Using an FDA-Approved, Anti-Arthritis Drug to Improve Outcomes in Pancreatic Ductal Adenocarcinoma (PDAC)


ASPIRE Award (2019-2022)

Cullen Taniguchi, MD, PhD (Principal); Anirban Maitra, MD; and Eugene Jon Koay, MD, The University of Texas MD Anderson Cancer Center

Pancreatic ductal adenocarcinoma (PDAC) is a rapidly metastasizing cancer of the pancreas. The only treatment options for patients with PDAC are radiation therapy or chemotherapy drugs, both of which can be highly toxic. One hallmark of PDAC is an increase in mitochondrial fission, a process during which mitochondria divide into more numerous, smaller organelles in response to oxidative stress or cell division, both of which are characteristics of KRAS-transformed PDAC. In contrast, healthy cells often have fewer and elongated mitochondria as a result of mitochondrial fusion, a process where mitochondria fuse together in response to damage to facilitate mitochondrial repair or removal. The Taniguchi lab has found by promoting mitochondrial fusion in murine PDAC models, either through genetic manipulation or treatment with leflunomide, an FDA-approved, anti-arthritic drug, oxygen consumption, ATP generation, and tumor growth are reduced, and overall survival increased. Studies are now being expanded to screen a library of FDA-approved drugs for additional activators of mitochondrial fusion that could be rapidly tested in PDAC clinical trials. To inform a future leflunomide PDAC clinical trial, the Taniguchi group will evaluate the therapeutic efficacy of leflunomide as monotherapy as well as in combination with gemcitabine/nab-paclitaxel, which is the current PDAC standard of care chemotherapy. Efficacy studies will be carried out in vitro and in vivo using patient-derived PDAC cell lines and organoids, and correlation of response with KRAS status, as predicted by preliminary data, will be assessed.

PUBLISHED RESEARCH

Kouzy R, Abi Jaoude J, Minsky BD, Das P, Koong AC, Subbiah IM, Ludmir EB, Taniguchi CM. Gastrointestinal malignancies and supportive care trials: a snapshot of the last two decades. BMJ Support Palliat Care. 2020.

García García CJ, Acevedo Diaz AC, Kumari N, Govindaraju S, de la Cruz Bonilla M, San Lucas FA, Nguyen ND, Jiménez Sacarello I, Piwnica-Worms H, Maitra A, Taniguchi CM. HIF2 Regulates Intestinal Wnt5a Expression. Front Oncol. 2021.

Lee JJ, Bernard V, Semaan A, Monberg ME, Huang J, Stephens BM, Lin D, Rajapakshe KI, Weston BR, Bhutani MS, Haymaker CL, Bernatchez C, Taniguchi CM, Maitra A, Guerrero PA. Elucidation of Tumor-Stromal Heterogeneity and the Ligand-Receptor Interactome by Single-Cell Transcriptomics in Real-world Pancreatic Cancer Biopsies. Clin Cancer Res. 2021.

Nguyen ND, Yu M, Reddy VY, Acevedo-Diaz AC, Mesarick EC, Abi Jaoude J, Yuan M, Asara JM, Taniguchi CM. Comparative Untargeted Metabolomic Profiling of Induced Mitochondrial Fusion in Pancreatic Cancer. Metabolites. 2021.

García García CJ, Huang Y, Fuentes NR, Turner MC, Monberg ME, Lin D, Nguyen ND, Fujimoto TN, Zhao J, Lee JJ, Bernard V, Yu M, Delahoussaye AM, Sacarello IJ, Caggiano EG, Phan JL, Deorukhkar A, Molkentine JM, Saur D, Maitra A, Taniguchi CM. Stromal HIF2 Regulates Immune Suppression in the Pancreatic Cancer Microenvironment. Gastroenterology. 2022.

Delahoussaye AM, Abi Jaoude J, Green M, Fujimoto TN, Molkentine J, Garcia Garcia CJ, Gay JP, Feng N, Marszalek J, Fowlkes N, Taniguchi CM. Feasibility of administering human pancreatic cancer chemotherapy in a spontaneous pancreatic cancer mouse model. BMC Cancer. 2022.

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