST- 2006/05/30 09:00 [pubmed]
PHST- 2006/07/11 09:00 [medline]
PHST- 2006/05/30 09:00 [entrez]
AID - S0093-7754(06)00172-2 [pii]
AID - 10.1053/j.seminoncol.2006.03.024 [doi]
PST - ppublish
SO  - Semin Oncol. 2006 Apr;33(2 Suppl 7):S18-25. doi: 
      10.1053/j.seminoncol.2006.03.024.