Browsing by Author "Ma, Wen Wee"

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    A phase I study of the anaplastic lymphoma kinase inhibitor ceritinib in combination with gemcitabine-based chemotherapy in patients with advanced solid tumors
    (Wiley, 2021) Fountzilas, Christos; Adjei, Alex; Opyrchal, Mateusz; Evans, Rachel; Ghasemi, Mohammad; Attwood, Kristopher; Groman, Adrienne; Bshara, Wiam; Goey, Andrew; Wilton, John; Ma, Wen Wee; Iyer, Renuka; Medicine, School of Medicine
    In this phase I, dose-escalation study, we sought to determine the maximum tolerated dose (MTD) of the anaplastic lymphoma kinase/c-ROS oncogene 1 receptor (ALK/ROS1) inhibitor ceritinib in combination with gemcitabine-based chemotherapy in patients with advanced solid tumors. Secondary objectives were characterization of the safety profile, pharmacokinetics and preliminary efficacy of these combinations, and identification of potential biomarkers of efficacy. Ceritinib was combined with gemcitabine (Arm 1), gemcitabine/nab-paclitaxel (Arm 2) or gemcitabine/cisplatin (Arm 3). Drug concentrations in plasma were measured by tandem mass spectrometric detection (LC-MS/MS). We analyzed archival tumor tissue for ALK, ROS1, hepatocyte growth factor receptor (c-MET) and c-Jun N-terminal kinase (JNK) expression by immunohistochemistry. Arm 2 closed early secondary to toxicity. Twenty-one patients were evaluable for dose-limiting toxicity (DLT). There was one DLT in Arm 1 (grade 3 ALT increase) and three DLTs in Arm 3 (grade 3 acute renal failure, grade 3 thrombocytopenia, grade 3 dyspnea). The MTD of ceritinib was determined to be 600 mg (Arm 1) and 450 mg orally daily (Arm 3). Main toxicities were hematologic, constitutional and gastrointestinal as expected by the chemotherapy backbone. The apparent clearance for ceritinib decreased substantially after repeated dosing; cisplatin did not significantly affect the pharmacokinetics of ceritinib. The overall response rate was 20%; the median progression-free survival was 4.8 months. Three out of five response-evaluable cholangiocarcinoma patients had clinical benefit. Increased expression of c-MET was associated with a lack of clinical benefit. Ceritinib in combination with gemcitabine and gemcitabine/cisplatin has a manageable toxicity profile. Further development of this strategy in tumors with ALK or ROS1 fusions is warranted.
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    Culture media composition influences patient-derived organoid ability to predict therapeutic responses in gastrointestinal cancers
    (American Society for Clinical Investigation, 2022-11-22) Hogenson, Tara L.; Xie, Hao; Phillips, William J.; Toruner, Merih D.; Li, Jenny J.; Horn, Isaac P.; Kennedy, Devin J.; Almada, Luciana L.; Marks, David L.; Carr, Ryan M.; Toruner, Murat; Sigafoos, Ashley N.; Koenig-Kappes, Amanda N.; Olson, Rachel Lo; Tolosa, Ezequiel J.; Zhang, Cheng; Li, Hu; Doles, Jason D.; Bleeker, Jonathan; Barrett, Michael T.; Boyum, James H.; Kipp, Benjamin R.; Mahipal, Amit; Hubbard, Joleen M.; Scheffler Hanson, Temperance J.; Petersen, Gloria M.; Dasari, Surendra; Oberg, Ann L.; Truty, Mark J.; Graham, Rondell P.; Levy, Michael J.; Zhu, Mojun; Billadeau, Daniel D.; Adjei, Alex A.; Dusetti, Nelson; Iovanna, Juan L.; Bekaii-Saab, Tanios S.; Ma, Wen Wee; Fernandez-Zapico, Martin E.; Anatomy, Cell Biology and Physiology, School of Medicine
    BACKGROUND: A patient-derived organoid (PDO) platform may serve as a promising tool for translational cancer research. In this study, we evaluated PDO’s ability to predict clinical response to gastrointestinal (GI) cancers. METHODS: We generated PDOs from primary and metastatic lesions of patients with GI cancers, including pancreatic ductal adenocarcinoma, colorectal adenocarcinoma, and cholangiocarcinoma. We compared PDO response with the observed clinical response for donor patients to the same treatments. RESULTS: We report an approximately 80% concordance rate between PDO and donor tumor response. Importantly, we found a profound influence of culture media on PDO phenotype, where we showed a significant difference in response to standard-of-care chemotherapies, distinct morphologies, and transcriptomes between media within the same PDO cultures. CONCLUSION: While we demonstrate a high concordance rate between donor tumor and PDO, these studies also showed the important role of culture media when using PDOs to inform treatment selection and predict response across a spectrum of GI cancers.