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1. Intensity-modulated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): 2-year toxicity results from an open-label, randomised, phase 3, non-inferiority trial

Author

Lartigau, E, Patton, S, Thompson, A, Winkler, M, Wells, P, Lymberiou, T, Saunders, D, Vilarino-Varela, M, Vavassis, P, Tsakiridis, T, Carlson, R, Rodrigues, G, Tanguay, J, Iqbal, S, Morgan, S, Mihai, A, Li, A, Din, O, Panades, M, Wade, R, Rimmer, Y, Oommen, N, Tree, Alison C, Ostler, Peter, van der Voet, Hans, Chu, William, Loblaw, Andrew, Ford, Daniel, Tolan, Shaun, Jain, Suneil, Martin, Alexander, Staffurth, John, Armstrong, John, Camilleri, Philip, Kancherla, Kiran, Frew, John, Chan, Andrew, Dayes, Ian S, Duffton, Aileen, Brand, Douglas H, Henderson, Daniel, Morrison, Kirsty, Brown, Stephanie, Pugh, Julia, Burnett, Stephanie, Mahmud, Muneeb, Hinder, Victoria, Naismith, Olivia, Hall, Emma, and van As, Nicholas

Published
2022
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2. Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial

Author

Dodds, D, Lartigau, E, Patton, S, Thompson, A, Winkler, M, Wells, P, Lymberiou, T, Saunders, D, Vilarino-Varela, M, Vavassis, P, Tsakiridis, T, Carlson, R, Rodrigues, G, Tanguay, J, Iqbal, S, Morgan, S, Mihai, A, Li, A, Din, O, Panades, M, Wade, R, Rimmer, Y, Armstrong, J, Oommen, N, Brand, Douglas H, Tree, Alison C, Ostler, Peter, van der Voet, Hans, Loblaw, Andrew, Chu, William, Ford, Daniel, Tolan, Shaun, Jain, Suneil, Martin, Alexander, Staffurth, John, Camilleri, Philip, Kancherla, Kiran, Frew, John, Chan, Andrew, Dayes, Ian S, Henderson, Daniel, Brown, Stephanie, Cruickshank, Clare, Burnett, Stephanie, Duffton, Aileen, Griffin, Clare, Hinder, Victoria, Morrison, Kirsty, Naismith, Olivia, Hall, Emma, and van As, Nicholas

Published
2019
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3. Progression-Free Survival as a Surrogate Endpoint of Overall Survival in Patients with Locally Advanced Non-Small Cell Lung Cancer Treated with Chemoradiotherapy: Trial-Level Meta-Analysis and Individual-Level Analysis of NRG/RTOG 0617 and PROCLAIM

Author

Hu, C., primary, Miccio, J.A., additional, Dignam, J.J., additional, Paulus, R., additional, Liu, C., additional, Skinner, H.D., additional, Tsakiridis, T., additional, Bradley, J.D., additional, and Machtay, M., additional

Published
2023
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5. LUSTRE: A Phase III Randomized Trial of Stereotactic Body Radiotherapy (SBRT) vs. Conventionally Hypofractionated Radiotherapy (CRT) for Medically Inoperable Stage I Non-Small Cell Lung Cancer (NSCLC)

Author

Swaminath, A., primary, Parpia, S., additional, Wierzbicki, M., additional, Kundapur, V., additional, Faria, S.L., additional, Okawara, G., additional, Tsakiridis, T., additional, Ahmed, N., additional, Bujold, A., additional, Hirmiz, K.J., additional, Owen, T.E., additional, Leong, N., additional, Ramchandar, K., additional, Filion, E.J., additional, Lau, H., additional, Louie, A.V., additional, Quan, K., additional, Levine, M., additional, Wright, J., additional, and Whelan, T.J., additional

Published
2022
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8. Intensity-modulated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): 2-year toxicity results from an open-label, randomised, phase 3, non-inferiority trial

Author

Tree, Alison C, primary, Ostler, Peter, additional, van der Voet, Hans, additional, Chu, William, additional, Loblaw, Andrew, additional, Ford, Daniel, additional, Tolan, Shaun, additional, Jain, Suneil, additional, Martin, Alexander, additional, Staffurth, John, additional, Armstrong, John, additional, Camilleri, Philip, additional, Kancherla, Kiran, additional, Frew, John, additional, Chan, Andrew, additional, Dayes, Ian S, additional, Duffton, Aileen, additional, Brand, Douglas H, additional, Henderson, Daniel, additional, Morrison, Kirsty, additional, Brown, Stephanie, additional, Pugh, Julia, additional, Burnett, Stephanie, additional, Mahmud, Muneeb, additional, Hinder, Victoria, additional, Naismith, Olivia, additional, Hall, Emma, additional, van As, Nicholas, additional, Lartigau, E, additional, Patton, S, additional, Thompson, A, additional, Winkler, M, additional, Wells, P, additional, Lymberiou, T, additional, Saunders, D, additional, Vilarino-Varela, M, additional, Vavassis, P, additional, Tsakiridis, T, additional, Carlson, R, additional, Rodrigues, G, additional, Tanguay, J, additional, Iqbal, S, additional, Morgan, S, additional, Mihai, A, additional, Li, A, additional, Din, O, additional, Panades, M, additional, Wade, R, additional, Rimmer, Y, additional, and Oommen, N, additional

Published
2022
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10. Stereotactic Body Radiotherapy (SBRT) vs. Conventional Fractionation External Beam Radiotherapy (EBRT) Boost for Unfavorable Intermediate and High-Risk Prostate Cancer; Early Results of PBS: A Phase II Randomized Trial (NCT03380806)

Author

Gouveia, A.G., Mesci, A., Isfahanian, N., Dayes, I., Quan, K., Goldberg, M., Schnarr, K.L., Lukka, H., Cuthbert, D., Hallock, A., Douvi, G., Wright, J., Swaminath, A., Chow, T., Diamond, K., Hajdok, G., Maharaj, L., Ewusive, J., and Tsakiridis, T.

Published
2024
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14. Metformin-induced reductions in tumor growth involves modulation of the gut microbiome.

Author

Broadfield, LA, Saigal, A, Szamosi, JC, Hammill, JA, Bezverbnaya, K, Wang, D, Gautam, J, Tsakiridis, EE, Di Pastena, F, McNicol, J, Wu, J, Syed, S, Lally, JSV, Raphenya, AR, Blouin, M-J, Pollak, M, Sacconi, A, Blandino, G, McArthur, AG, Schertzer, JD, Surette, MG, Collins, SM, Bramson, JL, Muti, P, Tsakiridis, T, Steinberg, GR, Broadfield, LA, Saigal, A, Szamosi, JC, Hammill, JA, Bezverbnaya, K, Wang, D, Gautam, J, Tsakiridis, EE, Di Pastena, F, McNicol, J, Wu, J, Syed, S, Lally, JSV, Raphenya, AR, Blouin, M-J, Pollak, M, Sacconi, A, Blandino, G, McArthur, AG, Schertzer, JD, Surette, MG, Collins, SM, Bramson, JL, Muti, P, Tsakiridis, T, and Steinberg, GR

Abstract

BACKGROUND/PURPOSE: Type 2 diabetes and obesity increase the risk of developing colorectal cancer. Metformin may reduce colorectal cancer but the mechanisms mediating this effect remain unclear. In mice and humans, a high-fat diet (HFD), obesity and metformin are known to alter the gut microbiome but whether this is important for influencing tumor growth is not known. METHODS: Mice with syngeneic MC38 colon adenocarcinomas were treated with metformin or feces obtained from control or metformin treated mice. RESULTS: We find that compared to chow-fed controls, tumor growth is increased when mice are fed a HFD and that this acceleration of tumor growth can be partially recapitulated through transfer of the fecal microbiome or in vitro treatment of cells with fecal filtrates from HFD-fed animals. Treatment of HFD-fed mice with orally ingested, but not intraperitoneally injected, metformin suppresses tumor growth and increases the expression of short-chain fatty acid (SCFA)-producing microbes Alistipes, Lachnospiraceae and Ruminococcaceae. The transfer of the gut microbiome from mice treated orally with metformin to drug naïve, conventionalized HFD-fed mice increases circulating propionate and butyrate, reduces tumor proliferation, and suppresses the expression of sterol response element binding protein (SREBP) gene targets in the tumor. CONCLUSION: These data indicate that in obese mice fed a HFD, metformin reduces tumor burden through changes in the gut microbiome.

Published
2022

18. Summary of international recommendations in 23 languages for patients with cancer during the COVID-19 pandemic

Author

Mauri, D., Kamposioras, K., Tolia, M., Alongi, F., Tzachanis, D., Petricevic, B., Chilingirova, N., Mihaylova, I., Tsakiridis, T., Salembier, C., Papadimitriou, K., De Mello, R. A., Amaral, G. A., Neves, N. M., Dias, R., Yi, J., Dedic Plavetic, N., Antunac, K., Kountourakis, P., Kopecky, J., Christopoulos, C., Pavese, I., Corradini, S., Zarkavelis, G., Papadaki, A., Gkantaifi, A., Theodorelos, V., Capizzello, A., Lovey, J., Cellini, Francesco, Dambrosio, M., Takeuchi, D., Saraireh, H. H., Rotterud, R., Chojnacka, M., Papachristos, A., Djan, I., Popovic, L., Grasic Kuhar, C., Strojan, P., Hindi, N., Valachis, A., Ahs, M., De Bari, B., Santa Cruz, O., Hameed, H., Takeuchi, E., Apostolidis, K., Cardone, A., Gono, P., Filis, P., Cellini F. (ORCID:0000-0002-2145-2300), Mauri, D., Kamposioras, K., Tolia, M., Alongi, F., Tzachanis, D., Petricevic, B., Chilingirova, N., Mihaylova, I., Tsakiridis, T., Salembier, C., Papadimitriou, K., De Mello, R. A., Amaral, G. A., Neves, N. M., Dias, R., Yi, J., Dedic Plavetic, N., Antunac, K., Kountourakis, P., Kopecky, J., Christopoulos, C., Pavese, I., Corradini, S., Zarkavelis, G., Papadaki, A., Gkantaifi, A., Theodorelos, V., Capizzello, A., Lovey, J., Cellini, Francesco, Dambrosio, M., Takeuchi, D., Saraireh, H. H., Rotterud, R., Chojnacka, M., Papachristos, A., Djan, I., Popovic, L., Grasic Kuhar, C., Strojan, P., Hindi, N., Valachis, A., Ahs, M., De Bari, B., Santa Cruz, O., Hameed, H., Takeuchi, E., Apostolidis, K., Cardone, A., Gono, P., Filis, P., and Cellini F. (ORCID:0000-0002-2145-2300)

Abstract

N/A

Published
2020

19. Patient and family support in the era of fake e-medicine : Food for thought from an international consensus panel

Author

Mauri, D., Kamposioras, K., Tzachanis, D., Tolia, M., Valachis, Antonis, Dambrosio, M., Alongi, F., De Mello, R. A., Lövey, J., Anthoney, A., Christopoulos, C., Saraireh, H. H., Kountourakis, P., Kampletsas, E., Tsali, L., Tsakiridis, T., Kosovitsas, I., Soukovelos, A., Lymperatou, D., Polyzos, N., Zarkavelis, G., Mauri, D., Kamposioras, K., Tzachanis, D., Tolia, M., Valachis, Antonis, Dambrosio, M., Alongi, F., De Mello, R. A., Lövey, J., Anthoney, A., Christopoulos, C., Saraireh, H. H., Kountourakis, P., Kampletsas, E., Tsali, L., Tsakiridis, T., Kosovitsas, I., Soukovelos, A., Lymperatou, D., Polyzos, N., and Zarkavelis, G.

Published
2020
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20. Randomized Phase II Trial of Metformin in Combination with Chemoradiotherapy (CRT) in Locally Advanced Non-Small Cell Lung Cancer (LA-NSCLC); the OCOG-ALMERA trial (NCT02115464)

Author

Tsakiridis, T., primary, Pond, G., additional, Wright, J., additional, Ellis, P., additional, Abdulkarim, B.S., additional, Ahmed, N., additional, Robinson, A.G., additional, Valdes, M., additional, Okawara, G., additional, Swaminath, A., additional, Wierzbicki, M., additional, and Levine, M., additional

Published
2020
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21. Impact of Pelvic Intensity-modulated Radiotherapy (IMRT) on Lymph Node Coverage and Dose to Critical Organs, Compare to Three-Dimensional Conformal Radiation Therapy (3D-CRT), in Localized High-Risk Prostate Cancer

Author

Isfahanian, N., primary, Douvi, G., additional, Arsenault, J., additional, Dayes, I., additional, Tolakanahalli, R.P., additional, Lukka, H., additional, Patel, M., additional, Chow, T., additional, Parpia, S., additional, and Tsakiridis, T., additional

Published
2020
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22. Canagliflozin Mediates Effective Blockade of the mTORC1 - HIF-1a Pathway, Inhibits Growth and Enhances Non-Small Cell Lung Cancer (NSCLC) Response to Radiotherapy (RT)

Author

Biziotis, O.D., primary, Tsakiridis, E.E., additional, Mekhaeil, B., additional, Wu, J., additional, Zacharidis, P., additional, Broadfield, L.A., additional, Menjolian, G., additional, Farrell, T., additional, Abdulkarim, B.S., additional, Muti, P., additional, Steinberg, G.R., additional, and Tsakiridis, T., additional

Published
2020
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24. Salicylate enhances the response of prostate cancer to radiotherapy.

Author

Broadfield, LA, Marcinko, K, Tsakiridis, E, Zacharidis, PG, Villani, L, Lally, JSV, Menjolian, G, Maharaj, D, Mathurin, T, Smoke, M, Farrell, T, Muti, P, Steinberg, GR, Tsakiridis, T, Broadfield, LA, Marcinko, K, Tsakiridis, E, Zacharidis, PG, Villani, L, Lally, JSV, Menjolian, G, Maharaj, D, Mathurin, T, Smoke, M, Farrell, T, Muti, P, Steinberg, GR, and Tsakiridis, T

Abstract

BACKGROUND: Radiotherapy (RT) is a key therapeutic modality for prostate cancer (PrCa), but RT resistance necessitates dose-escalation, often causing bladder and rectal toxicity. Aspirin, a prodrug of salicylate (SAL), has been associated with improved RT response in clinical PrCa cases, but the potential mechanism mediating this effect is unknown. SAL activates the metabolic stress sensor AMP-activated protein kinase (AMPK), which inhibits de novo lipogenesis, and protein synthesis via inhibition of Acetyl-CoA Carboxylase (ACC), and the mammalian Target of Rapamycin (mTOR), respectively. RT also activates AMPK through a mechanism distinctly different from SAL. Therefore, combining these two therapies may have synergistic effects on suppressing PrCa. Here, we examined the potential of SAL to enhance the response of human PrCa cells and tumors to RT. METHODS: Androgen-insensitive (PC3) and -sensitive (LNCaP) PrCa cells were subjected to proliferation and clonogenic survival assays after treatment with clinically relevant doses of SAL and RT. Balb/c nude mice with PC3 xenografts were fed standard chow diet or chow diet supplemented with 2.5 g/kg salsalate (SAL pro-drug dimer) one week prior to a single dose of 0 or 10 Gy RT. Immunoblotting analysis of signaling events in the DNA repair and AMPK-mTOR pathways and lipogenesis were assessed in cells treated with SAL and RT. RESULTS: SAL inhibited proliferation and clonogenic survival in PrCa cells and enhanced the inhibition mediated by RT. Salsalate, added to diet, enhanced the anti-tumor effects of RT in PC3 tumor xenografts. RT activated genotoxic stress markers and the activity of mTOR pathway and AMPK and mediated inhibitory phosphorylation of ACC. Interestingly, SAL enhanced the effects of RT on AMPK and ACC but blocked markers of mTOR activation. CONCLUSIONS: Our results show that SAL can enhance RT responses in PrCa. Salsalate is a promising agent to investigate this concept in prospective clinical trials of PrCa

Published
2019

25. Prostate-Specific Membrane Antigen (PSMA) Expression Predicts Need for Early Treatment in Prostate Cancer Patients Managed with Active Surveillance.

Author

Gouran-savadkoohi, Mohammad, Ahmadi, Elham, Isfahanian, Naghmeh, and Tsakiridis, T.

Subjects
PROSTATE-specific membrane antigen, PROSTATE cancer patients, WATCHFUL waiting, GLUCOSE transporters, GLEASON grading system
Abstract

Introduction: Metabolic dysregulation is an early event in carcinogenesis. Here, we examined the expression of enzymes involved in de novo lipogenesis (ATP - citrate lyase: ACLY), glucose uptake (Glucose Transporter 1: GLUT1), and folate - glutamate metabolism (Prostate - Specific Membrane Antigen: PSMA) as potential biomarkers of risk for early prostate cancer progression. Methods: Patients who were managed initially on active surveillance with a Gleason score of 6 or a low - volume Gleason score of 7 (3 + 4) were accrued from a prostate cancer diagnostic assessment program. Patients were asked to donate their baseline diagnostic biopsy tissues and permit access to their clinical data. PSMA, GLUT1, and ACLY expression were examined with immunohistochemistry (IHC) in baseline biopsies, quantitated by Histologic Score for expression in benign and malignant glands, and compared with patient time remaining on active surveillance (time - on - AS). Results: All three markers showed trends for elevated expression in malignant compared to benign glands, which was statistically significant for ACLY. On univariate analysis, increased PSMA and GLUT1 expression in malignant glands was associated with shorter time - on - AS (HR: 5.06, [CI 95%: 1.83 - 13.94] and HR: 2.44, [CI 95%: 1.10 - 5.44], respectively). Malignant ACLY and benign gland PSMA and GLUT1 expression showed non - significant trends for such association. On multivariate analysis, overexpression of PSMA in malignant glands was an independent predictor of early PC progression (p = 0.006). Conclusions: This work suggests that the expression of metabolic enzymes determined by IHC on baseline diagnostic prostate biopsies may have value as biomarkers of risk for rapid PC progression. PSMA may be an independent predictor of risk for progression and should be investigated further in systematic studies. [ABSTRACT FROM AUTHOR]

Published
2024

26. Disease Control Outcomes of Stereotactic Body Radiation Therapy or Moderate Hypo - Fractionation for Prostate Cancer: Real - World Experience at Two Canadian Centers.

Author

Gouran-savadkoohi, Mohammad, Hsin-Pei, and Tsakiridis, T.

Subjects
STEREOTACTIC radiotherapy, OVERALL survival, PROSTATE cancer, RADIOTHERAPY, DISEASE risk factors, SURVIVAL rate
Abstract

Introduction: Advantages of using stereotactic body radiation therapy to treat prostate cancer include short treatment times, decreased costs, and limited toxicity. Randomized trial outcomes comparing 5 - fraction stereotactic body radiation therapy to conventionally fractionated radiotherapy or hypo - fractionated radiation therapy are pending. Methods: Patients with low - or intermediate - risk prostate cancer treated with stereotactic body radiation therapy alone (35 - 40 Gy in 5 fractions) or hypo - fractionated radiation therapy alone (60 - 62 Gy in 20 fractions) in the period of July 2010 and June 2020. The biochemical relapse - free survival, PSA nadir, interval time to PSA nadir, time to biochemical recurrence (2 ng/ml above PSA nadir) and overall survival were reviewed. Outcomes between treatment groups were compared after propensity - matching by patient baseline characteristics. Kaplan - Meier curves were used to assess biochemical relapse - free survival and overall survival. Results: We identified 205 and 513 patients with low or intermediate - risk prostate cancer who were treated with stereotactic body radiation therapy or hypo - fractionation, respectively. Intermediate - risk category composed 81% and 95% of the stereotactic body radiation therapy and hypo - fractionated radiation therapy cohorts, respectively. After a median follow up of 58.6 months for the stereotactic body radiation therapy cohort and 45.0 months for the hypo - fractionated cohort, biochemical relapse - free survival and overall survival were not significantly different between treatment groups. The 5 - year biochemical relapse - free survival rates were 92.1% and 93.6% and overall survival rates were 96.4% and 95.0% for the stereotactic body radiation therapy and hypo - fractionated cohorts, respectively, after propensity - matching. Stereotactic body radiation therapy resulted in a significantly lower PSA nadir (0.18 ng/ml) compared to hypo - fractionated radiation therapy (0.48 ng/ml) in patients with low - risk prostate cancer. Mean time to biochemical recurrence was not different between treatment groups. Conclusions: Stereotactic body radiation therapy is an effective treatment option for low and intermediate - risk prostate cancer with encouraging biochemical relapse - free survival and overall survival rates comparable with hypo - fractionated radiation therapy. [ABSTRACT FROM AUTHOR]

Published
2024

27. Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial

Author

Brand, Douglas H, primary, Tree, Alison C, additional, Ostler, Peter, additional, van der Voet, Hans, additional, Loblaw, Andrew, additional, Chu, William, additional, Ford, Daniel, additional, Tolan, Shaun, additional, Jain, Suneil, additional, Martin, Alexander, additional, Staffurth, John, additional, Camilleri, Philip, additional, Kancherla, Kiran, additional, Frew, John, additional, Chan, Andrew, additional, Dayes, Ian S, additional, Henderson, Daniel, additional, Brown, Stephanie, additional, Cruickshank, Clare, additional, Burnett, Stephanie, additional, Duffton, Aileen, additional, Griffin, Clare, additional, Hinder, Victoria, additional, Morrison, Kirsty, additional, Naismith, Olivia, additional, Hall, Emma, additional, van As, Nicholas, additional, Dodds, D, additional, Lartigau, E, additional, Patton, S, additional, Thompson, A, additional, Winkler, M, additional, Wells, P, additional, Lymberiou, T, additional, Saunders, D, additional, Vilarino-Varela, M, additional, Vavassis, P, additional, Tsakiridis, T, additional, Carlson, R, additional, Rodrigues, G, additional, Tanguay, J, additional, Iqbal, S, additional, Morgan, S, additional, Mihai, A, additional, Li, A, additional, Din, O, additional, Panades, M, additional, Wade, R, additional, Rimmer, Y, additional, Armstrong, J, additional, and Oommen, N, additional

Published
2019
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28. OA12.03 Initial Reporting of NRG-LU001, Randomized Phase II Trial of Concurrent Chemoradiotherapy +/- Metformin HCL in Locally Advanced NSCLC

Author

Skinner, H., primary, Hu, C., additional, Tsakiridis, T., additional, Santana-Davila, R., additional, Lu, B., additional, Erasmus, J., additional, Doemer, A., additional, Videtic, G., additional, Coster, J., additional, Yang, A., additional, Lee, R., additional, Wasik, M. Werner, additional, Schaner, P., additional, Mccormack, S., additional, Esparaz, B., additional, Mcgarry, R., additional, Bazan, J., additional, Stuve, T., additional, and Bradley, J., additional

Published
2019
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32. 127TiP Phase I study of neo-adjuvant Stereotactic Body Radiotherapy (SBRT) in operable patients with borderline resectable locally advanced NSCLC (LA-NSCLC) (LINNEARRE I STUDY: NCT02433574)

Author

Tsakiridis, T., primary, Isfahanian, N., additional, Nguyen, N., additional, Wright, J., additional, Hanna, W., additional, Swaminath, A., additional, Shargal, Y., additional, Agzaraian, J., additional, Wierzbicki, M., additional, and Chow, T., additional

Published
2018
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34. Targeting metabolism and AMP-activated kinase with metformin to sensitize non-small cell lung cancer (NSCLC) to cytotoxic therapy: translational biology and rationale for current clinical trials.

Author

Troncone, M, Cargnelli, SM, Villani, LA, Isfahanian, N, Broadfield, LA, Zychla, L, Wright, J, Pond, G, Steinberg, GR, Tsakiridis, T, Troncone, M, Cargnelli, SM, Villani, LA, Isfahanian, N, Broadfield, LA, Zychla, L, Wright, J, Pond, G, Steinberg, GR, and Tsakiridis, T

Abstract

Lung cancer is the most fatal malignancy worldwide, in part, due to high resistance to cytotoxic therapy. There is need for effective chemo-radio-sensitizers in lung cancer. In recent years, we began to understand the modulation of metabolism in cancer and its importance in tumor progression and survival after cytotoxic therapy. The activity of biosynthetic pathways, driven by the Growth Factor Receptor/Ras/PI3k/Akt/mTOR pathway, is balanced by the energy stress sensor pathway of LKB1/AMPK/p53. AMPK responds both to metabolic and genotoxic stress. Metformin, a well-tolerated anti-diabetic agent, which blocks mitochondria oxidative phosphorylation complex I, became the poster child agent to elicit AMPK activity and tumor suppression. Metformin sensitizes NSCLC models to chemotherapy and radiation. Here, we discuss the rationale for targeting metabolism, the evidence supporting metformin as an anti-tumor agent and adjunct to cytotoxic therapy in NSCLC and we review retrospective evidence and on-going clinical trials addressing this concept.

Published
2017

35. A Phase 3, Multicenter, Randomized Trial to Evaluate the Symptomatic and Quality of Life Improvements in Lung Cancer Patients Receiving External Beam Radiation With or Without High Dose Rate Intraluminal Brachytherapy

Author

Sur, R., primary, Falkson, C.B., additional, Pan, M., additional, Pond, G., additional, Wright, J., additional, Bezjak, A., additional, Dagnault, A., additional, Hunter, R., additional, Yu, E., additional, Almahmudi, M., additional, Shahi, S., additional, Puksa, S., additional, Gopaul, D.D., additional, Tsakiridis, T., additional, Swaminath, A., additional, Ellis, P., additional, Cline, K., additional, Bucci, C., additional, Ahmed, S.N., additional, and Whelan, T.J., additional

Published
2017
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38. The diabetes medication Canagliflozin reduces cancer cell proliferation by inhibiting mitochondrial complex-I supported respiration.

Author

Villani, LA, Smith, BK, Marcinko, K, Ford, RJ, Broadfield, LA, Green, AE, Houde, VP, Muti, P, Tsakiridis, T, Steinberg, GR, Villani, LA, Smith, BK, Marcinko, K, Ford, RJ, Broadfield, LA, Green, AE, Houde, VP, Muti, P, Tsakiridis, T, and Steinberg, GR

Abstract

OBJECTIVE: The sodium-glucose transporter 2 (SGLT2) inhibitors Canagliflozin and Dapagliflozin are recently approved medications for type 2 diabetes. Recent studies indicate that SGLT2 inhibitors may inhibit the growth of some cancer cells but the mechanism(s) remain unclear. METHODS: Cellular proliferation and clonogenic survival were used to assess the sensitivity of prostate and lung cancer cell growth to the SGLT2 inhibitors. Oxygen consumption, extracellular acidification rate, cellular ATP, glucose uptake, lipogenesis, and phosphorylation of AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase, and the p70S6 kinase were assessed. Overexpression of a protein that maintains complex-I supported mitochondrial respiration (NDI1) was used to establish the importance of this pathway for mediating the anti-proliferative effects of Canagliflozin. RESULTS: Clinically achievable concentrations of Canagliflozin, but not Dapagliflozin, inhibit cellular proliferation and clonogenic survival of prostate and lung cancer cells alone and in combination with ionizing radiation and the chemotherapy Docetaxel. Canagliflozin reduced glucose uptake, mitochondrial complex-I supported respiration, ATP, and lipogenesis while increasing the activating phosphorylation of AMPK. The overexpression of NDI1 blocked the anti-proliferative effects of Canagliflozin indicating reductions in mitochondrial respiration are critical for anti-proliferative actions. CONCLUSION: These data indicate that like the biguanide metformin, Canagliflozin not only lowers blood glucose but also inhibits complex-I supported respiration and cellular proliferation in prostate and lung cancer cells. These observations support the initiation of studies evaluating the clinical efficacy of Canagliflozin on limiting tumorigenesis in pre-clinical animal models as well epidemiological studies on cancer incidence relative to other glucose lowering therapies in clinical populations.

Published
2016

40. Chronic modulation of AMP-Kinase, Akt and mTOR pathways by ionizing radiation in human lung cancer xenografts.

Author

Storozhuk, Y, Sanli, T, Hopmans, SN, Schultz, C, Farrell, T, Cutz, J-C, Steinberg, GR, Wright, J, Singh, G, Tsakiridis, T, Storozhuk, Y, Sanli, T, Hopmans, SN, Schultz, C, Farrell, T, Cutz, J-C, Steinberg, GR, Wright, J, Singh, G, and Tsakiridis, T

Abstract

INTRODUCTION: Earlier, we showed that in cancer cells, AMP-activated kinase (AMPK) participates in a signal transduction pathway involving ATM-AMPK-p53/p21cip1 which is activated by ionizing radiation (IR) to mediate G2-M arrest and enhanced cytotoxicity. We also observed that AMPK modulates ATM expression and activity and the IR response of the Akt-mTOR pathway. Since the ATM, AMPK and Akt pathways are key targets of novel radio-sensitizing therapeutics, we examined the chronic modultion of expression and activity of those pathways by IR alone in xenograft models of lung cancer. METHODS: Immuno-compromised mice were grafted with human lung A549 and H1299 cells, were treated with a single fraction of 0 or 10 Gy, and left to grow for 8 weeks. Extracted tumors were subjected to lysis and immunoblotting or fixation and immunohistochemical analysis. RESULTS: IR inhibited significantly xenograft growth and was associated with increased expression of Ataxia Telengiectasia Mutated (ATM) and enhanced phosphorylation of two ATM targets, H2Ax and checkpoint kinase Chk2. Irradiated tumours showed increased total AMPK levels and phosphorylation of AMPK and its substrate Acetyl-CoA Carboxylase (ACC). IR led to enhanced expression and phosphorylation of p53 and cyclin dependent kinase inhibitors p21cip1 and p27kip1. However, irradiated tumours had reduced phosphorylation of Akt, mTOR and it's target translation initiation inhibitor 4EBP1. Irradiated xenografts showed reduced microvessel density, reduced expression of CD31 but increased expression of hypoxia-induced factor 1A (HIF1a) compared to controls. CONCLUSION: IR inhibits epithelial cancer tumour growth and results in sustained expression and activation of ATM-Chk2, and AMPK-p53/p21cip1/p27kip1 but partial inhibition of the Akt-mTOR signaling pathways. Future studies should examine causality between those events and explore whether further modulation of the AMPK and Akt-mTOR pathways by novel therapeutics can sensitize lung

Published
2012

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