Sirolimus/Rapamycin

[Rich66]

JOP. 2009 Jul 6;10(4):393-5.
Sirolimus can reverse resistance to gemcitabine, capecitabine and docetaxel combination therapy in pancreatic cancer.

Sherman WH.
Columbia University, College Physicians and Surgeons, New York, NY, USA. whs4@columbia.edu
CONTEXT: Treating patients with metastatic carcinoma of the pancreas can lead to regression of disease, but the tumor becomes resistant to therapy within a few months. If resistance can be reversed or prevented, the chemotherapeutic benefit may be prolonged. CASE REPORTS: Two patients with metastatic pancreatic cancer progressed on gemcitabine, capecitabine and docetaxel (GTX). When sirolimus was added to this regimen at a dosage to achieve a serum level of at least 10 ng/dL at the time of the gemcitabine and docetaxel infusion, their tumors regressed. CONCLUSION: This demonstrates that the addition of sirolimus to a gemcitabine/docetaxel containing regimen can reverse tumor resistance in the clinical setting.

PMID: 19581741 [PubMed - indexed for MEDLINE]



Semin Oncol. 2009 Dec;36 Suppl 3:S46-58.
Evaluating temsirolimus activity in multiple tumors: a review of clinical trials.

Dancey JE, Curiel R, Purvis J.
The Ontario Institute for Cancer Research, MaRS Centre, 101 College Street, Toronto, ON, Canada. janet.dancey@oicr.on.ca
Activation of mammalian target of rapamycin (mTOR) signaling occurs in a wide variety of human tumors and can lead to increased susceptibility to mTOR inhibitors. Temsirolimus, a novel analog of rapamycin, has shown promising preclinical and early clinical anti-tumor activity in various solid and hematologic tumor types, either alone or in combination with chemotherapy or other targeted agents. Randomized phase III trials have already demonstrated significant clinical benefits of treatment with single-agent temsirolimus in advanced renal cell carcinoma and relapsed and/or refractory mantle cell lymphoma. Other malignancies studied in the phase I and II trial settings include glioblastoma, breast cancer, endometrial cancer, non-Hodgkin lymphomas, and multiple myeloma. This article reviews a comprehensive collection of the clinical trial results reported to date for temsirolimus in various solid and hematologic malignancies, as well as current strategies being tested in ongoing trials. The findings with temsirolimus in multiple tumors provide a valuable framework for future development of temsirolimus and other mTOR inhibitors.

PMID: 19963100 [PubMed - indexed for MEDLINE]

Distinguishing Friend from Foe in the Battle Against Cancer

http://www.physorg.com/news77201870.html

excerpt:

Rapamycin, an immunosuppressant used to block organ rejection after transplants, also inactivates proteins stimulating cell division and in clinical trials has been combined with other drugs to halt cancer cell growth.
But to cancer cells, rapamycin is both friend and foe. “Rapamycin is not as successful as initially expected in treating cancer,” explains Ghosh. “Instead of killing cells, you end up triggering a survival response in them.” This study, however, suggests that taking NF-kB out of the game would make rapamycin less “friendly.”
“A major problem of chemotherapy is that sooner or later cancer cells develop resistance, which requires higher and higher doses of chemotherapeutics,” observes Verma, who is also an American Cancer Society professor in Salk's Laboratory of Genetics. “Rapamycin-mediated killing of cancer cells could be increased by inhibiting the function of NF-kB proteins. Our studies provide the basis for arriving at this very important conclusion, which has enormous bearing on cancer treatment.”
Tergaonkar concurs. “Our studies suggest the potential use of NF-kB signaling inhibitors as adjuvants to maximize the effect of rapamycin-based therapeutics. These findings will have a significant impact on human health.”

Pair w/green tea?

Mol Pharmacol. 2010 Jan;77(1):17-25. Epub 2009 Oct 14.
Epigallocatechin-3-gallate inhibits osteoclastogenesis by down-regulating c-Fos expression and suppressing the nuclear factor-kappaB signal.

Lee JH, Jin H, Shim HE, Kim HN, Ha H, Lee ZH.
Department of Cell and Developmental Biology, School of Dentistry, Seoul National University, 28 Yeongon-Dong, Jongro-Gu, Seoul 110-749, Republic of Korea.
Epigallocatechin-3-gallate (EGCG), the major anti-inflammatory compound in green tea, has been shown to suppress osteoclast differentiation. However, the precise molecular mechanisms underlying the inhibitory action of EGCG in osteoclastogenesis and the effect of EGCG on inflammation-mediated bone destruction remain unclear. In this study, we found that EGCG inhibited osteoclast formation induced by osteoclastogenic factors in bone marrow cell-osteoblast cocultures but did not affect the ratio of receptor activator of nuclear factor kappaB (NF-kappaB) ligand (RANKL) to osteoprotegerin induced by osteoclastogenic factors in osteoblasts. We also found that EGCG inhibited osteoclast formation from bone marrow macrophages (BMMs) induced by macrophage colony-stimulating factor plus RANKL in a dose-dependent manner without cytotoxicity. Pretreatment with EGCG significantly inhibited RANKL-induced the gene expression of c-Fos and nuclear factor of activated T-cells (NFATc1), essential transcription factors for osteoclast development. EGCG suppressed RANKL-induced activation of c-Jun N-terminal protein kinase (JNK) pathway, among the three well known mitogen-activated protein kinases and also inhibited RANKL-induced phosphorylation of the NF-kappaB p65 subunit at Ser276 and NF-kappaB transcriptional activity without affecting the degradation of IkappaBalpha and NF-kappaB DNA-binding in BMMs. The inhibitory effect of EGCG on osteoclast formation was somewhat reversed by retroviral c-Fos overexpression, suggesting that c-Fos is a downstream target for antiosteoclastogenic action of EGCG. In addition, EGCG treatment reduced interleukin-1-induced osteoclast formation and bone destruction in mouse calvarial bone in vivo. Taken together, our data suggest that EGCG has an antiosteoclastogenic effect by inhibiting RANKL-induced the activation of JNK/c-Jun and NF-kappaB pathways, thereby suppressing the gene expression of c-Fos and NFATc1 in osteoclast precursors.

PMID: 19828731 [PubMed - indexed for MEDLINE]