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1. CELL BIOLOGY AND SIGNALING

Author

Agarwal, M., primary, Nitta, R., additional, Dovat, S., additional, Li, G., additional, Arita, H., additional, Narita, Y., additional, Fukushima, S., additional, Tateishi, K., additional, Matsushita, Y., additional, Yoshida, A., additional, Miyakita, Y., additional, Ohno, M., additional, Collins, V. P., additional, Kawahara, N., additional, Shibui, S., additional, Ichimura, K., additional, Kahn, S. A., additional, Gholamin, S., additional, Junier, M.-P., additional, Chneiweiss, H., additional, Weissman, I., additional, Mitra, S., additional, Cheshier, S., additional, Avril, T., additional, Hamlat, A., additional, Le Reste, P.-J., additional, Mosser, J., additional, Quillien, V., additional, Carrato, C., additional, Munoz-Marmol, A., additional, Serrano, L., additional, Pijuan, L., additional, Hostalot, C., additional, Villa, S. l., additional, Ariza, A., additional, Etxaniz, O., additional, Balana, C., additional, Benveniste, E. T., additional, Zheng, Y., additional, McFarland, B., additional, Drygin, D., additional, Bellis, S., additional, Bredel, M., additional, Lotsch, D., additional, Engelmaier, C., additional, Allerstorfer, S., additional, Grusch, M., additional, Pichler, J., additional, Weis, S., additional, Hainfellner, J., additional, Marosi, C., additional, Spiegl-Kreinecker, S., additional, Berger, W., additional, Bronisz, A., additional, Nowicki, M. O., additional, Wang, Y., additional, Ansari, K., additional, Chiocca, E. A., additional, Godlewski, J., additional, Brown, K., additional, Kwatra, M., additional, Bui, T., additional, Zhu, S., additional, Kozono, D., additional, Li, J., additional, Kushwaha, D., additional, Carter, B., additional, Chen, C., additional, Schulte, J., additional, Srikanth, M., additional, Das, S., additional, Zhang, J., additional, Lathia, J., additional, Yin, L., additional, Rich, J., additional, Olson, E., additional, Kessler, J., additional, Chenn, A., additional, Cherry, A., additional, Haas, B., additional, Lin, Y. H., additional, Ong, S.-E., additional, Stella, N., additional, Cifarelli, C. P., additional, Griffin, R. J., additional, Cong, D., additional, Zhu, W., additional, Shi, Y., additional, Clark, P., additional, Kuo, J., additional, Hu, S., additional, Sun, D., additional, Bookland, M., additional, Darbinian, N., additional, Dey, A., additional, Robitaille, M., additional, Remke, M., additional, Faury, D., additional, Maier, C., additional, Malhotra, A., additional, Jabado, N., additional, Taylor, M., additional, Angers, S., additional, Kenney, A., additional, Ren, X., additional, Zhou, H., additional, Schur, M., additional, Baweja, A., additional, Singh, M., additional, Erdreich-Epstein, A., additional, Fu, J., additional, Koul, D., additional, Yao, J., additional, Saito, N., additional, Zheng, S., additional, Verhaak, R., additional, Lu, Z., additional, Yung, W. K. A., additional, Gomez, G., additional, Volinia, S., additional, Croce, C., additional, Brennan, C., additional, Cavenee, W., additional, Furnari, F., additional, Lopez, S. G., additional, Qu, D., additional, Petritsch, C., additional, Gonzalez-Huarriz, M., additional, Aldave, G., additional, Ravi, D., additional, Rubio, A., additional, Diez-Valle, R., additional, Marigil, M., additional, Jauregi, P., additional, Vera, B., additional, Rocha, A. A. d. l., additional, Tejada-Solis, S., additional, Alonso, M. M., additional, Gopal, U., additional, Isaacs, J., additional, Gruber-Olipitz, M., additional, Dabral, S., additional, Ramkissoon, S., additional, Kung, A., additional, Pak, E., additional, Chung, J., additional, Theisen, M., additional, Sun, Y., additional, Monrose, V., additional, Franchetti, Y., additional, Shulman, D., additional, Redjal, N., additional, Tabak, B., additional, Beroukhim, R., additional, Zhao, J., additional, Buonamici, S., additional, Ligon, K., additional, Kelleher, J., additional, Segal, R., additional, Canton, D., additional, Diaz, P., additional, Scott, J., additional, Hara, K., additional, Kageji, T., additional, Mizobuchi, Y., additional, Kitazato, K., additional, Okazaki, T., additional, Fujihara, T., additional, Nakajima, K., additional, Mure, H., additional, Kuwayama, K., additional, Hara, T., additional, Nagahiro, S., additional, Hill, L., additional, Botfield, H., additional, Hossain-Ibrahim, K., additional, Logan, A., additional, Cruickshank, G., additional, Liu, Y., additional, Gilbert, M., additional, Kyprianou, N., additional, Rangnekar, V., additional, Horbinski, C., additional, Hu, Y., additional, Vo, C., additional, Li, Z., additional, Ke, C., additional, Ru, N., additional, Hess, K. R., additional, Linskey, M. E., additional, Zhou, Y.-a. H., additional, Hu, F., additional, Vinnakota, K., additional, Wolf, S., additional, Kettenmann, H., additional, Jackson, P. J., additional, Larson, J. D., additional, Beckmann, D. A., additional, Moriarity, B. S., additional, Largaespada, D. A., additional, Jalali, S., additional, Agnihotri, S., additional, Singh, S., additional, Burrell, K., additional, Croul, S., additional, Zadeh, G., additional, Kang, S.-H., additional, Yu, M. O., additional, Song, N.-H., additional, Park, K.-J., additional, Chi, S.-G., additional, Chung, Y.-G., additional, Kim, S. K., additional, Kim, J. W., additional, Kim, J. Y., additional, Kim, J. E., additional, Choi, S. H., additional, Kim, T. M., additional, Lee, S.-H., additional, Kim, S.-K., additional, Park, S.-H., additional, Kim, I. H., additional, Park, C.-K., additional, Jung, H.-W., additional, Koldobskiy, M., additional, Ahmed, I., additional, Ho, G., additional, Snowman, A., additional, Raabe, E., additional, Eberhart, C., additional, Snyder, S., additional, Gugel, I., additional, Bornemann, A., additional, Pantazis, G., additional, Mack, S., additional, Shih, D., additional, Sabha, N., additional, Tatagiba, M., additional, Krischek, B., additional, Schulte, A., additional, Liffers, K., additional, Kathagen, A., additional, Riethdorf, S., additional, Westphal, M., additional, Lamszus, K., additional, Lee, J. S., additional, Xiao, J., additional, Patel, P., additional, Schade, J., additional, Wang, J., additional, Deneen, B., additional, Song, H.-R., additional, Leiss, L., additional, Gjerde, C., additional, Saed, H., additional, Rahman, A., additional, Lellahi, M., additional, Enger, P. O., additional, Leung, R., additional, Gil, O., additional, Lei, L., additional, Canoll, P., additional, Sun, S., additional, Lee, D., additional, Ho, A. S. W., additional, Pu, J. K. S., additional, Zhang, X.-q., additional, Lee, N. P., additional, Dat, P. J. R., additional, Leung, G. K. K., additional, Loetsch, D., additional, Steiner, E., additional, Holzmann, K., additional, Pirker, C., additional, Hlavaty, J., additional, Petznek, H., additional, Hegedus, B., additional, Garay, T., additional, Mohr, T., additional, Sommergruber, W., additional, Lukiw, W. J., additional, Jones, B. M., additional, Zhao, Y., additional, Bhattacharjee, S., additional, Culicchia, F., additional, Magnus, N., additional, Garnier, D., additional, Meehan, B., additional, McGraw, S., additional, Hashemi, M., additional, Lee, T. H., additional, Milsom, C., additional, Gerges, N., additional, Trasler, J., additional, Pawlinski, R., additional, Mackman, N., additional, Rak, J., additional, Maherally, Z., additional, Thorne, A., additional, An, Q., additional, Barbu, E., additional, Fillmore, H., additional, Pilkington, G., additional, Tan, S. L., additional, Tan, S., additional, Choi, S., additional, Potts, C., additional, Ford, D. A., additional, Nahle, Z., additional, Kenney, A. M., additional, Matlaf, L., additional, Khan, S., additional, Zider, A., additional, Singer, E., additional, Cobbs, C., additional, Soroceanu, L., additional, McFarland, B. C., additional, Hong, S. W., additional, Rajbhandari, R., additional, Twitty, G. B., additional, Gray, G. K., additional, Yu, H., additional, Benveniste, E. N., additional, Nozell, S. E., additional, Minata, M., additional, Kim, S., additional, Mao, P., additional, Kaushal, J., additional, Nakano, I., additional, Mizowaki, T., additional, Sasayama, T., additional, Tanaka, K., additional, Mizukawa, K., additional, Nishihara, M., additional, Nakamizo, S., additional, Tanaka, H., additional, Kohta, M., additional, Hosoda, K., additional, Kohmura, E., additional, Moeckel, S., additional, Meyer, K., additional, Leukel, P., additional, Bogdahn, U., additional, Riehmenschneider, M. J., additional, Bosserhoff, A. K., additional, Spang, R., additional, Hau, P., additional, Mukasa, A., additional, Watanabe, A., additional, Ogiwara, H., additional, Aburatani, H., additional, Mukherjee, J., additional, Obha, S., additional, See, W., additional, Pieper, R., additional, Otsuka, R., additional, Kung, D., additional, Sinha, T., additional, Meares, G., additional, Nozell, S., additional, Ott, M., additional, Litzenburger, U., additional, Rauschenbach, K., additional, Bunse, L., additional, Pusch, S., additional, Ochs, K., additional, Sahm, F., additional, Opitz, C., additional, von Deimling, A., additional, Wick, W., additional, Platten, M., additional, Peruzzi, P., additional, Read, R., additional, Fenton, T., additional, Wykosky, J., additional, Vandenberg, S., additional, Babic, I., additional, Iwanami, A., additional, Yang, H., additional, Mischel, P., additional, Thomas, J., additional, Ronellenfitsch, M. W., additional, Thiepold, A. L., additional, Harter, P. N., additional, Mittelbronn, M., additional, Steinbach, J. P., additional, Rybakova, Y., additional, Kalen, A., additional, Sarsour, E., additional, Goswami, P., additional, Silber, J., additional, Harinath, G., additional, Aldaz, B., additional, Fabius, A. W. M., additional, Turcan, S., additional, Chan, T. A., additional, Huse, J. T., additional, Sonabend, A. M., additional, Bansal, M., additional, Guarnieri, P., additional, Soderquist, C., additional, Yun, J., additional, Kennedy, B., additional, Sisti, J., additional, Bruce, S., additional, Bruce, R., additional, Shakya, R., additional, Ludwig, T., additional, Rosenfeld, S., additional, Sims, P. A., additional, Bruce, J. N., additional, Califano, A., additional, Stockhausen, M.-T., additional, Kristoffersen, K., additional, Olsen, L. S., additional, Poulsen, H. S., additional, Stringer, B., additional, Day, B., additional, Barry, G., additional, Piper, M., additional, Jamieson, P., additional, Ensbey, K., additional, Bruce, Z., additional, Richards, L., additional, Boyd, A., additional, Sufit, A., additional, Burleson, T., additional, Le, J. P., additional, Keating, A. K., additional, Sundstrom, T., additional, Varughese, J. K., additional, Harter, P., additional, Prestegarden, L., additional, Petersen, K., additional, Azuaje, F., additional, Tepper, C., additional, Ingham, E., additional, Even, L., additional, Johnson, S., additional, Skaftnesmo, K. O., additional, Lund-Johansen, M., additional, Bjerkvig, R., additional, Ferrara, K., additional, Thorsen, F., additional, Takeshima, H., additional, Yamashita, S., additional, Yokogami, K., additional, Mizuguchi, S., additional, Nakamura, H., additional, Kuratsu, J., additional, Fukushima, T., additional, Morishita, K., additional, Tang, Y., additional, Vaka, D., additional, Chen, S., additional, Ponnuswami, A., additional, Cho, Y.-J., additional, Monje, M., additional, Nakamura, T., additional, Cahill, D., additional, Tiemann, K., additional, Hedman, H., additional, Niclou, S. P., additional, Timmer, M., additional, Tjiong, R., additional, Rohn, G., additional, Goldbrunner, R., additional, Stavrinou, P., additional, Perrech, M., additional, Tokita, M., additional, Mikheev, S., additional, Sellers, D., additional, Mikheev, A., additional, Kosai, Y., additional, Rostomily, R., additional, Tritschler, I., additional, Seystahl, K., additional, Schroeder, J. J., additional, Weller, M., additional, Wade, A., additional, Robinson, A. E., additional, Phillips, J. J., additional, Gong, Y., additional, Ma, Y., additional, Cheng, Z., additional, Thompson, R., additional, Fan, Q.-W., additional, Cheng, C., additional, Gustafson, W., additional, Charron, E., additional, Zipper, P., additional, Wong, R., additional, Chen, J., additional, Lau, J., additional, Knobbe-Thosen, C., additional, Jura, N., additional, Reifenberger, G., additional, Shokat, K., additional, Weiss, W., additional, Wu, S., additional, Hu, J., additional, Taylor, T., additional, Villa, G. R., additional, Mischel, P. S., additional, Gonias, S. L., additional, Yamashita, D., additional, Kondo, T., additional, Takahashi, H., additional, Inoue, A., additional, Kohno, S., additional, Harada, H., additional, Ohue, S., additional, Ohnishi, T., additional, Li, P., additional, Ng, J., additional, Yuelling, L., additional, Du, F., additional, Curran, T., additional, Yang, Z.-j., additional, Zhu, D., additional, Castellino, R. C., additional, Van Meir, E. G., additional, Begum, G., additional, Wang, Q., additional, Yang, S.-S., additional, Lin, S.-H., additional, and Kahle, K., additional

Published
2013
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2. P2-09-07: Metabolic Response by FDG-PET in Patients (pts) Receiving Trastuzumab (T) and Lapatinib (L) for HER2+ Metastatic Breast Cancer (MBC): Correlative Analysis of TBCRC 003.

Author

Yap, JT, primary, Locascio, T, additional, Najita, JS, additional, Mayer, IA, additional, Hobday, TJ, additional, Falkson, CI, additional, Dees, EC, additional, Gelman, RS, additional, Rimawi, MF, additional, Nanda, R, additional, Berkowitz, J, additional, Franchetti, Y, additional, Wolff, AC, additional, Winer, EP, additional, Lin, NU, additional, and Van den Abbeele, AD, additional

Published
2011
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3. Simultaneous Assessment of Hepatic Transport and Metabolism Pathways with a Single Probe Using Individualized PBPK Modeling of 14 CO 2 Production Rate Data.

Author

Franchetti Y and Nolin TD

Subjects
Breath Tests methods, Cytochrome P-450 CYP3A metabolism, Humans, Carbon Dioxide metabolism, Erythromycin pharmacokinetics, Hepatobiliary Elimination, Liver metabolism, Patient-Specific Modeling
Abstract

Erythromycin is a substrate of cytochrome P4503A4 (CYP3A4) and multiple drug transporters. Although clinical evidence suggests that uptake transport is likely to play a dominant role in erythromycin's disposition, the relative contributions of individual pathways are unclear. Phenotypic evaluation of multiple pathways generally requires a probe drug cocktail. This approach can result in ambiguous conclusions due to imprecision stemming from overlapping specificity of multiple drugs. We hypothesized that an individualized physiologically based pharmacokinetic modeling approach incorporating 14 CO 2 production rates (iPBPK-R) of the erythromycin breath test (ERMBT) would enable us to differentiate the contribution of metabolic and transporter pathways to erythromycin disposition. A seven-compartmental physiologically based pharmacokinetic (PBPK) model was built for 14 C-erythromycin administered intravenously. Transporter clearance and CYP3A4 clearance were embedded in hepatic compartments. 14 CO 2 production rates were simulated taking the first derivative of by-product 14 CO 2 concentrations. Parameters related to nonrenal elimination pathways were estimated by model fitting the ERMBT data of 12 healthy subjects individually. Optimized iPBPK-R models fit the individual rate data well. Using one probe, nine PBPK parameters were simultaneously estimated per individual. Maximum velocity of uptake transport, CYP3A4 clearance, total passive diffusion, and others were found to collectively control 14 CO 2 production rates. The median CYP3A4 clearance was 12.2% of the input clearance. Male subjects had lower CYP3A4 activity than female subjects by 11.3%. We applied iPBPK-R to ERMBT data to distinguish and simultaneously estimate the activity of multiple nonrenal elimination pathways in healthy subjects. The iPBPK-R framework is a novel tool for delineating rate-limiting and non-rate-limiting elimination pathways using a single probe. SIGNIFICANCE STATEMENT: Our developed individualized physiologically based pharmacokinetic modeling approach incorporating rate data (iPBPK-R) enabled us to distinguish and simultaneously estimate the activity of multiple nonrenal elimination pathways of erythromycin in healthy subjects. A new interpretation of erythromycin breath test (ERMBT) data was also obtained via iPBPK-R. We found that rate data have rich information allowing estimation of per-person PBPK parameters. This study serves as proof of principle that the iPBPK-R framework is a novel tool for delineating rate-limiting and non-rate-limiting elimination pathways using a single probe. iPBPK-R can be applied to other rate-derived data beyond ERMBT. Potential areas of application include drug-drug interaction, pathophysiological effects on drug disposition, and the role of biomarkers on hemodialysis efficiency utilizing estimated adjustment factors with correlation analysis., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)

Published
2019
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4. Trimethylamine N -Oxide and Cardiovascular Outcomes in Patients with ESKD Receiving Maintenance Hemodialysis.

Author

Stubbs JR, Stedman MR, Liu S, Long J, Franchetti Y, West RE 3rd, Prokopienko AJ, Mahnken JD, Chertow GM, and Nolin TD

Subjects
Adult, Aged, Angina, Unstable epidemiology, Calcimimetic Agents therapeutic use, Cinacalcet therapeutic use, Female, Hospitalization statistics & numerical data, Humans, Hyperparathyroidism, Secondary etiology, Kidney Failure, Chronic complications, Kidney Failure, Chronic therapy, Male, Middle Aged, Mortality, Myocardial Infarction epidemiology, Randomized Controlled Trials as Topic, Renal Dialysis, Stroke epidemiology, Cardiovascular Diseases mortality, Kidney Failure, Chronic blood, Methylamines blood
Abstract

Background and Objectives: Trimethylamine N -oxide (TMAO), a compound derived from byproducts of intestinal bacteria, has been shown to accelerate atherosclerosis in rodents. To date, there are conflicting data regarding the association of serum TMAO with cardiovascular outcomes in patients with ESKD, a population exhibiting both high serum TMAO and excessive atherosclerosis., Design, Setting, Participants, & Measurements: We measured baseline serum TMAO concentrations in a subset of participants ( n =1243) from the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial and conducted post hoc analyses evaluating the association between baseline serum TMAO and cardiovascular outcomes., Results: We observed a wide distribution of serum TMAO in our cohort, with approximately 80% of participants exhibiting TMAO concentrations ≥56 µ M and a maximum TMAO concentration of 1103.1 µ M. We found no association between TMAO and our primary outcome, a composite of cardiovascular mortality, myocardial infarction, peripheral vascular event, stroke, and hospitalization for unstable angina. Moreover, in unadjusted and adjusted analyses, we observed no relation between TMAO and all-cause mortality, the independent components of our composite outcome, or the original EVOLVE primary outcome. Although we did observe higher TMAO concentrations in white participants, further subgroup analyses did not confirm the previously identified interaction between TMAO and race observed in a prior study in patients receiving dialysis., Conclusions: We found no evidence linking TMAO to adverse clinical outcomes in patients receiving maintenance hemodialysis with moderate to severe secondary hyperparathyroidism., (Copyright © 2019 by the American Society of Nephrology.)

Published
2019
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5. 10% Tumor diameter shrinkage on the first follow-up computed tomography predicts clinical outcome in patients with advanced renal cell carcinoma treated with angiogenesis inhibitors: a follow-up validation study.

Author

Krajewski KM, Franchetti Y, Nishino M, Fay AP, Ramaiya N, Van den Abbeele AD, and Choueiri TK

Subjects
Adult, Aged, Aged, 80 and over, Carcinoma, Renal Cell diagnostic imaging, Carcinoma, Renal Cell mortality, Female, Humans, Kidney Neoplasms diagnostic imaging, Kidney Neoplasms mortality, Male, Middle Aged, Molecular Targeted Therapy methods, ROC Curve, Response Evaluation Criteria in Solid Tumors, Retrospective Studies, Tomography, X-Ray Computed, Treatment Outcome, Angiogenesis Inhibitors therapeutic use, Carcinoma, Renal Cell drug therapy, Kidney Neoplasms drug therapy, Vascular Endothelial Growth Factor A antagonists & inhibitors
Abstract

Vascular endothelial growth factor (VEGF)-targeted agents are standard therapies for metastatic renal cell carcinoma (mRCC), associated with variable tumor shrinkage. Response Evaluation Criteria in Solid Tumors (RECIST) is of limited utility in this setting, and other imaging changes are sought to reliably predict outcome early. We aim to validate 10% tumor shrinkage as the best early indicator of outcome. Methods. In this institutional review board-approved, Health Insurance Portability and Accountability Act-compliant study, 66 mRCC patients with 165 lesions on clinical trials of VEGF-targeted agents underwent thoracic and abdominal computed tomography at baseline and at first follow-up after therapy. Measurements were performed according to RECIST and tumor shrinkage of ≥10% decrease in sum of the longest diameter (-10%SLD). Correlation with time-to-treatment failure (TTF) and overall survival (OS) were compared and stratified by response to the radiologic criteria. Receiver-operating characteristics (ROC) analysis yielded the optimal threshold change in SLD, defining patients with prolonged survival. Results. More than -10%SLD significantly differentiated responders from nonresponders (median TTF 8.4 vs. 4.1 months, p = .001), whereas partial response by RECIST did not (median TTF 6.9 vs. 5.5 months in responders vs. nonresponders, p = .34). -10%SLD was also significantly predictive of OS (median OS 35.1 vs. 15.0 months in responders vs. nonresponders, p = .003). ROC curve analysis yielded -9.3% in SLD as the optimal threshold for response/no response. Conclusion. Ten percent tumor shrinkage is validated as a reliable early predictor of outcome in mRCC patients receiving VEGF-targeted therapies and may provide a practical measure to guide therapeutic decisions.

Published
2014
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6. Socio-demographic and lifestyle factors for child's physical growth and adiposity rebound of Japanese children: a longitudinal study of the 21st century longitudinal survey in newborns.

Author

Franchetti Y and Ide H

Subjects
Adiposity, Body Mass Index, Child, Preschool, Female, Gestational Age, Humans, Infant, Infant, Newborn, Japan, Longitudinal Studies, Male, Socioeconomic Factors, Weight Gain, Asian People, Child Development physiology, Growth physiology, Life Style, Pediatric Obesity physiopathology
Abstract

Background: It is unknown whether childhood physical development in Asian populations differs from western populations, since no longitudinal analysis has been performed in Asian countries yet. Utilizing the 21st Century Longitudinal Survey in Newborns, we studied the timing of adiposity rebound (AR) among Japanese children and determined whether AR occurs earlier in obese children compared to nonobese children. Furthermore, we identified important demographic, social, and lifestyle factors that affect their physical development., Methods: We used data from the annual surveillance of Japanese children born in 2001, with 45,392 eligible subjects. We applied survival analysis to evaluate the AR and a trajectory method for the BMI transition across 5 ½ years. Time-dependent and time-independent factors affecting BMI changes were investigated using longitudinal analysis. Accounting for the known difference in prevalence between Japanese and Western children, we adopted a 95th percentile of BMI as criterion for obesity., Results: Mean BMI at birth and at ages 1 ½, 2 ½, 3 ½, 4 ½, and 5 ½ years for all subjects were 12.6, 16.3, 16.1, 15.8, 15.5, and 15.4, respectively, showing a progressive reduction after 1 ½ years. However, among obese children at 5 ½ years, 39.6% had experienced AR as early as at age 4 ½ years. Controlling for sex, Cox's proportional hazards model showed that obese children had a 48.5% higher hazard to experience AR than nonobese children. The difference in BMI transition between obese and non-obese children was also captured by a trajectory method. In longitudinal analysis, BMI was lower for children who had a longer gestational period whereas children who received parental care from non-family members gained higher BMI values., Conclusions: With the 95th percentile cutoff for children obesity, obese Japanese children developed AR earlier than nonobese Japanese children, similar to those in Western countries reported in the literature. Primary caretakers and length of gestational period were the most important socio-demographic factors affecting physical development.

Published
2014
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7. Coordinate activation of Shh and PI3K signaling in PTEN-deficient glioblastoma: new therapeutic opportunities.

Author

Filbin MG, Dabral SK, Pazyra-Murphy MF, Ramkissoon S, Kung AL, Pak E, Chung J, Theisen MA, Sun Y, Franchetti Y, Sun Y, Shulman DS, Redjal N, Tabak B, Beroukhim R, Wang Q, Zhao J, Dorsch M, Buonamici S, Ligon KL, Kelleher JF, and Segal RA

Subjects
Aminopyridines administration & dosage, Animals, Biphenyl Compounds administration & dosage, Brain Neoplasms genetics, Cell Line, Tumor, Enzyme Inhibitors administration & dosage, Glioblastoma genetics, Hedgehog Proteins antagonists & inhibitors, Humans, Mice, Mice, Nude, Morpholines administration & dosage, PTEN Phosphohydrolase genetics, Phosphoinositide-3 Kinase Inhibitors, Pyridines administration & dosage, Ribosomal Protein S6 Kinases antagonists & inhibitors, Signal Transduction drug effects, Xenograft Model Antitumor Assays, Brain Neoplasms drug therapy, Brain Neoplasms metabolism, Glioblastoma drug therapy, Glioblastoma metabolism, Hedgehog Proteins metabolism, PTEN Phosphohydrolase deficiency, Phosphatidylinositol 3-Kinases metabolism
Abstract

In glioblastoma, phosphatidylinositol 3-kinase (PI3K) signaling is frequently activated by loss of the tumor suppressor phosphatase and tensin homolog (PTEN). However, it is not known whether inhibiting PI3K represents a selective and effective approach for treatment. We interrogated large databases and found that sonic hedgehog (SHH) signaling is activated in PTEN-deficient glioblastoma. We demonstrate that the SHH and PI3K pathways synergize to promote tumor growth and viability in human PTEN-deficient glioblastomas. A combination of PI3K and SHH signaling inhibitors not only suppressed the activation of both pathways but also abrogated S6 kinase (S6K) signaling. Accordingly, targeting both pathways simultaneously resulted in mitotic catastrophe and tumor apoptosis and markedly reduced the growth of PTEN-deficient glioblastomas in vitro and in vivo. The drugs tested here appear to be safe in humans; therefore, this combination may provide a new targeted treatment for glioblastoma.

Published
2013
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8. A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response.

Author

Chen Z, Cheng K, Walton Z, Wang Y, Ebi H, Shimamura T, Liu Y, Tupper T, Ouyang J, Li J, Gao P, Woo MS, Xu C, Yanagita M, Altabef A, Wang S, Lee C, Nakada Y, Peña CG, Sun Y, Franchetti Y, Yao C, Saur A, Cameron MD, Nishino M, Hayes DN, Wilkerson MD, Roberts PJ, Lee CB, Bardeesy N, Butaney M, Chirieac LR, Costa DB, Jackman D, Sharpless NE, Castrillon DH, Demetri GD, Jänne PA, Pandolfi PP, Cantley LC, Kung AL, Engelman JA, and Wong KK

Subjects
AMP-Activated Protein Kinases, Animals, Antineoplastic Combined Chemotherapy Protocols, Benzimidazoles therapeutic use, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Docetaxel, Drug Evaluation, Preclinical, Fluorodeoxyglucose F18, Genes, p53 genetics, Humans, Lung Neoplasms enzymology, Lung Neoplasms metabolism, MAP Kinase Signaling System drug effects, Mice, Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors, Mutation genetics, Positron-Emission Tomography, Protein Serine-Threonine Kinases deficiency, Protein Serine-Threonine Kinases genetics, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins p21(ras) genetics, Proto-Oncogene Proteins p21(ras) metabolism, Randomized Controlled Trials as Topic, Reproducibility of Results, Tomography, X-Ray Computed, Treatment Outcome, ras Proteins genetics, ras Proteins metabolism, Benzimidazoles pharmacology, Clinical Trials, Phase II as Topic, Disease Models, Animal, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Pharmacogenetics methods, Taxoids therapeutic use
Abstract

Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a 'co-clinical' trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies.

Published
2012
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