PURPOSE: Epichaperome network maintenance is vital to survival of tumors that express it. PU-H71 is an epichaperome inhibitor that binds to the ATP-binding site of HSP90 and has demonstrated antitumor activity in breast cancer xenograft models and clinical safety in patients. PU-positron emission tomography (PET) is a theragnostic imaging tool that allows visualization of the epichaperome target. In this phase Ib trial, we present safety and tolerability for PU-H71 plus nab-paclitaxel in HER2-negative patients with metastatic breast cancer (MBC) and the utility of PU-PET as a noninvasive predictive biomarker. METHODS: We performed a 3 + 3 dose-escalation study with escalating PU-H71 doses and standard nab-paclitaxel. The primary objective was to establish safety and determine maximum tolerated dose (MTD)/recommended phase 2 dose. Secondary objectives were to assess pharmacokinetics and clinical efficacy. Patients could enroll in a companion PU-PET protocol to measure epichaperome expression before treatment initiation to allow exploratory correlation with treatment benefit. RESULTS: Of the 12 patients enrolled, dose-limiting toxicity occurred in one patient (G3 neutropenic fever) at dose level 1; MTD of PU-H71 was 300 mg/m2 plus nab-paclitaxel 260 mg/m2 administered every 3 weeks. Common toxicities included diarrhea, fatigue, peripheral neuropathy, and nausea. PU-H71 systemic exposure was not altered by nab-paclitaxel administration. Two of 12 patients had partial response (overall response rate, 17%) and the clinical benefit rate was 42% (5 of 12). Time to progression was associated with baseline epichaperome positivity and PU-H71 peak standard uptake value (SUV), with more durable disease control observed with high epichaperome levels. CONCLUSION: The combination of PU-H71 and nab-paclitaxel was well tolerated, with evidence of clinical activity. More durable disease control without progression was observed in patients with high baseline epichaperome expression. A phase II trial of this combination with PU-PET as a companion diagnostic for patient selection is currently planned.
PURPOSE: Epichaperome network maintenance is vital to survival of tumors that express it. PU-H71 is an epichaperome inhibitor that binds to the ATP-binding site of HSP90 and has demonstrated antitumor activity in breast cancer xenograft models and clinical safety in patients. PU-positron emission tomography (PET) is a theragnostic imaging tool that allows visualization of the epichaperome target. In this phase Ib trial, we present safety and tolerability for PU-H71 plus nab-paclitaxel in HER2-negative patients with metastatic breast cancer (MBC) and the utility of PU-PET as a noninvasive predictive biomarker. METHODS: We performed a 3 + 3 dose-escalation study with escalating PU-H71 doses and standard nab-paclitaxel. The primary objective was to establish safety and determine maximum tolerated dose (MTD)/recommended phase 2 dose. Secondary objectives were to assess pharmacokinetics and clinical efficacy. Patients could enroll in a companion PU-PET protocol to measure epichaperome expression before treatment initiation to allow exploratory correlation with treatment benefit. RESULTS: Of the 12 patients enrolled, dose-limiting toxicity occurred in one patient (G3 neutropenic fever) at dose level 1; MTD of PU-H71 was 300 mg/m2 plus nab-paclitaxel 260 mg/m2 administered every 3 weeks. Common toxicities included diarrhea, fatigue, peripheral neuropathy, and nausea. PU-H71 systemic exposure was not altered by nab-paclitaxel administration. Two of 12 patients had partial response (overall response rate, 17%) and the clinical benefit rate was 42% (5 of 12). Time to progression was associated with baseline epichaperome positivity and PU-H71 peak standard uptake value (SUV), with more durable disease control observed with high epichaperome levels. CONCLUSION: The combination of PU-H71 and nab-paclitaxel was well tolerated, with evidence of clinical activity. More durable disease control without progression was observed in patients with high baseline epichaperome expression. A phase II trial of this combination with PU-PET as a companion diagnostic for patient selection is currently planned.
Authors: Tai Wang; Anna Rodina; Mark P Dunphy; Adriana Corben; Shanu Modi; Monica L Guzman; Daniel T Gewirth; Gabriela Chiosis Journal: J Biol Chem Date: 2018-11-08 Impact factor: 5.157
Authors: Marc Brehme; Cindy Voisine; Thomas Rolland; Shinichiro Wachi; James H Soper; Yitan Zhu; Kai Orton; Adriana Villella; Dan Garza; Marc Vidal; Hui Ge; Richard I Morimoto Journal: Cell Rep Date: 2014-10-23 Impact factor: 9.423
Authors: Mark P S Dunphy; Christina Pressl; Nagavarakishore Pillarsetty; Milan Grkovski; Shanu Modi; Komal Jhaveri; Larry Norton; Bradley J Beattie; Pat B Zanzonico; Danuta Zatorska; Tony Taldone; Stefan O Ochiana; Mohammad M Uddin; Eva M Burnazi; Serge K Lyashchenko; Clifford A Hudis; Jacqueline Bromberg; Heiko M Schöder; Josef J Fox; Hanwen Zhang; Gabriela Chiosis; Jason S Lewis; Steven M Larson Journal: Clin Cancer Res Date: 2020-05-04 Impact factor: 12.531
Authors: Peter Schmid; Sylvia Adams; Hope S Rugo; Andreas Schneeweiss; Carlos H Barrios; Hiroji Iwata; Véronique Diéras; Roberto Hegg; Seock-Ah Im; Gail Shaw Wright; Volkmar Henschel; Luciana Molinero; Stephen Y Chui; Roel Funke; Amreen Husain; Eric P Winer; Sherene Loi; Leisha A Emens Journal: N Engl J Med Date: 2018-10-20 Impact factor: 91.245
Authors: Eloisi Caldas-Lopes; Leandro Cerchietti; James H Ahn; Cristina C Clement; Ana I Robles; Anna Rodina; Kamalika Moulick; Tony Taldone; Alexander Gozman; Yunke Guo; Nian Wu; Elisa de Stanchina; Julie White; Steven S Gross; Yuliang Ma; Lyuba Varticovski; Ari Melnick; Gabriela Chiosis Journal: Proc Natl Acad Sci U S A Date: 2009-05-05 Impact factor: 11.205
Authors: Nagavarakishore Pillarsetty; Komal Jhaveri; Tony Taldone; Eloisi Caldas-Lopes; Blesida Punzalan; Suhasini Joshi; Alexander Bolaender; Mohammad M Uddin; Anna Rodina; Pengrong Yan; Anson Ku; Thomas Ku; Smit K Shah; Serge Lyashchenko; Eva Burnazi; Tai Wang; Nicolas Lecomte; Yelena Janjigian; Anas Younes; Connie W Batlevi; Monica L Guzman; Gail J Roboz; Jacek Koziorowski; Pat Zanzonico; Mary L Alpaugh; Adriana Corben; Shanu Modi; Larry Norton; Steven M Larson; Jason S Lewis; Gabriela Chiosis; John F Gerecitano; Mark P S Dunphy Journal: Cancer Cell Date: 2019-10-24 Impact factor: 31.743
Authors: M Nieves Calvo-Vidal; Nahuel Zamponi; Jan Krumsiek; Max A Stockslager; Maria V Revuelta; Jude M Phillip; Rossella Marullo; Ekaterina Tikhonova; Nikita Kotlov; Jayeshkumar Patel; Shao Ning Yang; Lucy Yang; Tony Taldone; Catherine Thieblemont; John P Leonard; Peter Martin; Giorgio Inghirami; Gabriela Chiosis; Scott R Manalis; Leandro Cerchietti Journal: Cancer Res Date: 2021-09-03 Impact factor: 12.701
Authors: Stephen D Ginsberg; Thomas A Neubert; Sahil Sharma; Chander S Digwal; Pengrong Yan; Calin Timbus; Tai Wang; Gabriela Chiosis Journal: FEBS J Date: 2021-06-12 Impact factor: 5.622
Authors: Suhasini Joshi; Erica DaGama Gomes; Tai Wang; Adriana Corben; Tony Taldone; Srinivasa Gandu; Chao Xu; Sahil Sharma; Salma Buddaseth; Pengrong Yan; Lon Yin L Chan; Askan Gokce; Vinagolu K Rajasekhar; Lisa Shrestha; Palak Panchal; Justina Almodovar; Chander S Digwal; Anna Rodina; Swathi Merugu; NagaVaraKishore Pillarsetty; Vlad Miclea; Radu I Peter; Wanyan Wang; Stephen D Ginsberg; Laura Tang; Marissa Mattar; Elisa de Stanchina; Kenneth H Yu; Maeve Lowery; Olivera Grbovic-Huezo; Eileen M O'Reilly; Yelena Janjigian; John H Healey; William R Jarnagin; Peter J Allen; Chris Sander; Hediye Erdjument-Bromage; Thomas A Neubert; Steven D Leach; Gabriela Chiosis Journal: Commun Biol Date: 2021-11-25
Authors: Alexander Bolaender; Danuta Zatorska; Huazhong He; Suhasini Joshi; Sahil Sharma; Chander S Digwal; Hardik J Patel; Weilin Sun; Brandon S Imber; Stefan O Ochiana; Maulik R Patel; Liza Shrestha; Smit K Shah; Shuo Wang; Rashad Karimov; Hui Tao; Pallav D Patel; Ananda Rodilla Martin; Pengrong Yan; Palak Panchal; Justina Almodovar; Adriana Corben; Andreas Rimner; Stephen D Ginsberg; Serge Lyashchenko; Eva Burnazi; Anson Ku; Teja Kalidindi; Sang Gyu Lee; Milan Grkovski; Bradley J Beattie; Pat Zanzonico; Jason S Lewis; Steve Larson; Anna Rodina; Nagavarakishore Pillarsetty; Viviane Tabar; Mark P Dunphy; Tony Taldone; Fumiko Shimizu; Gabriela Chiosis Journal: Nat Commun Date: 2021-08-03 Impact factor: 14.919