C01: Optimization and evaluation of cmyc – directed liver cancer therapy

In patients suffering from advanced hepatocellular carcinoma (HCC), sorafenib is currently the only approved systemic treatment that results in a small survival benefit. Therefore, novel therapies are urgently needed. Deregulated c-myc expression frequently occurs in human liver cancers, however, a better understanding of the molecular downstream targets and their respective functional pathways is required to select the appropriate patients for c-myc-targeted therapies. The first aim of this project is therefore to dissect the role of c-myc in established liver cancers. We will use a recently developed DsiRNA against cmyc and inducible c-myc shRNAs in in vitro and in vivo HCC models to elucidate whether and how inhibition of c-myc impacts tumor growth. First, we will determine how c-myc inhibition affects tumor cell proliferation, cell death sensitivity, metabolism, and the tumor environment in HCC and to identify cell lines that are sensitive or resistant to c-myc inhibition. By using Microarray analysis, ribosome profiling, we aim to identify those downstream c-myc targets and functional pathways that determine sensitivity and resistance to c-myc based therapies in HCC. Due the profound genetic heterogeneity of HCC, most likely combination therapies are required for sufficient anti-tumor efficacy. Thus, the second part of our proposal focuses on optimizing c-myc directed therapies for the treatment of HCC. We will first combine rational targeted- and chemotherapies with c-myc inhibition. Moreover, we will perform a functional genomic shRNA screen to identify additional pathways to enhance c-myc-directed anti-cancer therapies. Together, the experimental program aims to unravel the functional role of c-myc in HCCs and to identify collaborating pathways to optimize c-myc targeted therapies.

Publications

Endig J, Buitrago-Molina LE, Marhenke S, Reisinger F, Saborowski A, Schütt J, Limbourg F, Könecke C, Schreder A, Michael A, Misslitz AC, Healy ME, Geffers R, Clavel T, Unger K, Finegold M, Weber A, Manns MP, Longerich T, Heikenwälder M, Vogel A (2016) Dual role of the adaptive immune system in liver injury and hepatocellular carcinoma development. Cancer Cell 30(2):308-23.
Orlik J, Schüngel S, Buitrago-Molina LE, Geffers R, Endig J, Marhenke S, Lobschat K, Rössler S, Goeppert B, Manns MP, Gross A, Vogel A (2015) The BH3-only protein BID impairs the p38-mediated stress response and promotes hepatocarcinogenesis during chronic liver injury in mice. Hepatology 62(3):816-28.
Vogel A, Kasper S, Weichert W, Bitzer M, Block A, Riess H, Schulze-Bergkamen H, Moehler MH, Merx KE, Endris V, Schnoy E, Siveke J, Michl P, Waldschmidt D, Kuhlmann J, Geissler M, Kahl C, Kubicka S (2015) Panitumumab in combination with gemcitabine/cisplatin (GemCis) for patients with advanced kRAS WT biliary tract cancer: A randomized phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO). J Clin Oncol 33(15).
Marhenke S, Buitrago-Molina LE, Endig J, Orlik J, Schweitzer N, Longerich T, Geffers R, Sánchez Muñoz A, Dorrell C, Katz S, Lechel A, Weng H, Krech T, Lehmann U, Dooley S, Rudolph KL, Manns MP, Vogel A (2014) p21 promotes Liver Regeneration and Hepatocarcinogenesis in Chronic Cholestatic Liver Injury. GUT 63(9):1501-12.
Horwitz E, Stein I, Andreozzi M, Nemeth J, Shoham A, Pappo O, Schweitzer N, Tornillo L, Kanarek L, Quagliata L, Zreik F, Porat RM, Finkelstein R, Reuter H, Koschny R, Ganten T, Mogler C, Shibolet O, Hess J, Breuhahn K, Grunewald M, Schirmacher P, Vogel A, Terracciano L, Angel P, Ben-Neriah Y, Pikarsky E (2014) Human and mouse VEGFA-amplified hepatocellular carcinomas are highly sensitive to sorafenib treatment. Cancer Discov 4(6):730-43.
Buitrago-Molina LE, Marhenke S, Longerich T, Boukouris AE, Geffers R, Guigas B, Manns MP, Vogel A (2013) The degree of liver injury determines the role of p21 in liver regeneration and hepatocarcinogenesis. Hepatology 58(3):1143-1152.
Wuestefeld T, Pesic M, Longerich T, Kang TW, Yevsa T, Dauch D, Potapova A, Rittelmeier I, Jarek M, Geffers R, Scharfe M , Klawonn F, Malek NP, Schirmacher P, Ott M, Vogel A, Manns MP, Zender L (2013) A direct in vivo RNAi screen identifies MKK4 as a key regulator of liver regeneration. Cell 153(2):389-401.
Buitrago-Molina LE, Pothiraju D, Lamle J, Marhenke S, Kossatz U, Breuhahn K, Manns MP, Malek N, Vogel A (2009) Rapamycin delays tumor development in murine livers by inhibiting proliferation of hepatocytes with DNA damage. Hepatology 50:500-509.
Willenbring H, Sharma AD, Vogel A, Lee AY, Rothfuss A, Wang Z, Finegold M, Grompe M (2008) Loss of p21 permits carcinogenesis from chronically damaged liver and kidney epithelial cells despite unchecked apoptosis. Cancer Cell 14:59-67.
Marhenke S, Lamle J, Buitrago-Molina LE, Canon JM, Geffers R, Finegold M, Sporn M, Yamamoto M, Manns MP, Grompe M, Vogel A (2008) Activation of nuclear factor E2-related factor 2 in hereditary tyrosinemia type 1 and its role in survival and tumor development. Hepatology 48:487-496.