Dana E Rathkopf1,2, Steven M Larson2,3, Aseem Anand1,4, Michael J Morris1,2, Susan F Slovin1,2, David R Shaffer5, Glenn Heller6, Brett Carver7,8, Neal Rosen9, Howard I Scher1,2. 1. Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. 2. Weill Cornell Medical College, New York, New York. 3. Division of Nuclear Medicine, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York. 4. Division of Urological Cancers, Lund University, Lund, Sweden. 5. New York Oncology Hematology, Albany, New York. 6. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York. 7. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. 8. Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. 9. Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York.
Abstract
BACKGROUND: The effects of mammalian target of rapamycin (mTOR) inhibition are limited by feedback reactivation of receptor tyrosine kinase signaling in phosphatase and tensin homolog-null tumors. Thus, this study tested the combination of mTOR inhibition (everolimus) and epidermal growth factor receptor inhibition (gefitinib) in castration-resistant prostate cancer (CRPC). METHODS: In phase 1, 12 patients (10 with CRPC and 2 with glioblastoma) received daily gefitinib (250 mg) with weekly everolimus (30, 50, or 70 mg). In phase 2, 27 CRPC patients received gefitinib with everolimus (70 mg). RESULTS: Phase 1 revealed no pharmacokinetic interactions and no dose-limiting toxicities. In phase 2, 18 of 27 patients (67%) discontinued treatment before the 12-week evaluation because of progression as evidenced by prostate-specific antigen (PSA) levels (n = 6) or imaging (n = 5) or because of a grade 2 or higher toxicity (n = 7). Thirteen of the 37 CRPC patients (35%) exhibited a rapidly rising PSA level after they had begun treatment, and this declined upon discontinuation. Fluorodeoxyglucose positron emission tomography 24 to 72 hours after the initiation of treatment showed a decrease in the standardized uptake value consistent with mTOR inhibition in 27 of the 33 evaluable patients (82%); there was a corresponding rise in PSA in 20 of these 27 patients (74%). CONCLUSIONS: The combination of gefitinib and everolimus did not result in significant antitumor activity. The induction of PSA in tumors treated with mTOR inhibitors was consistent with preclinical data showing that phosphoinositide 3-kinase (PI3K) pathway signaling feedback inhibits the androgen receptor (AR). This clinical evidence of relief of feedback inhibition promoting enhanced AR activity supports future studies combining PI3K pathway inhibitors and second-generation AR inhibitors in CRPC.
BACKGROUND: The effects of mammalian target of rapamycin (mTOR) inhibition are limited by feedback reactivation of receptor tyrosine kinase signaling in phosphatase and tensin homolog-null tumors. Thus, this study tested the combination of mTOR inhibition (everolimus) and epidermal growth factor receptor inhibition (gefitinib) in castration-resistant prostate cancer (CRPC). METHODS: In phase 1, 12 patients (10 with CRPC and 2 with glioblastoma) received daily gefitinib (250 mg) with weekly everolimus (30, 50, or 70 mg). In phase 2, 27 CRPC patients received gefitinib with everolimus (70 mg). RESULTS: Phase 1 revealed no pharmacokinetic interactions and no dose-limiting toxicities. In phase 2, 18 of 27 patients (67%) discontinued treatment before the 12-week evaluation because of progression as evidenced by prostate-specific antigen (PSA) levels (n = 6) or imaging (n = 5) or because of a grade 2 or higher toxicity (n = 7). Thirteen of the 37 CRPC patients (35%) exhibited a rapidly rising PSA level after they had begun treatment, and this declined upon discontinuation. Fluorodeoxyglucose positron emission tomography 24 to 72 hours after the initiation of treatment showed a decrease in the standardized uptake value consistent with mTOR inhibition in 27 of the 33 evaluable patients (82%); there was a corresponding rise in PSA in 20 of these 27 patients (74%). CONCLUSIONS: The combination of gefitinib and everolimus did not result in significant antitumor activity. The induction of PSA in tumors treated with mTOR inhibitors was consistent with preclinical data showing that phosphoinositide 3-kinase (PI3K) pathway signaling feedback inhibits the androgen receptor (AR). This clinical evidence of relief of feedback inhibition promoting enhanced AR activity supports future studies combining PI3K pathway inhibitors and second-generation AR inhibitors in CRPC.
Authors: P Therasse; S G Arbuck; E A Eisenhauer; J Wanders; R S Kaplan; L Rubinstein; J Verweij; M Van Glabbeke; A T van Oosterom; M C Christian; S G Gwyther Journal: J Natl Cancer Inst Date: 2000-02-02 Impact factor: 13.506
Authors: H Young; R Baum; U Cremerius; K Herholz; O Hoekstra; A A Lammertsma; J Pruim; P Price Journal: Eur J Cancer Date: 1999-12 Impact factor: 9.162
Authors: K Podsypanina; R T Lee; C Politis; I Hennessy; A Crane; J Puc; M Neshat; H Wang; L Yang; J Gibbons; P Frost; V Dreisbach; J Blenis; Z Gaciong; P Fisher; C Sawyers; L Hedrick-Ellenson; R Parsons Journal: Proc Natl Acad Sci U S A Date: 2001-08-14 Impact factor: 11.205
Authors: M S Neshat; I K Mellinghoff; C Tran; B Stiles; G Thomas; R Petersen; P Frost; J J Gibbons; H Wu; C L Sawyers Journal: Proc Natl Acad Sci U S A Date: 2001-08-14 Impact factor: 11.205
Authors: Pradip K Majumder; Jen Jen Yeh; Daniel J George; Phillip G Febbo; Jennifer Kum; Qi Xue; Rachel Bikoff; Hongfeng Ma; Philip W Kantoff; Todd R Golub; Massimo Loda; William R Sellers Journal: Proc Natl Acad Sci U S A Date: 2003-06-10 Impact factor: 11.205
Authors: Roberto Bianco; Incheol Shin; Christoph A Ritter; F Michael Yakes; Andrea Basso; Neal Rosen; Junji Tsurutani; Phillip A Dennis; Gordon B Mills; Carlos L Arteaga Journal: Oncogene Date: 2003-05-08 Impact factor: 9.867
Authors: Pradip K Majumder; Phillip G Febbo; Rachel Bikoff; Raanan Berger; Qi Xue; Louis M McMahon; Judith Manola; James Brugarolas; Timothy J McDonnell; Todd R Golub; Massimo Loda; Heidi A Lane; William R Sellers Journal: Nat Med Date: 2004-05-23 Impact factor: 53.440
Authors: Andrew J Armstrong; Susan Halabi; Patrick Healy; Joshi J Alumkal; Carolyn Winters; Julie Kephart; Rhonda L Bitting; Carey Hobbs; Colleen F Soleau; Tomasz M Beer; Rachel Slottke; Kelly Mundy; Evan Y Yu; Daniel J George Journal: Eur J Cancer Date: 2017-05-11 Impact factor: 9.162
Authors: Emanuela Dylgjeri; Christopher McNair; Jonathan F Goodwin; Heather K Raymon; Peter A McCue; Ayesha A Shafi; Benjamin E Leiby; Renée de Leeuw; Vishal Kothari; Jennifer J McCann; Amy C Mandigo; Saswati N Chand; Matthew J Schiewer; Lucas J Brand; Irina Vasilevskaya; Nicolas Gordon; Talya S Laufer; Leonard G Gomella; Costas D Lallas; Edouard J Trabulsi; Felix Y Feng; Ellen H Filvaroff; Kristin Hege; Dana Rathkopf; Karen E Knudsen Journal: Clin Cancer Res Date: 2019-07-02 Impact factor: 12.531
Authors: Haeseong Park; Kerry Williams; Nikolaos A Trikalinos; Sarah Larson; Benjamin Tan; Saiama Waqar; Rama Suresh; Daniel Morgensztern; Brian A Van Tine; Ramaswamy Govindan; Jingqin Luo; A Craig Lockhart; Andrea Wang-Gillam Journal: Cancer Chemother Pharmacol Date: 2020-11-06 Impact factor: 3.333
Authors: Laura Graham; Kalyan Banda; Alba Torres; Brett S Carver; Yu Chen; Katie Pisano; Greg Shelkey; Tracy Curley; Howard I Scher; Tamara L Lotan; Andrew C Hsieh; Dana E Rathkopf Journal: Invest New Drugs Date: 2018-03-06 Impact factor: 3.651
Authors: Konrad H Stopsack; Ying Huang; Svitlana Tyekucheva; Travis A Gerke; Clyde Bango; Habiba Elfandy; Michaela Bowden; Kathryn L Penney; Thomas M Roberts; Giovanni Parmigiani; Philip W Kantoff; Lorelei A Mucci; Massimo Loda Journal: Clin Cancer Res Date: 2020-09-10 Impact factor: 12.531