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Old 11-13-2009, 02:03 AM   #1
Rich66
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Join Date: Feb 2008
Location: South East Wisconsin
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mTOR inhibitors

(Metformin, ridaforolimus, rapamycin, rap w/ LBH589(HDAC inhib), w/Paclitaxel, w/Cyclophosphamide, silibinin, curcumin etc, issue in many cancers, w/selenium, upregulates CD133/stemness?, w/methylnaltrexone, w/suppressed immune system?)

See potentially related endocrine resistance reversal

Metformin


Site about mTOR therapies
www.targetmtor.com



J Hematol Oncol. 2009 Oct 27;2:45.
Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy.

Yuan R, Kay A, Berg WJ, Lebwohl D.
Novartis Oncology, Florham Park, NJ, USA. yuanru@umdnj.edu.
ABSTRACT: The mammalian target of rapamycin (mTOR) is an intracellular serine/threonine protein kinase positioned at a central point in a variety of cellular signaling cascades. The established involvement of mTOR activity in the cellular processes that contribute to the development and progression of cancer has identified mTOR as a major link in tumorigenesis. Consequently, inhibitors of mTOR, including temsirolimus, everolimus, and ridaforolimus (formerly deforolimus) have been developed and assessed for their safety and efficacy in patients with cancer. Temsirolimus is an intravenously administered agent approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for the treatment of advanced renal cell carcinoma (RCC). Everolimus is an oral agent that has recently obtained US FDA and EMEA approval for the treatment of advanced RCC after failure of treatment with sunitinib or sorafenib. Ridaforolimus is not yet approved for any indication. The use of mTOR inhibitors, either alone or in combination with other anticancer agents, has the potential to provide anticancer activity in numerous tumor types. Cancer types in which these agents are under evaluation include neuroendocrine tumors, breast cancer, leukemia, lymphoma, hepatocellular carcinoma, gastric cancer, pancreatic cancer, sarcoma, endometrial cancer, and non-small-cell lung cancer. The results of ongoing clinical trials with mTOR inhibitors, as single agents and in combination regimens, will better define their activity in cancer.

PMID: 19860903 [PubMed - in process]





Nephrol. 2009 Jul-Aug;22(4):457-62.Antineoplastic effect of proliferation signal inhibitors: from biology to clinical application.

Bertoni E, Salvadori M.
Renal Unit, Careggi University Hospital, Florence, Italy. salvadorim@aou-careggi.toscana.it
The authors review the antineoplastic effect of mammalian target of rapamycin (mTOR) inhibitors and their biological basis. mTOR is an intracellular serine/threonine kinase that is a central controller of cell growth and proliferation. mTOR integrates signals from sources such as nutrients and growth factors. mTOR regulation can affect angiogenesis, cell growth, nutrient uptake and utilization, and metabolism. Growth factors such as insulin growth factor, epidermal growth factor, platelet-derived growth factor and vascular endothelial growth factor bind to and activate receptors located on the cell surface. Receptors activate intracellular signaling cascades phosphatidylinositol 3 kinase-serine-threonine kinase-mTOR (PI3K-AKT-mTOR) leading to protein synthesis. Activation of the mTOR pathway is linked to increased protein synthesis by modulating elements that are important in cellular processes, including growth, proliferation, angiogenesis and nutrient uptake. Many growth factor receptors and signaling pathway components are deregulated in cancer. Deregulations in mTOR-linked pathways increase the risk of developing cancer or have been identified in many human cancers. Deregulations include overexpression of growth factors, overexpression or mutations of growth factor receptors, loss of tumor suppressor genes, and gain-of-function mutations in mTOR-linked pathways. These deregulations permit the survival, growth, proliferation and migration of cancer cells and promote tumor angiogenesis. Targeting them has been a successful anticancer strategy. Targeting mTOR as well as these deregulated pathways could provide enhanced anticancer activity. The efficacy of mTOR inhibitors in preventing several types of cancers in transplanted patients or in recovering cancers developed in transplant patients has been documented in both trials and single reports.

PMID: 19662600 [PubMed - indexed for MEDLINE]




Clin Cancer Res. 2009 Nov 24. [Epub ahead of print] Inhibition of Mammalian Target of Rapamycin Is Required for Optimal Antitumor Effect of HER2 Inhibitors against HER2-Overexpressing Cancer Cells. Miller TW, Forbes JT, Shah C, Wyatt SK, Manning HC, Olivares MG, Sanchez V, Dugger TC, de Matos Granja N, Narasanna A, Cook RS, Kennedy JP, Lindsley CW, Arteaga CL. Authors' Affiliations: Departments of Medicine, Radiology and Radiological Sciences, Biomedical Engineering, Neurosurgery, Pathology, Cancer Biology, and Chemistry, Program in Chemical and Physical Biology, Vanderbilt University Institute of Imaging Science, and Breast Cancer Research Program, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University, Nashville, Tennessee. PURPOSE: A significant fraction of HER2-overexpressing breast cancers exhibit resistance to the HER2 antibody trastuzumab. Hyperactivity of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway confers trastuzumab resistance, and mammalian target of rapamycin (mTOR) is a major downstream effector of PI3K/AKT. Therefore, we examined whether mTOR inhibitors synergize with trastuzumab. EXPERIMENTAL DESIGN: Immunocompetent mice bearing HER2(+) mammary tumors were treated with trastuzumab, the mTOR inhibitor rapamycin, or the combination. Mice were imaged for tumor cell death using an optical Annexin-V probe and with [(18)F]FDG positron emission tomography. The signaling and growth effects of the mTOR inhibitor RAD001 on HER2(+) cells treated with trastuzumab or lapatinib were evaluated. RESULTS: Treatment of mice with trastuzumab plus rapamycin was more effective than single-agent treatments, inducing complete regression of 26 of 26 tumors. The combination induced tumor cell death (Annexin-V binding) and inhibited FDG uptake. Rapamycin inhibited mTOR and tumor cell proliferation as determined by phosphorylated S6 and Ki-67 immunohistochemistry, respectively. In culture, the combination of RAD001 plus trastuzumab inhibited cell growth more effectively than either drug alone. Trastuzumab partially decreased PI3K but not mTOR activity. Knockdown of TSC2 resulted in HER2-independent activation of mTOR and dampened the response to trastuzumab and lapatinib. Treatment with the HER2 inhibitor lapatinib decreased phosphorylated S6 and growth in TSC2-expressing cells but not in TSC2-knockdown cells. CONCLUSIONS: Inhibition of PI3K and mTOR are required for the growth-inhibitory effect of HER2 antagonists. These findings collectively support the combined use of trastuzumab and mTOR inhibitors for the treatment of HER2(+) breast cancer. (Clin Cancer Res 2009;15(23):7266-76). PMID: 19934303 [PubMed - as supplied by publisher]





Breast Cancer Res Treat. 2010 Feb 5. [Epub ahead of print]
Metformin and rapamycin have distinct effects on the AKT pathway and proliferation in breast cancer cells.

Zakikhani M, Blouin MJ, Piura E, Pollak MN.
Department of Oncology, McGill University, Montreal, QC, Canada.
Rapamycin and its analogues inhibit mTOR, which leads to decreased protein synthesis and decreased cancer cell proliferation in many experimental systems. Adenosine 5'- monophosphate-activated protein kinase (AMPK) activators such as metformin have similar actions, in keeping with the TSC2/1 pathway linking activation of AMPK to inhibition of mTOR. As mTOR inhibition by rapamycin is associated with attenuation of negative feedback to IRS-1, rapamycin is known to increase activation of AKT, which may reduce its anti-neoplastic activity. We observed that metformin exposure decreases AKT activation, an action opposite to that of rapamycin. We show that metformin (but not rapamycin) exposure leads to increased phosphorylation of IRS-1 at Ser(789), a site previously reported to inhibit downstream signaling and to be an AMPK substrate phosphorylated under conditions of cellular energy depletion. siRNA methods confirmed that reduction of AMPK levels attenuates both the IRS-1 Ser(789) phosphorylation and the inhibition of AKT activation associated with metformin exposure. Although both rapamycin and metformin inhibit mTOR (the former directly and the latter through AMPK signaling), our results demonstrate previously unrecognized differences between these agents. The data are consistent with the observation that
Quote:
maximal induction of apoptosis and inhibition of proliferation are greater for metformin than rapamycin.
PMID: 20135346 [PubMed - as supplied by publisher]




1: Clin Transl Oncol. 2009 Jul;11(7):455-9.Links
mTOR inhibitors and the anti-diabetic biguanide metformin: new insights into the molecular management of breast cancer resistance to the HER2 tyrosine kinase inhibitor lapatinib (Tykerb(R)).

Vázquez-Martín A, Oliveras-Ferraros C, Del Barco S, Martín-Castillo B, Menéndez JA.
The small molecule HER2 tyrosine kinase inhibitor (TKI) lapatinib (Tykerb(R)) is approved for the therapy of patients with HER2-positive breast carcinomas who have progressed on trastuzumab (Herceptin(R)). Unfortunately, the efficacy of this HER2 TKI is limited by both primary (inherent) and acquired resistance, the latter typically occurring within 12 months of starting therapy. One of the key factors limiting our understanding of the mechanisms involved in lapatinib resistance is the lack of published preclinical models. We herein review lapatinib-refractory models recently developed at the bench and the survival pathways discovered. As hyperactivation of the pharmacologically targetable PI3K/mTOR/p70S6K1 axis appears to be central to the occurrence of lapatinib resistance, preclinical data showing enhanced antitumour effects when combining lapatinib with mTOR inhibitors (e.g., rapamycin analogues and NVP-BEZ235) highlight the importance of translational work to yield clinically useful regimens capable of delaying or treating lapatinib resistance. The unexpected ability of the anti-type II diabetes drug metformin to inactivate mTOR and decrease p70S6K1 activity further reveals that this biguanide, generally considered non-toxic and remarkably inexpensive, might be considered for new combinatorial lapatinib-based protocols in HER2-overexpressing breast cancer patients.
Article LINK

Contact: Dama Kimmon
dama.kimmon@uc.edu
513-558-4519
University of Cincinnati Academic Health Center
Popular diabetes drug works differently than thought

CINCINNATI—The popular diabetes medication metformin works in different fashion than the current widely accepted view. This new finding could lead to wider use of the drug—particularly in people with cancer and diseases linked to TSC deficiency like tuberous sclerosis and lymphangioleiomyomatosis (LAM).
The results of this study, led by George Thomas, PhD, scientific director of UC's Metabolic Diseases Institute, are published in the May 5 edition of Cell Metabolism.
Metformin, marketed first by Bristol-Myers Squibb as Glucophage and now available in generic form and a number of combinations, is widely prescribed to people with type 2 diabetes and may be extended to the treatment of certain cancers. The drug blocks the production of glucose (sugar) and increases sensitivity to insulin—a hormone that converts sugar and other foods into energy within the body.
Researchers have thought that metformin, an energy-deprivation agent, disables the mTOR (mammalian target of rapamycin) complex by first activating the tuberous sclerosis complex (TSC) proteins through the enzyme AMPK.
Thomas' team determined that mTOR could actually be disabled without AMPK, and even without TSC. The team was able to determine that metformin works to knock out mTOR through another enzyme, RAG GTPase.
"We've poked a hole in dogma," says Thomas, a professor in the cancer and cell biology department. "Scientists can and should go back and ask about things they had crossed off their list."
The importance of this finding, says Thomas, is the possibility it holds for broader use of metformin.
"Metformin is already prescribed to 100 million people worldwide, and our study raises the question, 'Could this drug be used even more widely?'"
A drug like metformin, which improves insulin sensitivity, could be seen as a possible viable alternative to drugs that target mTOR, but that may have long-term deleterious effects on insulin production. Type 2 diabetes results from the body's inability to properly use insulin. If left unmanaged, diabetes can lead to vision loss, kidney failure, heart attack, stroke and nerve or blood vessel damage.

MORE ON METFORMIN



ridaforolimus may be able to overcome tumors that have become resistant to Traztuzumab.

LINK


Ariad posts positive early breast cancer test data

By: The Associated Press | 28 Jul 2009 | 10:23 AM ET

The Associated Press
| 28 Jul 2009 | 10:23 AM ET

CAMBRIDGE, Mass. - Ariad Pharmaceuticals Inc. on Tuesday said clinical trial results show its drug candidate ridaforolimus could be effective against breast cancer.
Aria said interim data showed ridaforolimus may be able to overcome tumors that have become resistant to the cancer drugs Herceptin and Avastin. The company reported results from a mid stage study of the drug in breast cancer, in combination with Herceptin, and an early stage trial of ridaforolimus and Avastin.
The news sent Ariad shares surging 54 cents, or 22 percent, to $2.99 in morning trading.
Ariad is testing ridaforolimus in a partnership with Merck & Co. The drug is designed to act on a protein called mTOR, which is involved in the growth, division, and metabolism of cells. Ariad is a development stage company with no products on the market, and it is also testing ridaforolimus as a treatment for sarcoma.
The company is conducting a mid stage study of ridaforolimus and Herceptin against breast cancer to see if the combination can shrink tumors that have become resistant to Herceptin alone. Ariad said 28 patients have enrolled in the trial, which started a year ago, and 15 have no disease progression. The company plans to enroll a total of 33 patients.
Ariad also said an early stage trial showed ridaforolimus and Avastin could benefit patients with solid tumors. That study tests the two drugs against solid metastasized tumors that have become resistant to Avastin. It said five of the 17 patients in the trial are still involved in the study and have no disease progression.
Avastin and Herceptin are marketed by Genentech, a unit of Swiss drugmaker Roche Holding.
Copyright 2009 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.
URL: http://www.cnbc.com/id/32186076/





Ann Oncol. 2009 Nov 9. [Epub ahead of print]
Phase Ib study of weekly mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) with weekly paclitaxel.

Sessa C, Tosi D, Viganň L, Albanell J, Hess D, Maur M, Cresta S, Locatelli A, Angst R, Rojo F, Coceani N, Rivera VM, Berk L, Haluska F, Gianni L.
Department of Medical Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
BACKGROUND: The additive cytotoxicity in vitro prompted a clinical study evaluating the non-prodrug rapamycin analogue ridaforolimus (AP23573; MK-8669; formerly deforolimus) administered i.v. combined with paclitaxel (PTX; Taxol). Materials and methods: Patients with taxane-sensitive solid tumors were eligible. The main dose escalation foresaw 50% ridaforolimus increments from 25 mg with a fixed PTX dose of 80 mg/m(2), both given weekly 3 weeks in a 4-week cycle. Collateral levels with a lower dose of either drug were planned upon achievement of the maximum tolerated dose in the main escalation. Pharmacodynamic studies in plasma, peripheral blood mononuclear cells (PBMCs) and skin biopsies and pharmacokinetic (PK) interaction studies at cycles 1 and 2 were carried out. RESULTS: Two recommended doses were determined: 37.5 mg ridaforolimus/60 mg/m(2) PTX and 12.5 mg/80 mg/m(2). Most frequent toxic effects were mouth sores (79%), anemia (79%), fatigue (59%), neutropenia (55%) and dermatitis (48%). Two partial responses were observed in pharyngeal squamous cell and pancreatic carcinoma. Eight patients achieved stable disease >/=4 months. No drug interaction emerged from PK studies. Decrease of eukaryotic initiation factor 4E-binding protein1 (4E-BP1) phosphorylation was shown in PBMCs. Similar inhibition of phosphorylation of 4E-BP1 and mitogen-activated protein kinase was present in reparative epidermis and vascular tissues, respectively. CONCLUSION: Potential antiangiogenic effects and encouraging antitumor activity justify further development of the combination.

PMID: 19901013 [PubMed - as supplied by publisher]




Eur J Cancer. 2010 Feb 13. [Epub ahead of print]
Treating triple-negative breast cancer by a combination of rapamycin and cyclophosphamide: An in vivo bioluminescence imaging study.

Zeng Q, Yang Z, Gao YJ, Yuan H, Cui K, Shi Y, Wang H, Huang X, Wong ST, Wang Y, Kesari S, Ji RR, Xu X.
Department of Radiology, Brigham and Women's Hospital, Boston, MA, USA.
Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, has been shown to inhibit the growth of oestrogen positive breast cancer. However, triple-negative (TN) breast cancer is resistant to rapamycin treatment in vitro. We set to test a combination treatment of rapamycin with DNA-damage agent, cyclophosphamide, in a TN breast cancer model. By binding to and disrupting cellular DNA, cyclophosphamide kills cells via interfering with their normal functions. We assessed the responses of nude mice bearing tumour xenografts of TN MDA-MB-231 cells to the combination of rapamycin and cyclophosphamide in both orthotopic mammary and lung-metastasis models. We tracked tumour growth and metastasis by bioluminescent imaging and examined the expression of Ki67, CD34 and HIF-1alpha in tumour tissues by immunohistochemistry and apoptosis index with TUNEL assay, and found that MDA-MB-231 cells are sensitive to rapamycin therapy in orthotopic mammary, but not in lung with metastasis. Rapamycin when combined with cyclophosphamide is found to have a more significant effect in reducing tumour volume and metastasis with a much improved survival rate. Our data also show that the sensitivity of TN tumours to rapamycin is associated with the microenvironment of the tumour cells. The data indicate that in a relatively hypoxic environment HIF-1alpha may play a role in mediating the anti-cancer effect of rapamycin and cyclophosphamide may prevent the feedback activation of Akt by rapamycin. Overall our results show that rapamycin plus cyclophosphamide can achieve an improved efficacy in suppressing tumour growth and metastasis, suggesting that the combination therapy can be a promising treatment option for TN cancer. Copyright © 2010 Elsevier Ltd. All rights reserved.

PMID: 20156674 [PubMed - as supplied by publisher]




Clin Cancer Res. 2009 Feb 15;15(4):1428-34.
A phase I trial to determine the safety, tolerability, and maximum tolerated dose of deforolimus in patients with advanced malignancies.

Hartford CM, Desai AA, Janisch L, Karrison T, Rivera VM, Berk L, Loewy JW, Kindler H, Stadler WM, Knowles HL, Bedrosian C, Ratain MJ.
Department of Pediatrics, Cancer Research Center, and Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, Illinois 60637, USA.
PURPOSE: This was a phase I trial to determine the maximum tolerated dose and toxicity of deforolimus (AP23573, MK-8669), an inhibitor of mammalian target of rapamycin (mTOR). The pharmacokinetics, pharmacodynamics, and antineoplastic effects were also studied. EXPERIMENTAL DESIGN: Deforolimus was administered intravenously over 30 min every 7 days according to a flat dosing schedule. Dose was escalated according to an accelerated titration design. Patients remained on study until disease progression as long as they tolerated the drug without significant toxicities. RESULTS: Forty-six patients were enrolled on the study. Common side effects included fatigue, anorexia, and mucositis. The maximum tolerated dose was 75 mg and mucositis was the dose-limiting toxicity. Similar to other mTOR inhibitors, deforolimus exhibited nonlinear pharmacokinetics and a prolonged half-life. Among 34 patients evaluable for response, 1 patient had a partial response, 21 patients had stable disease, and 12 had progressed. Percent change in tumor size was significantly associated with AUC (P=0.015). A significant association was also detected for maximum change in cholesterol within the first two cycles of therapy and change in tumor size (r=-0.38; P=0.029). CONCLUSIONS: Deforolimus was well tolerated on the schedule tested in this trial with toxicity and pharmacokinetic profiles that were similar to that of other mTOR inhibitors. Additional phase II studies are needed to determine if deforolimus is superior to other mTOR inhibitors in terms of efficacy. The change in serum cholesterol as a potential biomarker of activity should be studied further.

PMID: 19228743 [PubMed - indexed for MEDLINE]




Mol Cancer Ther. 2009 Jun;8(6):1606-12. Epub 2009 Jun 9.
Silibinin inhibits translation initiation: implications for anticancer therapy.

Lin CJ, Sukarieh R, Pelletier J.
McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada.
Silibinin is a nontoxic flavonoid reported to have anticancer properties. In this study, we show that silibinin exhibits antiproliferative activity on MCF-7 breast cancer cells. Exposure to silibinin leads to a concentration-dependent decrease in global protein synthesis associated with reduced levels of eukaryotic initiation factor 4F complex. Moreover, polysome profile analysis of silibinin-treated cells shows a decrease in polysome content and translation of cyclin D1 mRNA. Silibinin exerts its effects on translation initiation by inhibiting the mammalian target of rapamycin signaling pathway by acting upstream of TSC2. Our results show that silibinin blocks mammalian target of rapamycin signaling with a concomitant reduction in translation initiation, thus providing a possible molecular mechanism of how silibinin can inhibit growth of transformed cells.

PMID: 19509268 [PubMed - indexed for MEDLINE]


More on Silibinin/Milk Thistle HERE





Cancer Res. 2009 Feb 1;69(3):1000-8. Epub 2009 Jan 27.
Curcumin disrupts the Mammalian target of rapamycin-raptor complex.

Beevers CS, Chen L, Liu L, Luo Y, Webster NJ, Huang S.
Department of Biochemistry and Molecular Biology, Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932, USA.
Curcumin (diferuloylmethane), a polyphenol natural product of the plant Curcuma longa, is undergoing early clinical trials as a novel anticancer agent. However, the anticancer mechanism of curcumin remains to be elucidated. Recently, we have shown that curcumin inhibits phosphorylation of p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), two downstream effector molecules of the mammalian target of rapamycin complex 1 (mTORC1) in numerous cancer cell lines. This study was designed to elucidate the underlying mechanism. We observed that curcumin inhibited mTORC1 signaling not by inhibition of the upstream kinases, such as insulin-like growth factor 1 receptor (IGF-IR) and phosphoinositide-dependent kinase 1 (PDK1). Further, we found that curcumin inhibited mTORC1 signaling independently of protein phosphatase 2A (PP2A) or AMP-activated protein kinase AMPK-tuberous sclerosis complex (TSC). This is evidenced by the findings that curcumin was able to inhibit phosphorylation of S6K1 and 4E-BP1 in the cells pretreated with PP2A inhibitor (okadaic acid) or AMPK inhibitor (compound C), or in the cells expressing dominant-negative (dn) PP2A, shRNA to PP2A-A subunit, or dn-AMPKalpha. Curcumin did not alter the TSC1/2 interaction. Knockout of TSC2 did not affect curcumin inhibition of mTOR signaling. Finally, we identified that curcumin was able to dissociate raptor from mTOR, leading to inhibition of mTORC1 activity. Therefore, our data indicate that curcumin may represent a new class of mTOR inhibitor.

PMID: 19176385 [PubMed - indexed for MEDLINE


CURCUMIN thread HERE




April 27, 2009
Oncology News International.

Combination therapies throw up roadblocks to oncogenic signaling pathways

Shalmali Pal

DENVER—Forget the theory of diminishing returns: If one is good, then two must be better. As a result, cancer researchers are turning their attention to combination therapies, particularly for blocking tumor signaling pathways.

"Most people believe that in many forms of human cancer, this pathway is incredibly complicated," said Owen O'Connor, MD. "There are all sorts of new therapeutics, which target biology, that we didn't have before. We can now rationally combine them in a strategic way to block the ability of the cell to become resistant to these therapies."

Simultaneous blocking


The RAS/MAPK and PI3K pathways are necessary for malignant cell growth and survival and these pathways are frequently mutated in cancer. But targeting RAS directly poses a challenge. Two small molecules, a PI3K inhibitor (GDC-0941) and an MEK inhibitor (GDC-0973), are currently undergoing phase I studies.

"We're getting to the stage of trying to define and understand...how we can best combine these inhibitors to get the best efficacy and maintain the best safety profile," said Lori S. Friedman, PhD, director of cancer signaling and translational oncology at Genentech.

Dr. Friedman's group carried out in vitro and in vivo combination studies and found that concurrent daily dosing of MEK and PI3K inhibitors in vivo resulted in sustained efficacy in several xenograft tumor models. Intermittent dosing of both compounds also resulted in efficacy (abstract 1890).

"There's a lot of flexibility," she explained. "We can give them both as daily oral doses or as intermittent doses; either method will produce efficacy. We think this is because of the co-blocking of these two downstream pathways that support apoptosis."

HDAC and mTOR


Pancreatic cancers are resistant to almost all chemotherapy and radiation regimens, and even response to gemcitabine has been modest. Use of mTOR inhibitors as a single agent has demonstrated some clinical activity, but investigators at the Mayo Clinic in Rochester, Minn, report that cells from pancreatic cancer lines (MIAPaCa-2, Pnac-1 and BxPc-3) display persistent activation of the mTOR pathway.

"How can we overcome mTOR inhibitor-induced resistance?" asked Mamta Gupta, PhD.

They found success by combining rapamycin, an mTOR inhibitor, with LBH589, a histone deacetylase (HDAC) inhibitor to enhance mTOR-targeted therapy.

"The combined treatment with LBH and rapamycin synergistically inhibited growth of pancreatic cell lines and induced apoptosis," the investigators reported.

Specifically, the pharmacological inhibition of the mTOR pathway by rapamycin and LBH interfered with essential survival and proliferating pathways in pancreatic cancer cells (LB-261).

"We have the potential to use this new therapeutic intervention against this deadly disease," Dr. Gupta said. "The only thing we don't know is: What is the molecular mechanism behind this combination? We are working on that."

In other noteworthy research:
  • Oncogene-induced senescence represents a barrier to tumorigenesis that must be overcome for tumor development. UK-based researchers examined the effects of the expression of lymphoma-associated Nucleophosmin-Anaplastic Lymphoma Kinase (NPM-ALK) protein on cellular growth and proliferation in early-passage, primary murine embryonic fibroblasts (MEFs). Based on their findings, NPM-ALK induced a cell cycle arrest with features of senescence. NPM-ALK induced a senescent phenotype when expressed in primary cells. In turn, this implied a barrier to lymphomagenesis that must be overcome to enable transformation, they stated (abstract LB-27).
  • Spanish researchers investigated the mechanism by which inhibition of the PI3K pathway led to activation of MAPK kinase signaling in breast cancer cell lines and its relevance in tumor treatment. They noted that the activation of parallel pathways, under the condition of PI3K inhibition, may reduce potential benefits of anti-cancer treatments. They proposed the combination of an anti-HER2 therapy together with PI3K inhibitors for the treatment of HER2 positive tumors (LB-52).
  • A group in Japan has developed a novel PI3K inhibitor (ZSTK474) and demonstrated its efficacy in tumor models in vivo (J Natl Cancer Inst 2006;98:545-556). Pharmacological studies revealed that ZSTK474 could efficiently distribute to the brain, so the researchers examined the therapeutic efficacy of ZSTK474 against an orthotopic brain tumor model. They determined that orally administered ZSTK474 significantly inhibited the tumor growth in the brain and prolonged the survival of the brain tumor-bearing mice. The immediate decrease of p-AKT-positive tumor cells after ZSTK474 administration suggested that the antitumor efficacy resulted from PI3K inhibition (LB-213).
  • Researchers from Portland's Oregon Health & Science University and the University of Colorado Denver, investigated the in vivo roles of PIK3CA, PTEN, and AKT alterations in head and neck tumorigenesis and demonstrated an oncogenic role of PIK3CA and AKT, and a tumor-suppressive role of PTEN in head and neck tumorigenesis in vivo (LB-59).


To co-block HDAC w/mTOR, add Selenium?:

Cancer Prev Res (Phila Pa). 2009 Jul;2(7):683-93.
Alpha-keto acid metabolites of naturally occurring organoselenium compounds as inhibitors of histone deacetylase in human prostate cancer cells.

Lee JI, Nian H, Cooper AJ, Sinha R, Dai J, Bisson WH, Dashwood RH, Pinto JT.
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA.
Histone deacetylase (HDAC) inhibitors are gaining interest as cancer therapeutic agents. We tested the hypothesis that natural organoselenium compounds might be metabolized to HDAC inhibitors in human prostate cancer cells. Se-Methyl-L-selenocysteine (MSC) and selenomethionine are amino acid components of selenium-enriched yeast. In a cell-free system, glutamine transaminase K (GTK) and L-amino acid oxidase convert MSC to the corresponding alpha-keto acid, beta-methylselenopyruvate (MSP), and L-amino acid oxidase converts selenomethionine to its corresponding alpha-keto acid, alpha-keto-gamma-methylselenobutyrate (KMSB). Although methionine (sulfur analogue of selenomethionine) is an excellent substrate for GTK, selenomethionine is poorly metabolized. Structurally, MSP and KMSB resemble the known HDAC inhibitor butyrate. We examined androgen-responsive LNCaP cells and androgen-independent LNCaP C4-2, PC-3, and DU145 cells and found that these human prostate cancer cells exhibit endogenous GTK activities. In the corresponding cytosolic extracts, the metabolism of MSC was accompanied by the concomitant formation of MSP. In MSP-treated and KMSB-treated prostate cancer cell lines, acetylated histone 3 levels increased within 5 hours, and returned to essentially baseline levels by 24 hours, suggesting a rapid, transient induction of histone acetylation. In an in vitro HDAC activity assay, the selenoamino acids, MSC and selenomethionine, had no effect at concentrations up to 2.5 mmol/L, whereas MSP and KMSB both inhibited HDAC activity. We conclude that, in addition to targeting redox-sensitive signaling proteins and transcription factors, alpha-keto acid metabolites of MSC and selenomethionine can alter HDAC activity and histone acetylation status. These findings provide a potential new paradigm by which naturally occurring organoselenium might prevent the progression of human prostate cancer.

PMID: 19584079 [PubMed - indexed for MEDLINE]







Cancer Res. 2009 Sep 15;69(18):7160-4. Epub 2009 Sep 8.
mTOR signal and hypoxia-inducible factor-1 alpha regulate CD133 expression in cancer cells.

Matsumoto K, Arao T, Tanaka K, Kaneda H, Kudo K, Fujita Y, Tamura D, Aomatsu K, Tamura T, Yamada Y, Saijo N, Nishio K.
Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
The underlying mechanism regulating the expression of the cancer stem cell/tumor-initiating cell marker CD133/prominin-1 in cancer cells remains largely unclear, although knowledge of this mechanism would likely provide important biological information regarding cancer stem cells. Here, we found that the inhibition of mTOR signaling up-regulated CD133 expression at both the mRNA and protein levels in a CD133-overexpressing cancer cell line. This effect was canceled by a rapamycin-competitor, tacrolimus, and was not modified by conventional cytotoxic drugs. We hypothesized that hypoxia-inducible factor-1 alpha (HIF-1 alpha), a downstream molecule in the mTOR signaling pathway, might regulate CD133 expression; we therefore investigated the relation between CD133 and HIF-1 alpha. Hypoxic conditions up-regulated HIF-1 alpha expression and inversely down-regulated CD133 expression at both the mRNA and protein levels. Similarly, the HIF-1 alpha activator deferoxamine mesylate dose-dependently down-regulated CD133 expression, consistent with the effects of hypoxic conditions. Finally, the correlations between CD133 and the expressions of HIF-1 alpha and HIF-1 beta were examined using clinical gastric cancer samples. A strong inverse correlation (r = -0.68) was observed between CD133 and HIF-1 alpha, but not between CD133 and HIF-1 beta. In conclusion, these results indicate that HIF-1 alpha down-regulates CD133 expression and suggest that mTOR signaling is involved in the expression of CD133 in cancer cells. Our findings provide a novel insight into the regulatory mechanisms of CD133 expression via mTOR signaling and HIF-1 alpha in cancer cells and might lead to insights into the involvement of the mTOR signal and oxygen-sensitive intracellular pathways in the maintenance of stemness in cancer stem cells.

PMID: 19738050 [PubMed - indexed for MEDLINE]


Oncogene. 2010 Mar 1. [Epub ahead of print]
Single amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer.

Sato T, Nakashima A, Guo L, Coffman K, Tamanoi F.
Department of Microbiology, Immunology & Molecular Genetics, Molecular Biology Institute, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA.
Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates a variety of cellular functions such as growth, proliferation and autophagy. In a variety of cancer cells, overactivation of mTOR has been reported. In addition, mTOR inhibitors, such as rapamycin and its derivatives, are being evaluated in clinical trials as anticancer drugs. However, no active mutants of mTOR have been identified in human cancer. Here, we report that two different point mutations, S2215Y and R2505P, identified in human cancer genome database confer constitutive activation of mTOR signaling even under nutrient starvation conditions. S2215Y was identified in large intestine adenocarcinoma whereas R2505P was identified in renal cell carcinoma. mTOR complex 1 prepared from cells expressing the mutant mTOR after nutrient starvation still retains the activity to phosphorylate 4E-BP1 in vitro. The cells expressing the mTOR mutant show increased percentage of S-phase cells and exhibit resistance to cell size decrease by amino-acid starvation. The activated mutants are still sensitive to rapamycin. However, they show increased resistance to 1-butanol. Our study points to the idea that mTOR activating mutations can be identified in a wide range of human cancer.Oncogene advance online publication, 1 March 2010; doi:10.1038/onc.2010.28.

PMID: 20190810 [PubMed - as supplied by publisher]



Urol Oncol. 2010 Mar-Apr;28(2):134-8. Epub 2009 Jun 12.
Mammalian target of rapamycin: a new target in prostate cancer.

Rai JS, Henley MJ, Ratan HL.
Department of Urology, Derby City Hospital, Derby, United Kingdom.
Molecular targets in prostate cancer are continually being explored, especially in the poor-prognosis androgen-independent phase of the disease, for which there are currently few therapeutic options. One such target is the mammalian target of rapamycin (mTOR) protein. Activation of mTOR results in sequential activation of downstream molecules, which ultimately results in cell division. In this review, we consider the rationale for pursuing mTOR as a therapeutic target in prostate cancer and summarize preclinical and clinical studies of mTOR inhibition in prostate cancer. Copyright 2010 Elsevier Inc. All rights reserved.

PMID: 19523861 [PubMed - in process]
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Old 06-24-2010, 03:04 PM   #2
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Re: mTOR inhibitors

J Angiogenes Res. 2010 Feb 19;2(1):5.
Methylnaltrexone potentiates the anti-angiogenic effects of mTOR inhibitors.

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Singleton PA, Mambetsariev N, Lennon FE, Mathew B, Siegler JH, Moreno-Vinasco L, Salgia R, Moss J, Garcia JG.
Department of Medicine, University of Chicago, 5841 S Maryland Avenue, W604, Chicago, IL 60637, USA. psinglet@medicine.bsd.uchicago.edu



Abstract

BACKGROUND: Recent cancer therapies include drugs that target both tumor growth and angiogenesis including mammalian target of rapamycin (mTOR) inhibitors. Since mTOR inhibitor therapy is associated with significant side effects, we examined potential agents that can reduce the therapeutic dose. METHODS: Methylnaltrexone (MNTX), a peripheral mu opioid receptor (MOR) antagonist, in combination with the mTOR inhibitors temsirolimus and/or rapamycin, was evaluated for inhibition of VEGF-induced human pulmonary microvascular endothelial cell (EC) proliferation and migration as well as in vivo angiogenesis (mouse Matrigel plug assay). RESULTS: MNTX inhibited VEGF-induced EC proliferation and migration with an IC50 of approximately 100 nM. Adding 10 nM MNTX to EC shifted the IC50 of temsirolimus inhibition of VEGF-induced proliferation and migration from approximately 10 nM to approximately 1 nM and from approximately 50 to approximately 10 nM respectively. We observed similar effects with rapamycin. On a mechanistic level, we observed that MNTX increased EC plasma membrane-associated tyrosine phosphate activity. Inhibition of tyrosine phosphatase activity (3,4-dephostatin) blocked the synergy between MNTX and temsirolimus and increased VEGF-induced tyrosine phosphorylation of Src with enhanced PI3 kinase and mTOR Complex 2-dependent phosphorylation of Akt and subsequent activation of mTOR Complex 1 (rapamycin and temsirolimus target), while silencing Src, Akt or mTOR complex 2 components blocked VEGF-induced angiogenic events. CONCLUSIONS: Our data indicate that MNTX exerts a synergistic effect with rapamycin and temsirolimus on inhibition of VEGF-induced human EC proliferation and migration and in vivo angiogenesis. Therefore, addition of MNTX could potentially lower the dose of mTOR inhibitors which could improve therapeutic index.

PMID: 20298531 [PubMed]PMCID: PMC2831839Free PMC Article



Transplant Proc. 2008 Dec;40(10 Suppl):S32-5.
The impact of mTOR inhibitors on the development of malignancy.

Geissler EK.
University of Regensburg, Regensburg, Germany. edward.geissler@klinik.uni-regensburg.de
Abstract

Although continuous improvements have been made in fighting rejection with immunosuppressive drugs in transplant recipients, this success story has been tempered by an associated high incidence of cancer. The latest projections are that cancer might exceed cardiovascular disease as the leading cause of death among transplant recipients. Indeed, immunosuppression reduces our natural ability to destroy cancer cells and to inhibit viral infections potentially linked to cancer development. Therefore, a strategy to counter the problem of cancer in transplantation is needed. Recently, mammalian target of rapamycin (mTOR) inhibitors have demonstrated potential as both immunosuppressive and anticancer agents. Although mTOR inhibitors prevent organ transplant rejection, this class of drugs has potential anticancer properties that may be useful in the "balance of effects" toward cancer-free survival in transplant recipients. Mechanisms of mTOR inhibitors' anticancer effects are multiple, affecting processes including angiogenesis, cell proliferation, cell survival, and molecular oncogenic signaling. Importantly, experimental work supports the view that tumor inhibition can be accomplished with mTOR inhibitors while protecting allografts against rejection. Most recently, prospective randomized clinical studies have been initiated to test the concept that mTOR inhibitors reduce cancer while simultaneously inhibiting allograft rejection. One such study, the SiLVER trial, examines hepatocellular carcinoma recurrence in mTOR inhibitor-treated liver transplant patients. More robust evidence as to whether cancer risk can be reduced in transplant recipients with mTOR inhibitors may come from such clinical trials.

PMID: 19100904 [PubMed - indexed for MEDLINE]
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