Oncology Intelligence


mTOR mTOR(10)

mTOR is a serine/threonine kinase encoded by the gene mTOR, is part of the PI3K-related kinase protein family, and regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, angiogenesis, and transcription.(1, 2) mTOR integrates the input from upstream pathways, including IGF-1 and IGF-2.(1)
mTOR is the catalytic subunit of two structurally distinct complexes: MTORC1 and MTORC2.(3) Both complexes localize to different subcellular compartments, thus affecting their activation and function.(2, 4) mTOR Complex 1 (mTORC1) is composed of mTOR, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the non-core components PRAS40 and DEPTOR. This complex functions as a nutrient/energy/redox sensor and controlling protein synthesis.(2, 5) mTOR Complex 2 (mTORC2) is composed of mTOR, rapamycin-insensitive companion of mTOR, MLST8, and mammalian stress-activated protein kinase interacting protein 1 (mSIN1). The activity of mTORC1 is stimulated by insulin, growth factors, serum, phosphatidic acid, amino acids, and oxidative stress.(2, 5) mTORC2 has been shown to function as an important regulator of the cytoskeleton through its stimulation of F-actin stress fibers, paxillin, RhoA, Rac1, Cdc42, and PKC?. mTORC2 also phosphorylates Akt/PKB at the serine residue S473, thus affecting metabolism and survival.(6)
Rapamycin inhibits mTORC1, and this appears to provide most of the beneficial effects of the drug. Rapamycin has a more complex effect on mTORC2, inhibiting it only in certain cell types under prolonged exposure. Disruption of mTORC2 produces the diabetic-like symptoms of decreased glucose tolerance and insensitivity to insulin.(2, 7) The mTORC2 signaling pathway is less clearly defined than the mTORC1 signaling pathway. Rapamycin has been shown to interact with a number of proteins, including: ABL1, AKT1, STAT1, STAT3, and UBQLN1.(2)
Class I PI3K and TORC2 provide essential inputs to activate AKT. The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as RTKs. Targeting these pathways is often complex and can result in pathway activation depending on the presence of upstream mutations and rapamycin can induce Akt activation.(8) Akt2 is an important signaling molecule in the insulin signaling pathway. It is required to induce glucose transport.(9) Akt2 is also involved in the PI3K/AKT/mTOR pathway and other signaling pathways.(9) The role of Akt3 is less clear, though it appears to be predominantly expressed in the brain.(9)

Marketed Drugs
Generic Code Old Code Brand Company Indication trials
everolimus RAD 001 Afinitor, Certican, Votubia, Zortres Novartis Mkt: RCC, astrocytoma, BC, pancreatic; P3: NET, BC, CRC, brain, gastric, lymphoma, HCC; P2: MM, NSCLC, PC, leukemia, sarcoma, melanoma, bladder, ovarian, endometrial, thyroid, mesothelioma, adenoid cystic; P1: MDS, HNN, solid; SCLC, esophageal trials
temsirolimus CCI779 Torisel Pfizer Mkt: RCC; P3: lymphoma, BC (terminated); P2: CRC, MM, pancreatic, gastric, sarcoma, leukemia, HCC, PC, lung, melanoma, CNS, NET, endometrial, ovary; P1: solid trials
Trial Drugs/Interactions
Generic Code Old Code Brand Company Indication trials
rapamycin, nab, sirolimus ABI-009 Rapamune Abraxis Filed/rejected (pursued as combination); P3: HCC, leukemia, ependymoma, melanoma; P2: MM, MDS, GBM, sarcoma, RCC, lung, pancreatic, PC, BC, endometrial, CRC, lymphoma, HNN; P1/2: bladder; P1: solid trials
copanlisib BAY 80-6946 Bayer P3: NHL; P2: lymphoma; P1: various trials
ridaforolimus, deforolimus MK-8669 AP23573 Taltorvic, Jenzyl Merck P3: sarcoma; P2: MDS, PC, leukemia, NSCLC, lymphoma, BC, endometrial, solid; P1: CNS trials
apitolisib RG00007422 GDC-0980 Roche P2: NHL, RCC, solid; P1: BC trials
dactolisib BEZ-235 NVP-BEZ235 Novartis P2: pNET, BC, endometrial, transitional cell; P1/2: PC, solid, RCC; P1: ALL trials
salirasib KD032 Ono P2: NSCLC trials
AZD2014 AstraZeneca P2: BC, RCC, NSCLC; P1: solid trials
LY3023414 Eli Lilly P2: PC; P1: NHL, BC, mesothelioma trials
MLN0128 INK128 Millennium. Intellikine P2: PC; P1/2: BC; P1: solid, MM, WM trials
PF-05212384 PKI-587 Pfizer P2: endometrial, CRC; P1: solid, NSCLC, ovarian trials
PX-866 Oncothryeon P2: PC, GBM; P1/2: solid, CRC trials
SAR245408 XL147 Sanofi P2: endometrial; P1/2: NSCLC, ovarian, BC; P1: solid trials
SAR245409 XL765 Sanofi P2: ovarian, lymphoma; P1/2: BC; P1: NSCLC, solid, glioma, GBM, astrocytoma trials
AZD8055 AstraZeneca P1/2: solid, lymphoma; P1: GBM, HCC trials
CC-223 TORKi Abraxis P1/2: solid, NHL, MM; P1: NCSLC trials
ME-344 MEI P1/2: solid; P1: SCLC, ovarian trials
AR-12 OSU-03012c Arno P1: solid, lymphoma, BC, endometrial trials
CC-115 Abraxis P1: GBM, HNN, Ewing's, CLL trials
DS-3078 Daiichi P1: solid, lymphoma trials
DS-7423 Daiichi P1: solid, CRC, endometrial trials
GDC-0349 Roche P1: solid, NHL trials
P7170 Piramal P1: solid trials
PQR309 PIQUR P1: solid, lymphoma trials
PWT33597 Pathway P1: various trials
RG7666 GDC-0084 Roche P1: glioma, GBM trials
SF1126 Semafore P1: solid, neuroblastoma trials
VS-5584 SB-2343 Verastem P1: solid, lymphoma, mesothelioma trials
WX-037 Wilex P1: solid trials
Failed drugs
Generic Code Old Code Brand Company Indication trials
diethylnorspermine Tocris No new trial since 2006; P1/2: HCC; P1: lymphoma trials
BGT-226 Novartis Last new trial started in 2008; P1/2: solid, BC trials
GSK1059615 GSK615 GSK terminated; P1: solid, BC, lymphoma, endometrial trials
GSK2126458 GSK458 GSK terminated; P1: solid, lymphoma trials
MKC-1 Ro 31-7453 Entremed Last new trial started in 2008; P2: ovarian, endometrial, pancreatic, BC, CRC; P1/2: NSCLC; P1: MDS, leukemia, solid trials
OSI-027 Astellas (OSI) Last new trial started in 2008; P1: solid, lymphoma trials
PF-04691502 Pfizer terminated; P2: BC; P1: various, solid trials


1. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes & Development. 2004;18(16):1926-45.

2. H N. Pathophysiological response to hypoxia - from the molecular mechanisms of malady to drug discovery: drug discovery for targeting the tumor microenvironment. J Pharmacol Sci. 20111;115(4):446-52. PMCID: 21422725.

3. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124(3):471-84.

4. Betz C, Hall MN. Where is mTOR and what is it doing there? The Journal of cell biology. 2013;203(4):563-74.

5. Fang Y, Vilella-Bach M, Bachmann R, Flanigan A, Chen J. Phosphatidic acid-mediated mitogenic activation of mTOR signaling. Science. 2001;294(5548):1942-5.

6. Betz C, Stracka D, Prescianotto-Baschong C, Frieden M, Demaurex N, Hall MN. mTOR complex 2-Akt signaling at mitochondria-associated endoplasmic reticulum membranes (MAM) regulates mitochondrial physiology. Proceedings of the National Academy of Sciences. 2013;110(31):12526-34.

7. Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science. 2012;335(6076):1638-43.

8. McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Franklin RA, Montalto G, et al. Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascade inhibitors: how mutations can result in therapy resistance and how to overcome resistance. Oncotarget. 2012;3(10):1068.

9. Ward EM, Thun MJ, Hannan LM, Jemal A. Interpreting cancer trends. Annals of the New York Academy of Sciences. 2006;1076(1):29-53.

10. Bandyopadhyay A RS. Defining the role of integrin alphavbeta6 in cancer. Curr Drug Targets. 2009;10(7):645-52. PMCID: 19601768.

11:00 PM|Levavasseur, Matthieu; Darras, Sophie; Mortier, Laurent; Goeminne, Céline; Auffret, Marine; Bertrand, Marie|Melanoma Research - Most Popular Articles|Labels: BRAF, mTOR, melanoma
imageMelanoma is a major public health problem. In recent years, it has been shown that melanoma can be characterized by specific oncogenes mutations such as the BRAF mutation, leading to the development of new therapeutic drugs. Dabrafenib is an inhibitor of BRAF, approved as a first-line treatment of metastatic or unresectable stage 3 or 4 melanoma with the BRAF mutation. Few studies have evaluated the drug interaction potential of dabrafenib. This molecule is an enzyme inducer that increases the synthesis of drug-metabolizing enzymes, including CYP3A4, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and UGT enzymes. Accordingly, the plasma concentrations of drugs metabolized by these enzymes are decreased. The decrease in plasma concentrations may cause a reduction or even loss of the clinical effect of these drugs. Many drugs metabolized by these enzymes may be affected, especially midazolam, warfarin, or rifampicin. However, interactions with immunosuppressants have not been described. Everolimus and tacrolimus are two immunosuppressive drugs metabolized by CYP3A4. We report a case of drug interaction between dabrafenib and immunosuppressive drugs (everolimus, tacrolimus), observed in a transplanted heart patient, requiring dosage adjustment of its immunosuppressive treatment to avoid graft rejection.
Friday, September 16, 2016 10:23 AM|Chia-Ing Jan, Ming-Hsui Tsai, Chang-Fang Chiu, Yi-Ping Huang, Chia Jen Liu, Nai Wen Chang|International Journal of Biological Sciences|Labels: AKT, mTOR, pharyngeal

One anticancer strategy suggests targeting mitochondrial metabolism to trigger cell death through slowing down energy production from the Warburg effect. Fenofibrate is a clinical lipid-lowering agent and an effective anticancer drug. In the present study, we demonstrate that fenofibrate provided novel mechanisms for delaying oral tumor development via the reprogramming of metabolic processes. Fenofibrate induced cytotoxicity by decreasing oxygen consumption rate (OCR) that was accompanied with increasing extracellular acidification rate (ECAR) and reducing ATP content. Moreover, fenofibrate caused changes in the protein expressions of hexokinase II (HK II), pyruvate kinase, pyruvate dehydrogenase, and voltage-dependent anion channel (VDAC), which are associated with the Warburg effect. In addition, fenofibrate reprogrammed the metabolic pathway by interrupting the binding of HK II to VDAC. In an oral cancer mouse model, fenofibrate exhibited both preventive and therapeutic efficacy on oral tumorigenesis. Fenofibrate administration suppressed the incidence rate of tongue lesions, reduced the tumor sizes, decreased the tumor multiplicity, and decreased the immunoreactivities of VDAC and mTOR. The molecular mechanisms involved in fenofibrate's ability to delay tumor development included the down-regulation of mTOR activity via TSC1/2-dependent signaling through activation of AMPK and inactivation of Akt, or via a TSC1/2-independent pathway through direct suppression of raptor. Our findings provide a molecular rationale whereby fenofibrate exerts anticancer and additional beneficial effects for the treatment of oral cancer patients.

Friday, September 16, 2016 10:17 AM|Onclive Articles|Labels: mTOR, VEGF, kidney cancer
The European Commission has approved lenvatinib (Kisplyx) in combination with everolimus for patients with advanced renal cell carcinoma following 1 prior VEGF-targeted therapy.
Thursday, September 15, 2016 1:00 AM|MIT Biotech Group - Essential Biotech RSS Feed|Labels: mTOR, kidney cancer
The European Commission approved Kisplyx lenvatinib from Eisai Co. Ltd. (Tokyo:4523) in combination with Afinitor everolimus to treat advanced renal cell carcinoma (RCC) in patients previously treated with a VEGF inhibitor.In May, FDA approved the inhibitor of multiple VEGF receptor tyrosine kinases for the same indication. The drug is marketed for thyroid cancer in the U.S. and EU, and is known as Lenvima in some countries.Novartis AG (NYSE:NVS; SIX:NOVN) markets Afinitor, an oral mammalian target of rapamycin (mTOR; FRAP; RAFT1) protein inhibitor.
Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, “Eisai”) announced that its European regional headquarters Eisai Europe Ltd. (Location: U.K.) has received license from the European Commission for anticancer agent Kisplyx(R) ▼ (generic name: lenvatinib mesylate, “lenvatinib”) in combination with everolimus for the treatment of adult patients with advanced renal cell carcinoma following one prior vascular endothelial growth factor (VEGF) targeted therapy. Following the United States, Europe marks the second region where lenvatinib has been licensed for the advanced renal cell carcinoma indication.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: mTOR, ALL
Laboratory and other studies suggest that, the study drug, Everolimus (RAD001), may prevent tumor cell growth and also may increase the efficacy of other chemotherapy drugs. Everolimus is approved for use in the United States for certain types of cancer, such as kidney cancer. It has been extensively studied in people with various types of cancer as a single agent (a drug that is used alone to treat the cancer) or in combination with a number of other drugs. Studies in adults with cancer have also evaluated Everolimus in combination with other anti-tumor drugs. Information from lab studies and some other clinical trials suggests that Everolimus may kill leukemia cells on its own, and also make it more likely that steroids (such as prednisone) are able to kill leukemia cells. In this research study, we are looking to learn more about how Everolimus works in combination with other drugs which are commonly used to treat relapsed acute lymphoblastic leukemia (prednisone, vincristine, PEG-asparaginase, and doxorubicin). The main goal of the study is to evaluate the side effects of this treatment combination in order to determine a safe dose of Everolimus which can be given with these other 4 drugs.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: mTOR, brain cancer
This research study is a Feasibility clinical trial. In this trial, researchers are trying to figure out whether a medication can be chosen based on rapid testing done on tumor tissue. Information from a feasibility or pilot trial will hopefully help researchers plan larger trials in the future to determine the effect of this therapy.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: EGFR, mTOR, breast cancer, clinical trial
RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using tamoxifen citrate, goserelin acetate, leuprolide acetate, anastrozole, letrozole, or exemestane, may fight breast cancer by lowering the amount of estrogen the body makes. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet know whether hormone therapy is more effective when given with or without everolimus in treating breast cancer. PURPOSE: This randomized phase III trial studies how well giving hormone therapy together with or without everolimus work in treating patients with breast cancer.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: INT, mTOR, PI3K, brain cancer
SF1126 is a novel inhibitor of PI3 kinase and mTOR that includes an active moiety (consisting of LY294002) linked to an RGDS tetrapeptide that targets the active agent to integrin expressing tissues. In this first pediatric phase 1 trial of SF1126, dose escalation will follow a 3+3 dose escalation design. Once a recommended phase 2 pediatric dose is identified, an expansion cohort of 10 patients with tumors with MYCN amplification, Mycn expression, or Myc expression will be treated.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: mTOR, brain cancer, clinical trial
This is an open label study of everolimus in children with recurrent or progressive low-grade glioma.
Wednesday, September 14, 2016 11:10 AM|Mayo Clinic Cancer Center - Research news|Labels: mTOR, lymphoma
ROCHESTER, Minn. — The targeted therapy everolimus may be safely combined with R-CHOP for new, untreated diffuse large B-cell lymphoma according to the results of a pilot study by Mayo Clinic researchers published in the Lancet Haematology. R-CHOP is a combination of drugs used to treat lymphoma. The combination includes rituximab, cyclophosphamide, doxorubicin, vincristine and [...]
Wednesday, September 14, 2016 11:10 AM|Brian Shuch, Srinivas Vourganti, Julia C. Friend, Lee M. Zehngebot, W. Marston Linehan, Ramaprasad Srinivasan|Journal of Cancer|Labels: mTOR, kidney cancer

Chromophobe kidney cancer accounts for approximately 5% of cases of renal cell carcinoma (RCC). While the genetics of clear cell RCC has been a major focus of research, little is known about the biology of chromophobe tumors. There is ample preclinical rationale for the use of targeted therapy in clear cell tumors, and agents targeting the VHL/HIF pathway are now widely used in clinical practice. However, there is limited experience with targeted agents in non-clear cell tumors. Recently, a few case reports have emerged which report the use of mTOR inhibitors in chromophobe tumors. Here, we report our experience with targeted therapy in a patient with advanced chromophobe RCC who had a durable partial response to temsirolimus. We also include a literature review summarizing the published experience with targeted therapeutic approaches in chromophobe RCC. Additionally, the preclinical rationale for the use of mTOR inhibitors in this population based on our characterization of the hereditary form of chromophobe kidney cancer, Birt-Hogg-Dube syndrome, is discussed.

Tuesday, September 13, 2016 11:38 PM|Christof Achermann, Frank Stenner, Sacha I. Rothschild|Journal of Cancer|Labels: mTOR, kidney cancer

In Switzerland efficient availability of novel drugs for renal cell cancer (RCC) has been granted early. Since the advent of the targeted agents for RCC the usage of these drugs has been reported to improve progression free survival. Here, we find that patients who are able to receive sequential targeted therapy, including tyrosine kinase inhibitors (TKI) and mTOR inhibitors (mTORi), have a largely better outcome than those who have less exposure to these agents. The value of the prognostic scores developed by Motzer and Heng is fully reflected by the outcomes according to prognostic risk groups in our unselected patient cohort. Also, the use of surgical intervention appears to be an important prognostic factor, however with a somehow diminished effect by novel systemic therapies. The importance of multiple lines of targeted therapies is underlined by this retrospective analysis. For patients with metastatic RCC not receiving targeted therapy the median OS was 22.6 months compared to those with one TKI 25.4 months. Patients receiving a second-line therapy (median overall survival 27.6 months) and those patients with three or more lines of therapy (43.8 months) have the greatest benefit. Also, exposure to a mTORi improves survival versus non-exposure to mTORi (63.3 vs. 22.3 months, p=0.038). In conclusion a trend towards improved survival is confirmed for an unselected population when the full variety of therapeutic options is available and can be used for the individual patient.

Tuesday, September 13, 2016 8:19 PM|Florian Ewald, Dominik Nörz, Astrid Grottke, Johanna Bach, Christiane Herzberger, Bianca T. Hofmann, Björn Nashan, Manfred Jücker|Journal of Cancer (RSS 2.0)|Labels: AKT, MEK, mTOR, liver cancer

Hepatocellular carcinoma (HCC) is the sixth most common cancer, and the third most common cause of cancer related death worldwide. The multi-kinase inhibitor Sorafenib represents the only systemic treatment option until today, and results from clinical trials with allosteric mTOR inhibitors were sobering. Since the PI3K/AKT/mTOR and RAF/MEK/ERK signaling pathways are frequently upregulated in HCC, we have analyzed the effects of AKT inhibitor MK-2206, MEK inhibitor AZD6244 (ARRY 142886) and mTOR kinase inhibitor AZD8055, given as single drugs or in combination, on proliferation and apoptosis of three HCC cell lines in vitro. We show that all three inhibitor combinations synergistically inhibit proliferation of the three HCC cell lines, with the strongest synergistic effect observed after vertical inhibition of AKT and mTORC1/2. We demonstrate that AKT kinase activity is restored 24h after blockade of mTORC1/2 by increased phosphorylation of T308, providing a rationale for combined targeting of AKT and mTOR inhibition in HCC. Our data suggest that a combination of inhibitors targeting those respective pathways may be a viable approach for future application in patients with hepatocellular carcinoma.

Tuesday, September 13, 2016 8:19 PM|Ruolin Zhao, Meijuan Chen, Zequn Jiang, Fengming Zhao, Beili Xi, Xu Zhang, Haian Fu, Kunfu Zhou|Journal of Cancer (RSS 2.0)|Labels: AKT, mTOR, PI3K, lung cancer

Platycodin-D (PD) is an effective triterpene saponin extracted from the root of Platycodon grandiflorum which has been used clinically to treat pulmonary diseases in traditional Chinese medicine. Recently, it has been reported that PD has anti-tumor effects in various cancer models through the induction of apoptosis. However, whether PD induces autophagy in both cell lines and its molecular mechanisms have not been elucidated. Here, our present study confirmed that PD induced autophagy in both NCI-H460 and A549 cells via up-regulating the expression levels of Atg-3, Atg-7 and Beclin-1. Meanwhile, PD contributed to the up-regulation of LC3-II at both protein and mRNA levels. Further detection of the PI3K/Akt/mTOR signaling pathway compared to LY294002 (PI3K kinase inhibitor), RAP (mTOR kinase inhibitor) and insulin (an activator of PI3K/Akt/mTOR signaling pathway) showed that PD induced autophagy through inhibiting the pathway at p-Akt (Ser473), p-p70S6K (Thr389) and p-4EBP1 (Thr37/46) in both cell lines. Moreover, the examination of MAPK signaling pathway showed that PD treatment increased the phosphorylation of JNK and p38 MAPK, while decreased the phosphorylation of Erk1/2 in both cell lines. Additionally, the effects assessed with a panel of pharmacologic inhibitors, including U0126 (Erk1/2 kinase inhibitor), SP600125 (JNK kinase inhibitor) and SB203580 (p38 MAPK kinase inhibitor) suggested that the activation of JNK and p38 MAPK participated in PD-induced autophagy. Taken together, these findings suggested that PD induced autophagy in NCI-H460 and A549 cells through inhibiting PI3K/Akt/mTOR signaling pathway and activating JNK and p38 MAPK signaling pathways. Therefore, PD may be an alternative compound for NSCLC therapy.

Tuesday, September 13, 2016 8:19 PM|Antonino Grassadonia, Marta Caporale, Nicola Tinari, Marinella Zilli, Michele DeTursi, Teresa Gamucci, Patrizia Vici, Clara Natoli|Journal of Cancer (RSS 2.0)|Labels: mTOR, breast cancer

Inhibition of aberrantly activated pathways cross-talking with hormone receptor (HR) improves response to endocrine therapy in patients with HR-positive advanced breast cancer. We performed a Pubmed database systematic review to ascertain the existence of a better clinical response when combining endocrine therapy with targeted agents in the neoadjuvant setting. Preclinical studies or trials evaluating toxicity were excluded.

We found nine phase II trials that fulfilled the research criteria. The endocrine agents used were third generation aromatase inhibitors (AIs), anastrozole, letrozole or exemestane. The investigated targeted agents were inhibitors of tyrosine kinase receptors such as gefitinib, imatinib or trastuzumab/lapatinib, inhibitors of mTOR, such as everolimus, inhibitors of COX-2, such as celecoxib, and inhibitors of angiogenesis, such as bevacizumab. The response rate (RR) observed combining endocrine and targeted agents ranged between 36% and 90%.

Overall the studies failed to show a remarkable advantage in RR in the combination group compared to historical control subjects receiving AIs alone.

Tuesday, September 13, 2016 8:19 PM|Wenzhi Li, Fengfu Guo, Meng Gu, Guangjian Wang, Xiangfei He, Juan Zhou, Yubing Peng, Zhong Wang, Xiang Wang|Journal of Cancer (RSS 2.0)|Labels: AKT, mTOR, prostate cancer

Background: Golgi phosphoprotein 3 (GOLPH3) is a metastasis-associated gene, however its role in cell proliferation of prostate cancer (PCa) has not yet been elucidated.

Methods: The level of expression of GOLPH3 and other genes was examined by quantitative real-time PCR (QPCR) and western blot analysis. Furthermore, we performed a comprehensive analysis of the expression of GOLPH3 in PCa using a tissue microarray (TMA) and correlated our findings with pathological parameters of PCa. RNA interference (RNAi) was used to silence the expression of GOLPH3 in PC-3 cells and to measure the effects on proliferation and cell cycle using the CCK-8 assay and flow cytometry. Western blots were also employed to assess AKT-mTOR and cell cycle-related proteins.

Results: We showed that the expression of GOLPH3 was located at the trans-Golgi membranes in PCa cells. We found that GOLPH3 was expressed in all PCa cells and was significantly higher in two androgen-independent cell lines, DU145 and PC-3. TMA immunohistochemistry showed that GOLPH3 was positive in 64% of cancer tissue samples compared with 20% in normal and 30% in benign samples (P<0.05). In vitro, silencing GOLPH3 expression inhibited cell proliferation and arrested the cell cycle at the G2/M phase. Silencing GOLPH3 also activated P21 expression but suppressed the expression of CDK1/2 and cyclinB1 protein together with the phosphorylation of AKT and mTOR.

Conclusions: The expression of the GOLPH3 protein was significantly elevated in PCa. GOLPH3 can promote cell proliferation by enhancing the activity of AKT-mTOR signaling. Altogether, these findings suggest that GOLPH3 play important roles in proliferation and cell cycle regulation in PCa and might serve as promising biomarkers for PCa progression as well as potential therapeutic targets.

Tuesday, September 13, 2016 2:05 PM|Zhenwei Zhang, Lei Miao, Xin Wu, Guangze Liu, Yuting Peng, Xiaoming Xin, Binghua Jiao, Xiangping Kong|Journal of Cancer|Labels: AKT, mTOR, gastric

Carnosine (β-alanyl-L-histidine), described as an enigmatic peptide for its antioxidant, anti-aging and especially antiproliferation properties, has been demonstrated to play an anti-tumorigenic role in certain types of cancer. However, its function in human gastric carcinoma remains unclear. In this study, the effect of carnosine on cell proliferation and its underlying mechanisms were investigated in the cultured human gastric carcinoma cells. The mTOR signaling axis molecules were analyzed in carnosine treated cells. The results showed that treatment with carnosine led to proliferation inhibition, cell cycle arrest in the G0/G1 phase, apoptosis increase, and inhibition of mTOR signaling activation by decreasing the phosphorylation of Akt, mTOR and p70S6K, suggesting that proliferation inhibition of carnosine in human gastric carcinoma was through the inhibition of Akt/mTOR/p70S6K pathway, and carnosine would be a mimic of rapamycin.

Tuesday, September 13, 2016 1:08 PM| Jianing Xu, Can G. Pham, Steven K. Albanese, Yiyu Dong, Toshinao Oyama, Chung-Han Lee, Vanessa Rodrik-Outmezguine, Zhan Yao, Song Han, David Chen, Daniel L. Parton, John D. Chodera, Neal Rosen, Emily H. Cheng, James J. Hsieh |The Journal of Clinical Investigation -- Current Issue|Labels: mTOR
Genomic studies have linked mTORC1 pathway–activating mutations with exceptional response to treatment with allosteric inhibitors of mTORC1 called rapalogs. Rapalogs are approved for selected cancer types, including kidney and breast cancers. Here, we used sequencing data from 22 human kidney cancer cases to identify the activating mechanisms conferred by mTOR mutations observed in human cancers and advance precision therapeutics. mTOR mutations that clustered in focal adhesion kinase targeting domain (FAT) and kinase domains enhanced mTORC1 kinase activity, decreased nutrient reliance, and increased cell size. We identified 3 distinct mechanisms of hyperactivation, including reduced binding to DEP domain–containing MTOR-interacting protein (DEPTOR), resistance to regulatory associated protein of mTOR–mediated (RAPTOR-mediated) suppression, and altered kinase kinetics. Of the 28 mTOR double mutants, activating mutations could be divided into 6 complementation groups, resulting in synergistic Rag- and Ras homolog enriched in brain–independent (RHEB-independent) mTORC1 activation. mTOR mutants were resistant to DNA damage–inducible transcript 1–mediated (REDD1-mediated) inhibition, confirming that activating mutations can bypass the negative feedback pathway formed between HIF1 and mTORC1 in the absence of von Hippel–Lindau (VHL) tumor suppressor expression. Moreover, VHL-deficient cells that expressed activating mTOR mutants grew tumors that were sensitive to rapamycin treatment. These data may explain the high incidence of mTOR mutations observed in clear cell kidney cancer, where VHL loss and HIF activation is pathognomonic. Our study provides mechanistic and therapeutic insights concerning mTOR mutations in human diseases.
Tuesday, September 6, 2016 1:13 PM|Bent, E. H., Gilbert, L. A., Hemann, M. T.|Genes & Development current issue|Labels: AKT, mTOR, PI3K

Cancer therapy targets malignant cells that are surrounded by a diverse complement of nonmalignant stromal cells. Therapy-induced damage of normal cells can alter the tumor microenvironment, causing cellular senescence and activating cancer-promoting inflammation. However, how these damage responses are regulated (both induced and resolved) to preserve tissue homeostasis and prevent chronic inflammation is poorly understood. Here, we detail an acute chemotherapy-induced secretory response that is self-limiting in vitro and in vivo despite the induction of cellular senescence. We used tissue-specific knockout mice to demonstrate that endothelial production of the proinflammatory cytokine IL-6 promotes chemoresistance and show that the chemotherapeutic doxorubicin induces acute IL-6 release through reactive oxygen species-mediated p38 activation in vitro. Doxorubicin causes endothelial senescence but, surprisingly, without a typical senescence secretory response. We found that endothelial cells repress senescence-associated inflammation through the down-regulation of PI3K/AKT/mTOR signaling and that reactivation of this pathway restores senescence-associated inflammation. Thus, we describe a mechanism by which damage-associated paracrine secretory responses are restrained to preserve tissue homeostasis and prevent chronic inflammation.

Friday, September 2, 2016 6:35 AM|Ying, Z. X., Jin, M., Peterson, L. F., Bernard, D., Saiya-Cork, K., Yildiz, M., Wang, S., Kaminski, M. S., Chang, A. E., Klionsky, D. J., Malek, S. N.|Clinical Cancer Research Online First Articles|Labels: mTOR, lymphoma

Purpose: This study was performed to further our understanding of the biological and genetic basis of follicular lymphoma and to identify potential novel therapy targets.

Experimental Design: We analyzed previously generated whole exome sequencing data of 23 follicular lymphoma cases and one transformed follicular lymphoma case and expanded findings to a combined total of 125 follicular lymphoma/3 transformed follicular lymphoma. We modeled the three-dimensional location of RRAGC-associated hotspot mutations. We performed functional studies on novel RRAGC mutants in stable retrovirally transduced HEK293T cells, stable lentivirally transduced lymphoma cell lines, and in Saccharomyces cerevisiae.

Results: We report recurrent mutations, including multiple amino acid hotspots, in the small G-protein RRAGC, which is part of a protein complex that signals intracellular amino acid concentrations to MTOR, in 9.4% of follicular lymphoma cases. Mutations in RRAGC distinctly clustered on one protein surface area surrounding the GTP/GDP–binding sites. Mutated RRAGC proteins demonstrated increased binding to RPTOR (raptor) and substantially decreased interactions with the product of the tumor suppressor gene FLCN (folliculin). In stable retrovirally transfected 293T cells, cultured in the presence or absence of leucine, multiple RRAGC mutations demonstrated elevated MTOR activation as evidenced by increased RPS6KB/S6-kinase phosphorylation. Similar activation phenotypes were uncovered in yeast engineered to express mutations in the RRAGC homolog Gtr2 and in multiple lymphoma cell lines expressing HA-tagged RRAGC-mutant proteins.

Conclusions: Our discovery of activating mutations in RRAGC in approximately 10% of follicular lymphoma provides the mechanistic rationale to study mutational MTOR activation and MTOR inhibition as a potential novel actionable therapeutic target in follicular lymphoma. Clin Cancer Res; 1–11. ©2016 AACR.

Sunday, August 14, 2016 10:05 PM|Morrison Joly, M., Hicks, D. J., Jones, B., Sanchez, V., Estrada, M. V., Young, C., Williams, M., Rexer, B. N., Sarbassov, D. D., Muller, W. J., Brantley-Sieders, D., Cook, R. S.|Cancer Research recent issues|Labels: AKT, EGFR, mTOR, breast cancer
HER2 overexpression drives Akt signaling and cell survival and HER2-enriched breast tumors have a poor outcome when Akt is upregulated. Akt is activated by phosphorylation at T308 via PI3K and S473 via mTORC2. The importance of PI3K-activated Akt signaling is well documented in HER2-amplified breast cancer models, but the significance of mTORC2-activated Akt signaling in this setting remains uncertain. We report here that the mTORC2 obligate cofactor Rictor is enriched in HER2-amplified samples, correlating with increased phosphorylation at S473 on Akt. In invasive breast cancer specimens, Rictor expression was upregulated significantly compared with nonmalignant tissues. In a HER2/Neu mouse model of breast cancer, genetic ablation of Rictor decreased cell survival and phosphorylation at S473 on Akt, delaying tumor latency, penetrance, and burden. In HER2-amplified cells, exposure to an mTORC1/2 dual kinase inhibitor decreased Akt-dependent cell survival, including in cells resistant to lapatinib, where cytotoxicity could be restored. We replicated these findings by silencing Rictor in breast cancer cell lines, but not silencing the mTORC1 cofactor Raptor (RPTOR). Taken together, our findings establish that Rictor/mTORC2 signaling drives Akt-dependent tumor progression in HER2-amplified breast cancers, rationalizing clinical investigation of dual mTORC1/2 kinase inhibitors and developing mTORC2-specific inhibitors for use in this setting. Cancer Res; 76(16); 4752–64. ©2016 AACR.
Sunday, August 14, 2016 6:00 PM|Sheng-Tang Wu, Guang-Huan Sun, Tai-Lung Cha, Chien-Chang Kao, Sun-Yran Chang, Sheng-Chu Kuo and Tzong-Der Way|Most Recent Articles: Journal of Biomedical Science|Labels: mTOR, breast cancer
Triple-negative breast cancer (TNBC) lacks specific therapeutic target and limits to chemotherapy and is essential to develop novel therapeutic regimens. Increasing studies indicated that tamoxifen, a selectiv...
Tuesday, August 9, 2016 1:03 PM|Miyoshi, T., Umemura, S., Matsumura, Y., Mimaki, S., Tada, S., Ishii, G., Udagawa, H., Matsumoto, S., Yoh, K., Niho, S., Ohmatsu, H., Aokage, K., Hishida, T., Yoshida, J., Nagai, K., Goto, K., Tsuboi, M., Tsuchihara, K.|Clinical Cancer Research Online First Articles|Labels: EGFR, mTOR, lung cancer

Purpose:Although large-cell neuroendocrine carcinoma (LCNEC) of the lung shares many clinical characteristics with small-cell lung cancer (SCLC), little is known about its molecular features. We analyzed lung LCNECs to identify biologically relevant genomic alterations. Experimental Design:We performed targeted capture sequencing of all the coding exons of 244 cancer-related genes on 78 LCNEC samples (65 surgically resected cases, including 10 LCNECs combined with non-small cell lung cancer [NSCLC] types analyzed separately, and biopsies of 13 advanced cases). Frequencies of genetic alterations were compared with those of 141 SCLCs (50 surgically resected cases and biopsies of 91 advanced cases). Results:We found a relatively high prevalence of inactivating mutations in TP53 (71%) and RB1 (26%), but the mutation frequency in RB1 was lower than that in SCLCs (40%, P = 0.039). Additionally, genetic alterations in the PI3K/AKT/mTOR pathway were detected in 12 (15%) of the tumors: PIK3CA 3%, PTEN 4%, AKT2 4%, RICTOR 5% and mTOR 1%. Other activating alterations were detected in KRAS (6%), FGFR1 (5%), KIT (4%), ERBB2 (4%), HRAS (1%) and EGFR (1%). Five of ten cases of LCNECs combined with NSCLCs harbored previously reported driver gene alterations, all of which were shared between the two components. The median concordance rate of candidate somatic mutations between the two components was 71% (range 60-100%). Conclusions:LCNEC have a similar genomic profile to SCLC, including promising therapeutic targets such as the PI3K/AKT/mTOR pathway and other gene alterations. Sequencing-based molecular profiling is warranted in LCNEC for targeted therapies.

Monday, August 1, 2016 12:09 PM|Wick, W., Gorlia, T., Bady, P., Platten, M., van den Bent, M. J., Taphoorn, M. J. B., Steuve, J., Brandes, A. A., Hamou, M.-F., Wick, A., Kosch, M., Weller, M., Stupp, R., Roth, P., Golfinopoulos, V., Frenel, J.-S., Campone, M., Ricard, D., Marosi, C., Villa, S., Weyerbrock, A., Hopkins, K., Homicsko, K., Lhermitte, B., Pesce, G., Hegi, M. E.|Clinical Cancer Research Online First Articles|Labels: mTOR, brain cancer, clinical trial

Purpose: EORTC 26082 assessed the activity of temsirolimus in patients with newly diagnosed glioblastoma harboring an unmethylated O6 methylguanine-DNA-methyltransferase (MGMT) promoter.

Experimental Design: Patients (n = 257) fulfilling eligibility criteria underwent central MGMT testing. Patients with MGMT unmethylated glioblastoma (n = 111) were randomized 1:1 between standard chemo-radiotherapy with temozolomide or radiotherapy plus weekly temsirolimus (25 mg). Primary endpoint was overall survival at 12 months (OS12). A positive signal was considered >38 patients alive at 12 months in the per protocol population. A noncomparative reference arm of 54 patients evaluated the assumptions on OS12 in a standard-treated cohort of patients. Prespecified post hoc analyses of markers reflecting target activation were performed.

Results: Both therapies were administered per protocol with a median of 13 cycles of maintenance temsirolimus. Median age was 55 and 58 years in the temsirolimus and standard arms, the WHO performance status 0 or 1 for most patients (95.5%). In the per protocol population, 38 of 54 patients treated with temsirolimus reached OS12. The actuarial 1-year survival was 72.2% [95% confidence interval (CI), 58.2–82.2] in the temozolomide arm and 69.6% (95% CI, 55.8–79.9) in the temsirolimus arm [hazard ratio (HR) 1.16; 95% CI, 0.77–1.76; P = 0.47]. In multivariable prognostic analyses of clinical and molecular factors, phosphorylation of mTORSer2448 in tumor tissue (HR 0.13; 95% CI, 0.04–0.47; P = 0.002), detected in 37.6%, was associated with benefit from temsirolimus.

Conclusions: Temsirolimus was not superior to temozolomide in patients with an unmethylated MGMT promoter. Phosphorylation of mTORSer2448 in the pretreatment tumor tissue may define a subgroup benefitting from mTOR inhibition. Clin Cancer Res; 1–10. ©2016 AACR.

Sunday, July 31, 2016 10:05 PM|Cormerais, Y., Giuliano, S., LeFloch, R., Front, B., Durivault, J., Tambutte, E., Massard, P., de la Ballina, L. R., Endou, H., Wempe, M. F., Palacin, M., Parks, S. K., Pouyssegur, J.|Cancer Research recent issues|Labels: INT, mTOR
The CD98/LAT1 complex is overexpressed in aggressive human cancers and is thereby described as a potential therapeutic target. This complex promotes tumorigenesis with CD98 (4F2hc) engaging β-integrin signaling while LAT1 (SLC7A5) imports essential amino acids (EAA) and promotes mTORC1 activity. However, it is unclear as to which member of the heterodimer carries the most prevalent protumoral action. To answer this question, we explored the tumoral potential of each member by gene disruption of CD98, LAT1, or both and by inhibition of LAT1 with the selective inhibitor (JPH203) in six human cancer cell lines from colon, lung, and kidney. Each knockout respectively ablated 90% (CD98KO) and 100% (LAT1KO) of Na+-independent leucine transport activity. LAT1KO or JPH203-treated cells presented an amino acid stress response with ATF4, GCN2 activation, mTORC1 inhibition, and severe in vitro and in vivo tumor growth arrest. We show that this severe growth phenotype is independent of the level of expression of CD98 in the six tumor cell lines. Surprisingly, CD98KO cells with only 10% EAA transport activity displayed a normal growth phenotype, with mTORC1 activity and tumor growth rate undistinguishable from wild-type cells. However, CD98KO cells became extremely sensitive to inhibition or genetic disruption of LAT1 (CD98KO/LAT1KO). This finding demonstrates that the tumoral potential of CD98KO cells is due to residual LAT1 transport activity. Therefore, these findings clearly establish that LAT1 transport activity is the key growth-limiting step of the heterodimer and advocate the pharmacology development of LAT1 transporter inhibitors as a very promising anticancer target. Cancer Res; 76(15); 4481–92. ©2016 AACR.
Thursday, July 28, 2016 12:06 AM|Yasuhiro Ohshima, Kyoichi Kaira, Aiko Yamaguchi, Noboru Oriuchi, Hideyuki Tominaga, Shushi Nagamori, Yoshikatsu Kanai, Takehiko Yokobori, Tatsuya Miyazaki, Takayuki Asao, Yoshito Tsushima, Hiroyuki Kuwano, Noriko S. Ishioka|Cancer Science|Labels: mTOR, esophageal cancer
System L amino acid transporter 1 (LAT1) is highly expressed in various types of human cancer, and contributes to cancer growth and survival. Recently, we have shown that LAT1 expression is closely related to the growth and aggressiveness of esophageal cancer, and is an independent marker of poor prognosis. However, it remains unclear whether LAT1 inhibition could suppress the esophageal cancer growth. In this study, we investigated the tumor suppressive effects by the inhibition of LAT1. Both LAT1 and CD98, which covalently associates to LAT1 on the membrane, are expressed in human esophageal cancer cell lines, KYSE30 and KYSE150. Quantitative PCR analysis showed that the expression of LAT1 was extremely higher than other subtypes of LAT. A selective inhibitor of LAT, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), suppressed cellular uptake of L-14C-leucine and cell proliferation in a dose-dependent manner. BCH also suppressed phosphorylation of mammalian target of rapamycin (mTOR), 4E-BP1, and p70S6K protein, and induced cell cycle arrest at G1 phase. These results suggest that suppression of both mTOR signaling and cell cycle progression is involved in BCH-induced growth inhibition. In tumor-bearing mice, daily administration of BCH significantly delayed tumor growth and decreased glucose metabolism, indicating that LAT1 inhibition potentially suppresses esophageal cancer growth in vivo. Thus, our results suggest that LAT1 inhibition would be a promising molecular target for the therapy of esophageal cancer. This article is protected by copyright. All rights reserved.
Wednesday, July 27, 2016 12:43 PM|Mao, Y., van Hoef, V., Zhang, X., Wennerberg, E., Lorent, J., Witt, K., Masvidal Sanz, L., Liang, S., Murray, S., Larsson, O., Kiessling, R., Lundqvist, A.|BLOOD First Edition Papers|Labels: mTOR, IL

Treatment of hematological malignancies by adoptive transfer of activated natural killer (NK) cells is limited by poor post-infusion persistence. We compared the ability of interleukin-2 (IL-2) and IL-15 to sustain human NK cell functions following cytokine withdrawal to model post-infusion performance. In contrasts to IL-2, IL-15 mediated stronger signaling through the IL-2/15 receptor complex and provided cell function advantages. Genome-wide analysis of cytosolic and polysome-associated mRNA revealed cytokine dependent differential mRNA levels and translation during cytokine activation but also that most gene expression differences were primed by IL-15 and only manifested after cytokine withdrawal. IL-15 augmented mTOR signaling, which correlated with increased expression of genes related to cell metabolism and respiration. Consistently, mTOR inhibition abrogated IL-15-induced cell function advantages. Moreover, mTOR-independent STAT-5 signaling contributed to improved NK cell function during cytokine activation but not following cytokine withdrawal. The superior performance of IL-15 stimulated NK cells was also observed using a clinically applicable protocol for NK cell expansion in vitro and in vivo. Finally, expression of IL-15 correlated with cytolytic immune functions in patients with B cell lymphoma and favorable clinical outcome. These findings highlight the importance of mTOR regulated metabolic processes for immune cell functions and argue for implementation of IL-15 in adoptive NK cell cancer therapy.

Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, “Eisai”) announced today that its European regional headquarters Eisai Europe Ltd. (Location: U.K.) has received a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) on anticancer agent lenvatinib mesylate (generic name, “lenvatinib”) in combination with everolimus for the treatment of adult patients with advanced renal cell carcinoma (RCC) following one prior vascular endothelial growth factor (VEGF) targeted therapy. If approved, lenvatinib will be launched under the brand name Kisplyx(R) for this indication.
Tuesday, July 19, 2016 9:22 AM|Qian, D. C., Xiao, X., Byun, J., Suriawinata, A. A., Her, S., Amos, C. I., Barth, R.|Clinical Cancer Research Online First Articles|Labels: AKT, mTOR, PI3K, CRC

Purpose: We have previously demonstrated that metastatic colorectal cancer patients who exhibit immune responses to a dendritic cell (DC) vaccine have superior recurrence-free survival following surgery, compared to patients in whom responses do not occur. We sought to characterize the patterns of T lymphocyte infiltration and somatic mutations in metastases that are associated with and predictive of response to the DC vaccine. Experimental Design: Cytotoxic, memory, and regulatory T cells in resected metastases and surrounding normal liver tissue from 22 patients (11 responders and 11 non-responders) were enumerated by immunohistochemistry prior to vaccine administration. In conjunction with tumor sequencing, the Combined Multivariate and Collapsing method was used to identify gene mutations that are associated with vaccine response. We also derived a response prediction score for each patient using his/her tumor genotype data and variant association effect sizes computed from the other 21 patients; greater weighting was placed on gene products with cell membrane-related functions. Results: There was no correlation between vaccine response and intra-tumor, peri-tumor, or hepatic densities of T cell subpopulations. Associated genes were found to be enriched in the PI3K/Akt/mTOR signaling axis (P < 0.001). Applying a consistent prediction score cutoff over 22 rounds of leave-one-out cross-validation correctly inferred vaccine response in 21 of 22 patients (95%). Conclusions: Adjuvant dendritic cell vaccination has shown promise as a form of immunotherapy for patients with metastatic colorectal cancer. Its efficacy may be influenced by somatic mutations that affect pathways involving PI3K, Akt, and mTOR, as well as tumor surface proteins.

Thursday, June 30, 2016 10:05 PM|Unknown Author|Cancer Discovery recent issues|Labels: mTOR, VEGF, kidney cancer, regulatory

The FDA has approved the combination of lenvatinib and everolimus to treat advanced or metastatic renal cell carcinoma. The approval marks the first time that tyrosine kinase and mTOR inhibitors have been combined successfully as second-line treatment for renal cell carcinoma following prior VEGF-targeted therapy.

Thursday, June 30, 2016 10:05 PM|Moore, E. C., Cash, H. A., Caruso, A. M., Uppaluri, R., Hodge, J. W., Van Waes, C., Allen, C. T.|Cancer Immunology Research recent issues|Labels: mTOR, PD-1/PD-L1, pharyngeal

Significant subsets of patients with oral cancer fail to respond to single-agent programmed death (PD) blockade. Syngeneic models of oral cancer were used to determine if blocking oncogenic signaling improved in vivo responses to PD-L1 monoclonal antibody (mAb). Anti–PD-L1 enhanced durable primary tumor control and survival when combined with mTOR (rapamycin), but not in combination with MEK inhibition (PD901) in immunogenic MOC1 tumors. Conversely, PD-L1 mAb did not enhance tumor control in poorly immunogenic MOC2 tumors. Rapamycin enhanced expansion of peripheral antigen-specific CD8 T cells and IFN production following ex vivo antigen stimulation. More CD8 T cells infiltrated and were activated after PD-L1 mAb treatment in mice with immunogenic MOC1 tumors, which were stable or increased by the addition of rapamycin, but suppressed when PD901 was added. Rapamycin increased IFN production capacity in peripheral and tumor-infiltrating CD8 T cells. In vivo antibody depletion revealed a CD8 T-cell–dependent, and not NK cell–dependent mechanism of tumor growth inhibition after treatment with rapamycin and PD-L1 mAb, ruling out significant effects from NK cell–mediated antibody-dependent cellular cytotoxicity. Rapamycin also enhanced IFN or PD-L1 mAb treatment–associated induction of MHC class I expression on MOC1 tumor cells, an effect abrogated by depleting infiltrating CD8 T cells from the tumor microenvironment. These data conflict with traditional views of rapamycin as a universal immunosuppressant, and when combined with evidence of enhanced antitumor activity with the combination of rapamycin and PD-L1 mAb, suggest that this treatment combination deserves careful evaluation in the clinical setting. Cancer Immunol Res; 4(7); 611–20. ©2016 AACR.

Friday, June 24, 2016 10:45 AM|Morrow, J. J., Mendoza, A., Koyen, A., Lizardo, M., Ren, L., Waybright, T. J., Hansen, R. J., Gustafson, D. L., Zhou, M., Fan, T. M., Scacheri, P., Khanna, C.|Clinical Cancer Research Online First Articles|Labels: mTOR, sarcoma

Purpose: To successfully metastasize, tumor cells must respond appropriately to biological stressors encountered during metastatic progression. We sought to test the hypothesis that enhanced efficiency of mRNA translation during periods of metastatic stress is required for metastatic competence of osteosarcoma and that this metastasis-specific adaptation is amenable to therapeutic intervention. Experimental Design: We employ novel reporter and proteomic systems that enable tracking of mRNA translation efficiency and output in metastatic osteosarcoma cells as they colonize the lungs. We test the potential to target mRNA translation as an anti-metastatic therapeutic strategy through pharmacokinetic studies and pre-clinical assessment of the prototypic mTOR inhibitor, rapamycin, across multiple models of metastasis. Results: Metastatic osteosarcoma cells translate mRNA more efficiently than non-metastatic cells during critical stressful periods of metastatic colonization of the lung. Rapamycin inhibits translational output during periods of metastatic stress, mitigates lung colonization, and prolongs survival. mTOR-inhibiting exposures of rapamycin are achievable in mice using treatment schedules that correspond to human doses well below the maximum tolerated doses defined in human patients, and as such are very likely to be tolerated over long exposures alone and in combination with other agents. Conclusions: Metastatic competence of osteosarcoma cells is dependent on efficient mRNA translation during stressful periods of metastatic progression and the mTOR inhibitor, rapamycin, can mitigate this translation and inhibit metastasis in vivo. Our data suggest that mTOR pathway inhibitors should be reconsidered in the clinic using rationally designed dosing schedules and clinical metrics related to metastatic progression.

Saturday, June 18, 2016 12:05 PM|Elsevier|JournalTOCs API - The Lancet Oncology (50 articles)|Labels: MET, mTOR, VEGF, kidney cancer, clinical trial

Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial

The Lancet Oncology, Vol. , No. (2016) pp. -
Publication date: Available online 5 June 2016 Source:The Lancet Oncology Author(s): Toni K Choueiri, Bernard Escudier, Thomas Powles, Nizar M Tannir, Paul N Mainwaring, Brian I Rini, Hans J Hammers, Frede Donskov, Bruce J Roth, Katriina Peltola, Jae Lyun Lee, Daniel Y C Heng, Manuela Schmidinger, Neeraj Agarwal, Cora N Sternberg, David F McDermott, Dana T Aftab, Colin Hessel, Christian Scheffold, Gisela Schwab, Thomas E Hutson, Sumanta Pal, Robert J Motzer Background Cabozantinib is an oral inhibitor of tyrosine kinases including MET, VEGFR, and AXL. The randomised phase 3 METEOR trial compared the efficacy and safety of cabozantinib versus the mTOR inhibitor everolimus in patients with advanced renal cell carcinoma who progressed after previous VEGFR tyrosine-kinase inhibitor treatment. Here, we report the final overall survival results from this study based on an unplanned second interim analysis. Methods In this open-label, randomised phase 3 trial, we randomly assigned (1:1) patients aged 18 years and older with advanced or metastatic clear-cell renal cell carcinoma, measurable disease, and previous treatment with one or more VEGFR tyrosine-kinase inhibitors to receive 60 mg cabozantinib once a day or 10 mg everolimus once a day. Randomisation was done with an interactive voice and web response system. Stratification factors were Memorial Sloan Kettering Cancer Center risk group and the number of previous treatments with VEGFR tyrosine-kinase inhibitors. The primary endpoint was progression-free survival as assessed by an independent radiology review committee in the first 375 randomly assigned patients and has been previously reported. Secondary endpoints were overall survival and objective response in all randomly assigned patients assessed by intention-to-treat. Safety was assessed per protocol in all patients who received at least one dose of study drug. The study is closed for enrolment but treatment and follow-up of patients is ongoing for long-term safety evaluation. This trial is registered with, number NCT01865747. Findings Between Aug 8, 2013, and Nov 24, 2014, 658 patients were randomly assigned to receive cabozantinib (n=330) or everolimus (n=328). The median duration of follow-up for overall survival and safety was 18·7 months (IQR 16·1–21·1) in the cabozantinib group and 18·8 months (16·0–21·2) in the everolimus group. Median overall survival was 21·4 months (95% CI 18·7–not estimable) with cabozantinib and 16·5 months (14·7–18·8) with everolimus (hazard ratio [HR] 0·66 [95% CI 0·53–0·83]; p=0·00026). Cabozantinib treatment also resulted in improved progression-free survival (HR 0·51 [95% CI 0·41–0·62]; p&lt;0·0001) and objective response (17% [13–22] with cabozantinib vs 3% [2–6] with everolimus; p&lt;0·0001) per independent radiology review among all randomised patients. The most common grade 3 or 4 adverse events were hypertension (49 [15%] in the cabozantinib group vs 12 [4%] in the everolimus group), diarrhoea (43 [13%] vs 7 [2%]), fatigue (36 [11%] vs 24 [7%]), palmar-plantar erythrodysaesthesia syndrome (27 [8%] vs 3 [1%]), anaemia (19 [6%] vs 53 [17%]), hyperglycaemia (3 [1%] vs 16 [5%]), and hypomagnesaemia (16 [5%] vs none). Serious adverse events grade 3 or worse occurred in 130 (39%) patients in the cabozantinib group and in 129 (40%) in the everolimus group. One treatment-related death occurred in the cabozantinib group (death; not otherwise specified) and two occurred in the everolimus group (one aspergillus infection and one pneumonia aspiration). Interpretation Treatment with cabozantinib increased overall survival, delayed disease progression, and improved the objective response compared with everolimus. Based on these results, cabozantinib should be considered as a new standard-of-care treatment option for previously treated patients with advanced renal cell carcinoma. Patients should be monitored for adverse events that might require dose modifications. Funding Exelixis Inc.

Friday, June 17, 2016 11:15 PM|News-Medical.Net Kidney Cancer News Feed|Comments|Labels: MET, mTOR, VEGF
Patients with advanced or metastatic renal cell carcinoma derive a significant overall survival benefit from second-line treatment with the multi-tyrosine kinase inhibitor cabozantinib relative to everolimus.
Tuesday, June 7, 2016 6:23 AM|News-Medical.Net Kidney Cancer News Feed|Comments|Labels: MET, mTOR, VEGF
Data presented today at the American Society of Clinical Oncology congress showed that cabozantinib, a next generation tyrosine kinase inhibitor (TKI) can extend the lives of patients by nearly two years following failure of one or more anti-angiogenic therapies almost five months longer than everolimus, a current standard of care therapy.
Monday, June 6, 2016 4:58 AM|KIM, J. Y., HEO, S.-H., SONG, I. H., PARK, I. A., KIM, Y.-A., GONG, G., LEE, H. J.|Anticancer Research recent issues|Labels: EGFR, mTOR, breast cancer

Background: We evaluated endoplasmic reticulum stress and unfolded protein response (UPR) activation, as possible mechanisms for influx of tumor infiltrating lymphocytes (TILs), and the correlation between UPR activation and mammalian target of rapamycin (mTOR) pathway activation. Materials and Methods: TILs and the immunohistochemical expression of protein kinase RNA-like endoplasmic reticulum kinase (PERK), phospho-eukaryotic translation initiation factor 2α (p-eIF2α) and phosphorylated S6 (pS6) were evaluated in 447 human epidermal growth factor receptor 2 (HER2)-positive breast cancer tissues. Results: High expression of PERK, p-eIF2α and pS6 was observed in 270 (60.4%), 259 (57.9%), and 187 (41.8%) cases, respectively, and was significantly associated with a high histological grade, high numbers of TILs, peritumoral lymphocytic infiltration, and tertiary lymphoid structures in HER2-positive breast cancer tissues. Conclusion: The results suggest endoplasmic reticulum stress and UPR activation as possible mechanisms for the influx of TILs in HER2-positive breast cancer. Evaluation of PERK and p-eIF2α expression might be important in identifying targets for cancer therapies in modulating endoplasmic reticulum stress.

Thursday, June 2, 2016 10:05 PM|Unknown Author|Cancer Discovery recent issues|Labels: MET, mTOR, kidney cancer

The FDA has approved cabozantinib, a tyrosine kinase inhibitor, for patients with advanced renal cell carcinoma who have received prior antiangiogenic therapy. In a randomized phase III trial, participants who received cabozantinib did better across three efficacy endpoints—progression-free survival, overall survival, and objective response rate—than those given the mTOR inhibitor everolimus.

Wednesday, May 25, 2016 10:04 AM|Soler, A., Figueiredo, A. M., Castel, P., Martin, L., Monelli, E., Angulo-Urarte, A., Mila-Guasch, M., Vinals, F., Baselga, J., Casanovas, O., Graupera, M.|Clinical Cancer Research Online First Articles|Labels: mTOR, PI3K, pancreatic cancer

Purpose: Mutations in the PI3-kinase (PI3K) pathway occur in 16% of patients with pancreatic neuroendocrine tumors (PanNETs), which suggests that these tumors are an exciting setting for PI3K/AKT/mTOR pharmacological intervention. Everolimus, an mTOR inhibitor, is being used to treat patients with advanced PanNETs. However, resistance to mTOR targeted therapy is emerging partially due to the loss of mTOR-dependent feedback inhibition of AKT. In contrast, the response to PI3K inhibitors in PanNETs is unknown Experimental Design: In the present study, we assessed the frequency of PI3K pathway activation in human PanNETs and in RIP1-Tag2 mice, a preclinical tumor model of PanNETs, and we investigated the therapeutic efficacy of inhibiting PI3K in RIP1-Tag2 mice using a combination of pan (GDC-0941) and p110α selective (GDC-0326) inhibitors and isoform specific PI3K kinase-dead mutant mice Results: Human and mouse PanNETs showed enhanced pAKT, pPRAS40 and pS6 positivity compared to normal tissue. While treatment of RIP1-Tag2 mice with GDC-0941 led to reduced tumor growth with no impact on tumor vessels, the selective inactivation of the p110α PI3K isoform, either genetically or pharmacologically, reduced tumor growth as well as vascular area. Furthermore, GDC-0326 reduced the incidence of liver and lymph node (LN) metastasis compared to vehicle treated mice. We also demonstrated that tumor and stromal cells are implicated in the anti-tumor activity of GDC-0326 in RIP1-Tag2 tumors Conclusions: Our data provide a rationale for p110α selective intervention in PanNETs and unravel a new function of this kinase in cancer biology through its role in promoting metastasis.

Monday, May 23, 2016 8:34 AM|Olow, A., Mueller, S., Yang, X., Hashizume, R., Meyerowitz, J., Weiss, W. A., Resnick, A. C., Waanders, A. J., Stalpers, L. J. A., Berger, M. S., Gupta, N., James, C. D., Petritsch, C. K., Haas-Kogan, D. A.|Clinical Cancer Research Online First Articles|Labels: BRAF, mTOR, brain cancer, clinical trial

Purpose: Alteration of the BRAF/MEK/MAPK pathway is the hallmark of pediatric low-grade gliomas (PLGG) and mTOR activation has been documented in the majority of these tumors. We investigated combinations of MEK1/2, BRAFV600E and mTOR inhibitors in gliomas carrying specific genetic alterations of the MAPK pathway. Experimental Design: We used human glioma lines containing BRAFV600E (adult high-grade: AM-38, DBTRG, PLGG: BT40), or wild-type BRAF (pediatric high-grade: SF188, SF9427, SF8628) and isogenic systems of KIAA1549:BRAF-expressing NIH/3T3 cells and BRAFV600E-expressing murine brain tumors. Signaling inhibitors included everolimus (mTOR), PLX4720 (BRAFV600E), and AZD6244 (MEK1/2). Proliferation was determined using ATP-based assays. In vivo inhibitor activities were assessed in the BT40 PLGG xenograft model. Results: In BRAFV600E cells, the three possible doublet combinations of AZD6244, everolimus and PLX4720 exhibited significantly greater effects on cell viability. In BRAFWT cells, everolimus+AZD6244 was superior compared to respective monotherapies. Similar results were found using isogenic murine cells. In KIAA1549:BRAF cells, MEK1/2 inhibition reduced cell viability and S-phase content, effects that were modestly augmented by mTOR inhibition. In vivo experiments in the BRAFV600E pediatric xenograft model BT40 showed the greatest survival advantage in mice treated with AZD6244+PLX4720 (p<0.01). Conclusions: In BRAFV600E tumors, combination of AZD6244+PLX4720 is superior to monotherapy and to other combinatorial approaches. In BRAFWT pediatric gliomas everolimus+AZD6244 is superior to either agent alone. KIAA1549:BRAF-expressing tumors display marked sensitivity to MEK1/2 inhibition. Application of these results to PLGG treatment must be exercised with caution since the dearth of PLGG models necessitated only a single patient-derived PLGG (BT40) in this study.

Thursday, May 12, 2016 10:05 PM|Zhou, X., Guo, J., Ji, Y., Pan, G., Liu, T., Zhu, H., Zhao, J.|Molecular Cancer Research recent issues|Labels: EGFR, mTOR, lung cancer

The epidermal growth factor receptor (EGFR) activates downstream mTOR phosphorylation to promote the progression of many different tumor types, thus making it a prime therapeutic target. However, the role of DEP domain-containing mTOR-interacting protein (DEPTOR), a natural mTOR inhibitor, remains unclear in this process. Here, it is reported that EGFR expression is significantly increased in tumors of lung adenocarcinoma patients and is negatively correlated with the expression of DEPTOR. Activation of EGFR signaling, by EGF, in A549 lung adenocarcinoma cells (overexpressing EGFR) significantly enhanced the function of the mTOR autoamplification loop, consisting of S6K, mTOR, CK1α, and βTrCP1, which resulted in downregulation of DEPTOR expression. Gefitinib, a specific EGFR inhibitor, stimulated DEPTOR accumulation by downregulating the function of the mTOR autoamplification loop. Furthermore, a series of assays conducted in DEPTOR knockout or ectopic expression in A549 cells confirmed that DEPTOR inhibited proliferation, migration, and invasion as well as the in vivo tumor growth of lung adenocarcinoma. Importantly, tumor progression mediated by EGFR ectopic expression was diminished by transfection with DEPTOR. This study uncovers the important inhibitory role of DEPTOR in lung adenocarcinoma progression and reveals a novel mechanism that EGFR downregulates DEPTOR expression to facilitate tumor growth.

Implications: DEPTOR acts as a tumor suppressor by limiting EGFR-driven lung adenocarcinoma progression. Mol Cancer Res; 14(5); 448–57. ©2016 AACR.

Thursday, May 12, 2016 1:54 PM|Berns, K., Sonnenblick, A., Gennissen, A., Brohee, S., Hijmans, M. E., Evers, B., Fumagalli, D., Desmedt, C., Loibl, S., Denkert, C., Neven, P., Guo, W., Zhang, F., Knijnenburg, T. A., Bosse, T., van der Heijden, M. S., Hindriksen, S., Nijkamp, W., Wessels, L. F. A., Joensuu, H., Mills, G. B., Beijersbergen, R. L., Sotiriou, C., Bernards, R.|Clinical Cancer Research Online First Articles|Labels: AKT, EGFR, mTOR, breast cancer, biomarker diagnostic

Purpose: Despite the substantial progress in the development of targeted anti-cancer drugs, treatment failure due to primary or acquired resistance is still a major hurdle in the effective treatment of most advanced human cancers. Understanding these resistance mechanisms will be instrumental to improve personalized cancer treatment. Experimental Design: Genome wide loss-of-function genetic screens were performed to identify genes implicated in resistance to HER2/PI3K/mTOR targeting agents in HER2+ breast cancer cell lines. Expression and adjuvant trastuzumab response data from the HER2+ breast cancer trials FINHER and Responsify were used to validate our findings in patient series. Results: We find that reduced ARID1A expression confers resistance to several drugs that inhibit the HER2/PI3K/mTOR signaling cascade at different levels. We demonstrate that ARID1A loss activates AnnexinA1 (ANXA1) expression, which is required for drug resistance through its activation of AKT. We find that the AKT inhibitor MK2206 restores sensitivity of ARID1A knockdown breast cancer cells to both the mTOR kinase inhibitor AZD8055 and trastuzumab. Consistent with these in vitro data, we find in two independent HER2+ breast cancer patient series that high ANXA1 expression is associated with resistance to adjuvant trastuzumab based therapy. Conclusions: Our findings provide a rationale for why tumors accumulate ARID1A mutations and identify high ANXA1 expression as a predictive biomarker for trastuzumab-based treatment. Our findings also suggest strategies to treat breast cancers with elevated ANXA1 expression.

Wednesday, May 11, 2016 12:23 PM|Choueiri, T. K., Fishman, M., Escudier, B., McDermott, D. F., Drake, C. G., Kluger, H. M., Stadler, W. M., Perez-Gracia, J. L., McNeel, D. G., Curti, B. D., Harrison, M. R., Plimack, E. R., Appleman, L., Fong, L., Albiges, L., Cohen, L. J., Young, T. C., Chasalow, S. D., Ross-MacDonald, P., Srivastava, S., Jure-Kunkel, M., Kurland, J. F., Simon, J. S., Sznol, M.|Clinical Cancer Research Online First Articles|Labels: mTOR, PD-1/PD-L1, kidney cancer

Purpose: Nivolumab, an anti-PD-1 immune checkpoint inhibitor, improved overall survival versus everolimus in a phase 3 trial of previously treated patients with metastatic renal cell carcinoma (mRCC). We investigated immunomodulatory activity of nivolumab in a hypothesis-generating, prospective mRCC trial. Experimental Design: Nivolumab was administered intravenously every 3 weeks at 0.3, 2.0, or 10 mg/kg to previously treated patients and 10 mg/kg to treatment-naïve patients with mRCC. Baseline and on-treatment biopsies and blood were obtained. Clinical activity, tumor-associated lymphocytes, PD-L1 expression (Dako immunohistochemistry; {greater than or equal to}5% vs. <5% tumor membrane staining), tumor gene expression (Affymetrix U219), serum chemokines, and safety were assessed. Results: In 91 treated patients, median overall survival (95% CI) was 16.4 months (10.1-not reached [NR]) for nivolumab 0.3 mg/kg, NR for 2 mg/kg, 25.2 months (12.0-NR) for 10 mg/kg, and NR for treatment-naïve patients. Median percent change from baseline in tumor-associated lymphocytes was 69% (CD3+), 180% (CD4+), and 117% (CD8+). Of 56 baseline biopsies, 32% had {greater than or equal to}5% PD-L1 expression, and there was no consistent change from baseline to on-treatment biopsies. Transcriptional changes in tumors on treatment included up-regulation of interferon--stimulated genes (e.g., CXCL9). Median increases in chemokine levels from baseline to C2D8 were 101% (CXCL9) and 37% (CXCL10) in peripheral blood. No new safety signals were identified. Conclusions: Immunomodulatory effects of PD-1 inhibition were demonstrated through multiple lines of evidence across nivolumab doses. Biomarker changes from baseline reflect nivolumab pharmacodynamics in the tumor microenvironment. These data may inform potential combinations.

Tuesday, March 29, 2016 12:07 AM|Cancer|Cancer via|Comments|Labels: mTOR, prostate cancer
CONCLUSIONSThe combination of bicalutamide and everolimus has encouraging efficacy in men with bicalutamide‐naive CRPC, thus warranting further investigation. A substantial number of patients experienced everolimus‐related toxicity. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
Friday, March 25, 2016 10:33 AM|Oncotarget|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: mTOR, lung cancer
Authors: Wang CI, Chen YY, Wang CL, Yu JS, Chang YS, Yu CJ Abstract Karyopherin subunit alpha-2 (KPNA2) is overexpressed in various human cancers and is associated with cancer invasiveness and poor prognosis in patient. Nevertheless, the regulation of KPNA2 expression in cancers remains unclear. We herein applied epidermal growth factor (EGF) and five EGF receptor (EGFR)-related kinase inhibitors to investigate the role of EGFR signaling in KPNA2 expression in non-small cell lung cancer (NSCLC) cells. We found that EGFR signaling, particularly the mammalian target of rapamycin (mTOR) activity was positively correlated with KPNA2 protein levels in NSCLC cells. The mTOR inhibitors and mTOR knockdown reduced the protein and mRNA levels of KPNA2 in NSCLC and breast cancer cells. Specif...
Thursday, February 18, 2016 5:58 PM|Current Cancer Drug Targets|MedWorm: Cancer Therapy|Comments|Labels: AKT, mTOR, PI3K, VEGF
In conclusion, our data demonstrated that the chimeric VEGF121-VEGF165 arrests the tube formation of endothelial cells and interferes with tumor cell growth, migration and invasion, suggesting that it could be a potential drug as an angiogenesis antagonist in cancer therapy. The VEGF121-VEGF165 targets not only paracrine angiogenic cascade of endothelial cells but also autocrine PI3K-AKT-mTOR-mediated VEGFR2-HIF-1α- VEGF165/Lon signaling that drives drug resistance in tumor cells. Our study will open up the patient opportunities to combat drug resistance to antiangiogenic therapy. PMID: 26882030 [PubMed - in process] (Source: Current Cancer Drug Targets)
Thursday, February 11, 2016 4:00 PM|PLoS One|MedWorm: Cancer Therapy|Comments|Labels: mTOR
by Jingwen Cao, Wenlong Huang The mechanistic target of rapamycin complex 1 (mTORC1) plays a crucial role in controlling cell growth and homeostasis. Deregulation of mTOR signaling is frequently observed in some cancers, making it an attractive drug target for cancer therapy. Although mTORC1 inhibitor rapalog-based therapy has shown positive results in various pre-clinical animal cancer studies, tumors rebound upon treatment discontinuation. Moreover, several recent clinical trials showed that the mTORC1 inhibitors rapamycin and rapalog only reduce the capacity for cell proliferation without promoting cell death, consistent with the concept that rapamycin is cytostatic and reduces disease progression but is not cytotoxic. It is imperative that rapamycin-regulated events and additional tar...
Monday, February 1, 2016 4:00 PM|British Journal of Cancer|MedWorm: Transitional Cell Carcinoma|Comments|Labels: mTOR, kidney cancer
Regulator of cullins-1 expression knockdown suppresses the malignant progression of muscle-invasive transitional cell carcinoma by regulating mTOR/DEPTOR pathway British Journal of Cancer 114, 305 (02 February 2016). doi:10.1038/bjc.2015.444 Authors: W Wang, H Chen, Z Liu, P Qu, J Lan, H Chen, L Zou & J Qiu (Source: British Journal of Cancer)
Tuesday, January 26, 2016 4:00 PM|Cellular Signalling|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: AKT, mTOR, PI3K
Authors: Hong SY, Yu FX, Luo Y, Hagen T Abstract Oncogenic activation of the PI3K/Akt pathway is known to play an important role in promoting glucose metabolism in cancer cells. However, the molecular mechanism through which the PI3K/Akt signalling pathway promotes glucose utilisation in cancer cells is still not well understood. It has recently been shown that the oncogenic activation of the PI3K/Akt/mTOR signalling in lung adenocarcinoma is important in promoting the localisation of glucose transporter 1 (GLUT1) at the plasma membrane. We thus hypothesised that the effect of constitutive activation of the PI3K/AKT signalling on glucose metabolism is mediated by thioredoxin interacting protein (TXNIP), a known regulator of the GLUT1 plasma membrane localisation. Consistent with pr...
Monday, January 18, 2016 3:16 AM|Chemotherapy|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: mTOR, lung cancer, clinical trial
Conclusion: The combination of pemetrexed and temsirolimus is feasible and well tolerated. This combination may be further evaluated in patients with mTOR pathway activation, particularly in those with TSC1 or STK11 mutations.Chemotherapy 2015–16;61:144–147 (Source: Chemotherapy)
Thursday, January 14, 2016 4:00 PM|Molecular Cancer Research|MedWorm: Cancer Therapy|Comments|Labels: mTOR, brain cancer
Aerobic glycolysis (the Warburg effect), first recognized almost a century ago, by Otto Warburg is a core hallmark of cancer. The Warburg effect describes a switch in glucose metabolism from oxidative phosphorylation to glycolysis. Recently links have been established between the oncogenic pathways that drive tumorigenesis and the mechanistic basis of tumor cell metabolism. The kinase mTOR is a major driver of tumor metabolism and proliferation of cancer cells, acts downstream of numerous oncogenic pathways. Several drugs targeting the mTOR pathway are being developed, however the most common drug rapamycin does not inhibit mTOR complex-2. Therefore in the current study, we examined the potential benefit of MLN0128, a novel potent mTOR ATP competitive inhibitor, as a therapeutic strategy f...
Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Cancer Therapy|Comments|Labels: mTOR, prostate cancer
The mTOR pathway is frequently over-activated in human cancers. However, classic allosteric mTOR inhibitors rapamycin and its analogs only exert limited clinical benefits in patients. It has been shown that many tumors either fail to respond to rapamycin initially or are able to acquire resistance after the initial treatment of rapamycin. Such primary and secondary resistances remain as major concerns in rapamycin-based anti-cancer therapies that may inevitably lead to therapeutic failure. We have previously shown that the ATP-competitive dual mTOR kinase inhibitor AZD8055 can significantly inhibit malignant behaviors in parental cells however its functional efficacies in the rapamycin-resistance setting remains unclear.Cancer cells with wildtype PTEN were selected as models of primary rap...
Conclusions: The combination of VAN and EV was reasonably well tolerated at the highest doses of each of the drugs. Evidence of response was noted in heavily pre-treated patients with refractory solid tumors and targetable genomic aberrations specifically RET. The combination has CNS penetration in RET fusion NSCLC.Citation Format: Tina Cascone, Kenneth R. Hess, Sarina Piha-Paul, David S. Hong, Michael Roxas, Ishwaria M. Subbiah, Siquing Fu, Aung Naing, Filip Janku, Daniel Karp, Steven I. Sherman, Funda Meric-Bernstam, John V. Heymach, Vivek Subbiah. A phase I study of everolimus (mTOR inhibitor) in combination with vandetanib (multikinase inhibitor of VEGFR, EGFR, and RET) in advanced solid tumors including molecularly matched aberrations. [abstract]. In: Proceedings of the AACR-NCI-EORTC...
Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: AKT, mTOR, kidney cancer
Conclusion: These results suggest that ibrutinib, a kinase inhibitor with immune modulatory properties, has anti-tumor activity against RCC when combined with mTOR inhibitors or pazopanib with different target spectrums. Although EGFR is not critical for proliferation in these untreated RCC lines, ibrutinib may prevent ErbB kinases from contributing to feedback up-regulation of Akt/Erk pathways by established drugs. These results provide a preclinical rationale for investigation of ibrutinib as a novel agent for RCC through positive interaction with mTOR inhibitors and/or pazopanib.Citation Format: Jun Chen, Jeff Hsu, Yujun Huang, Danelle F. James, Taisei Kinoshita, Betty Y. Chang. Ibrutinib potentiates the effects of mTOR inhibitors and pazopanib in renal cell carcinoma in vitro and in vi...
Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: MET, mTOR, lung cancer
Lung cancer is the most common cause of cancer death globally with a significant, unmet need for more efficacious treatments. Aberrant receptor tyrosine kinase (RTK) signaling is a well-documented driver of disease onset and progression in multiple cancer types, including non-small cell lung cancer (NSCLC), where the cMET RTK contributes to tumor progression, maintenance and resistance to targeted therapies. Here, we explore the therapeutic potential of the potent and selective cMET inhibitor savolitinib (volitinib, AZD6094, HMPL-504) in NSCLC and begin to elucidate mechanisms of acquired savolitinib resistance in preclinical models. Using in vitro proliferation assays and immunoblot analysis, we determine that savolitinib rapidly inhibits cMET auto-phosphorylation/activation and reduces t...
Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: mTOR
Conclusions: CB-839 has been well tolerated when administered BID with food at and above doses that produced robust inhibition of GLS in platelets and in tumors. Evidence of prolonged SD in pts receiving single agent CB-839, together with strong preclinical data in combination with SOC agents including paclitaxel, everolimus and erlotinib, provides a clear rationale for continued evaluation of CB-839 in several tumor types, as a single agent and in combination with SOC therapies.Citation Format: Funda Meric-Bernstam, Angela DeMichele, Melinda L. Telli, Pamela Munster, Keith W. Orford, George D. Demitri, Gary K. Schwartz, Othon Iliopoulos, James W. Mier, Taofeek K. Owonikoko, Mark K. Bennett, Manish R. Patel, Jeffery R. Infante, James J. Harding. Phase 1 study of CB-839, a first-in-class, o...
Tuesday, January 5, 2016 4:00 PM|Cancer Prevention Research|MedWorm: Transitional Cell Carcinoma|Comments|Labels: mTOR, bladder cancer
Urothelial tumors, accompanied by mutations of the tumor suppressor protein TP53 and dysregulation of mTOR signaling, are frequently associated with aggressive growth and invasiveness. We investigated whether targeting these two pathways would inhibit urothelial tumor growth and progression. Six-week-old transgenic UPII-SV40T male mice (n = 15/group) were fed control diet (AIN-76A) or experimental diets containing mTOR inhibitor (rapamycin, 8 or 16 ppm), p53 stabilizing agent [CP31398 (CP), 150 ppm], or a combination. Mice were euthanized at 40 weeks of age. Urinary bladders were collected and evaluated to determine tumor weight and histopathology. Each agent alone, and in combination, significantly inhibited tumor growth. Treatment with rapamycin alone decreased tumor weight up to 67% (P ...

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