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Response prediction of neoadjuvant therapy in advanced pancreatic cancer (NeoResponse-Trial)

Summary of the Project

Pancreatic ductal adenocarcinoma (PDAC) is still one of the most deadliest cancers, and many patients present with locally advanced or metastasized disease. The treatment of choice in non-metastasized PDAC is surgical resection with tumor-free resection margins (R0). Locally-advanced tumor growth involving adjacent vascular structures (stage 3) can limit R0-resection. In these cases, intensified neoadjuvant chemotherapy protocols are increasingly applied to reduce the tumor mass, thus enabling complete resection in selected patients. After neoadjuvant FOLFIRINOX or nab-paclitaxel/gemcitabine protocols, response rates of up to 30% have been observed using standard imaging modalities. Nevertheless, definite resectability - assessed by surgical exploration and intraoperative frozen section analysis - was achieved in 50-90% of the cases.

    Organoids of a Pancreatic adenocarcinoma @ VTG   

    Thus, standard imaging criteria did not adequately predict tumor response after intensified neoadjuvant treatment. PDAC responds to intensified neoadjuvant treatment regimen with scar formation, which is often indistinguishable by conventional computed tomography (CT) analysis from viable tumor masses. We aim to explore a novel set of biomarkers and imaging modalities for response prediction during and after a neoadjuvant treatment course. Biological response will be assessed using dual time point PET-MRI, tumor-derived exosome glypican-1 levels, synchronous chemotherapy response of patient-derived 3D cell cultures (organoids), and serum-based quantification of KRAS-mutation load. The results will be correlated with intraoperative findings during surgical exploration and histopathology after completed neoadjuvant treatment. The overreaching goal is to better stratify patients after neoadjuvant therapy to either resection or continued intensified neoadjuvant treatment. Continued treatment could either be a change in the chemotherapy regiment or an addition of radiotherapy. 

    Scientific Goals

    • Identify a subset of biomarkers, which accurately indicate pathological response of patients with locally advanced PDAC.
    • Establish dual time point PET-MRI and/or response of 3D cultures (organoids) to treatment and/or cancer exosome markers and/or quantification of KRAS mutation load in the serum as biomarkers for improved response evaluation.
    • Prevent surgical explorations of non-responders which receive instead a continued neoadjuvant treatment with a change in the treatment modalities, and to accurately identify patients with biological tumor response enabling complete surgical resection.

    Mierke F, Hempel S, Distler M, Aust DE, Saeger HD, Weitz J, Welsch T.
    Impact of Portal Vein Involvement from Pancreatic Cancer on Metastatic Pattern After Surgical Resection.
    Ann Surg Oncol. 2016 Dec;23(Suppl 5):730-736.

    Klein K, Werner K, Teske C, Schenk M, Giese T, Weitz J, Welsch T.
    Role of TFEB-driven autophagy regulation in pancreatic cancer treatment.
    Int J Oncol. 2016 Jul;49(1):164-72. doi: 10.3892/ijo.2016.3505.

    van den Hoff J, Oehme L, Schramm G, Maus J, Lougovski A, Petr J, Beuthien-Baumann B, Hofheinz F.
    The PET-derived tumor-to-blood standard uptake ratio (SUR) is superior to tumor SUV as a surrogate parameter of the metabolic rate of FDG.
    EJNMMI Res. 2013 Nov 23;3(1):77.

    Melo SA1, Luecke LB1, Kahlert C1, Fernandez AF2, Gammon ST3, Kaye J1, LeBleu VS1, Mittendorf EA4, Weitz J5, Rahbari N5, Reissfelder C5, Pilarsky C5, Fraga MF6, Piwnica-Worms D3, Kalluri R1.
    Glypican-1 identifies cancer exosomes and detects early pancreatic cancer.
    Nature. 2015 Jul 9;523(7559):177-82.

    Stange DE, Koo BK, Huch M, Sibbel G, Basak O, Lyubimova A, Kujala P, Bartfeld S, Koster J, Geahlen JH, Peters PJ, van Es JH, van de Wetering M, Mills JC, Clevers H.
    Differentiated Troy+ chief cells act as reserve stem cells to generate all lineages of the stomach epithelium.
    Cell. 2013 Oct 10;155(2):357-68.

    Contact

    Prof. Dr. med. Thilo Welsch
    Dept. of Visceral-, Thoracic and Vascular Surgery,
    University Hospital Dresden
    Phone: + 49 (0)351 458 18283
    thilo.welsch(at)uniklinikum-dresden.de