Rozsiany rak nerkowokomórkowy współczesne wyzwania w terapiach celowanych

Transkrypt

1 Rozsiany rak nerkowokomórkowy współczesne wyzwania w terapiach celowanych KSIĄŻKA ABSTRAKTÓW SEROCK, listopada 2013 r. Niniejsze materiały konferencyjne zostały przygotowane na podstawie abstraktów nadesłanych przez uczestników Międzynarodowego Sympozjum Rozsiany rak nerkowokomórkowy współczesne wyzwania w terapiach celowanych 1

2 Informacje Ogólne o Sympozjum Organizator: Fundacja Onkologii Doświadczalnej i Klinicznej Termin: listopada 2013 r. Miejsce: Hotel Narvil, ul. Czesława Miłosza 14a Serock Informacje o Sympozjum na www: Biuro Sympozjum: Elżbieta Bernatowicz ul. Mokotowska 4/ Warszawa tel. kom tel./fax / biuro@fodik.org Wydawnictwo: Fundacja Onkologii Doświadczalnej i Klinicznej Projekt graficzny okładki: MroowLab.com Druk: SCRIPT.S.C ul.teligi 6/ Warszawa ISBN

3 Międzynarodowe Sympozjum Rozsiany rak nerkowokomórkowy współczesne wyzwania w terapiach celowanych Komitet Naukowy Sympozjum: Prof. dr hab. n. med. Cezary Szczylik Przewodniczący Prof. dr hab. n. med. Piotr Wysocki dr hab. n. med. Gabriel Wcisło dr hab. n. med. Rafał Stec dr n. med. Anna Czarnecka dr n. med. Piotr Tomczak Komitet Organizacyjny Sympozjum: dr hab. n. med. Rafał Stec, drrafals@wp.pl; tel. 22/ dr hab. n. med. Gabriel Wcisło, gwcislo@wim.mil.pl; tel. 22/ dr n. med. Marcin Świerkowski, mswierkowski@wim.mil.pl; tel. 22/ dr Katarzyna Kamińska, biuro@fodik.org; tel. 22/ lek. Waleed Abumoammar, waleedmn@tlen.pl; tel. 22/ lek. Beata Młot, beatamlot@op.pl; tel. kom lek. Anna Waśko-Grabowska, anna.wasko@autograf.pl; tel. 22/ mjr lek. Przemysław Langiewicz, plangiewicz@wim.mil.pl; tel. 22/ mgr Aleksandra Klemba, biuro@fodik.org; tel. 22/ Redakcja naukowa: Prof. dr hab. n. med. Cezary Szczylik Redakcja pomocnicza: dr inż. Elżbieta Bernatowicz dr Katarzyna Kamińska mgr Aleksandra Klemba 3

4 Sponsorzy: Główny partner Patron medialny: 4

5 Szanowni Państwo, W imieniu własnym jak i pozostałych organizatorów mam zaszczyt zaprosić Państwa na międzynarodowe sympozjum naukowe Rozsiany rak nerkowokomórkowy współczesne wyzwania w terapiach celowanych, które odbędzie się listopada 2013 r. w Hotelu Narvil w Serocku. Celem Sympozjum jest obok przedstawienia aktualnego stanu wiedzy na temat diagnostyki i leczenia miejscowo zaawansowanego i rozsianego raka nerkowokomórkowego zaprezentowanie nowych kierunków badań nad jego biologią molekularną, a następnie przedstawienie najnowszych wyników badań klinicznych, które w istocie zmieniły znane nam już standardy leczenia tego nowotworu. Niezmienną od lat intencją Organizatorów jest tworzenie jednolitego systemu standardów opieki nad tymi chorymi w skali kraju. Ostatnie lata przyniosły wiele korzystnych wyników badań klinicznych dotyczących nowych leków i schematów postepowania terapeutycznego w rozsianej postaci tego nowotworu. Po erze leków I generacji sorafenibie i sunitinibie, pokazały się leki uderzające w nowe cele molekularne, o odmiennych profilach toksyczności. Pojawiły się też wyniki badań wskazujących na miejsce opisanych i zbadanych dotąd leków w leczeniu sekwencyjnym. Nowe badania wskazują też, że leki I generacji są nadal bardzo interesującymi i aktywnymi cząsteczkami w leczeniu rozsianego raka nerki. Wiemy już, że ten rodzaj leczenia może wielokrotnie wydłużyć czasy przeżycia tych chorych. W chwili obecnej zarejestrowanych jest już 8 leków, a kolejne są w finalnych etapach badań klinicznych. Jest więc z czym się zapoznać, a także zadać pytania wybitnym praktykom i naukowcom zaangażowanym w badania podstawowe. Przedstawienie rezultatów badań klinicznych raka nerki nowymi terapeutykami jest istotnym wkładem w utrzymaniu wysokich standardów leczenia chorych na tę nieuleczalną do niedawna chorobę. Dotychczasowym sukcesem naszej aktywności jest m.in. wzrost liczby zarejestrowanych przypadków raka nerki o 30% na przestrzeni ostatnich 5 lat, przy jednoczesnym tylko 5% wzroście liczby zgonów. Zachęcam Państwa do czynnego udziału w tym Sympozjum poprzez zadawanie pytań i do udziału w dyskusjach. W imieniu Komitetu Naukowego i Organizacyjnego Cezary Szczylik 5

6 O FUNDACJI Fundacja powstała 19 kwietnia 1994 r. pod nazwą Fundacja Onkologii Doświadczalnej i Klinicznej. Celem Fundacji jest wspieranie rozwoju nowoczesnej profilaktyki, diagnostyki i leczenia chorób nowotworowych w oparciu o osiągnięcia światowej biologii, medycyny i psychologii ze statutu Fundacji, przyjętego przez Sąd Rejonowy dla m.st. Warszawy, Wydział XVI Gospodarczy Rejestrowy, 12 maja 1994 r.. Fundacja realizuje swoje cele, między innymi: finansując wyjazdy lekarzy i naukowców na praktyki, staże, sympozja, konferencje i zjazdy naukowe, finansując działania mające na celu upowszechnienie wiedzy o chorobach nowotworowych (kursy, szkolenia, wykłady, publikacje) wśród personelu medycznego, przyznając środki finansowe i rzeczowe instytucjom medycznym zajmującym się onkologią kliniczną na poprawę stanu profilaktyki, diagnostyki i leczenia, przyznając środki finansowe i rzeczowe instytucjom naukowym na badania w zakresie poznania istoty, profilaktyki, diagnostyki i leczenia chorób nowotworowych /onkologia doświadczalna/ oraz na wdrażanie nowych metod profilaktycznych. diagnostycznych i terapeutycznych, upowszechniając w środowisku medycznym i naukowym oraz w społeczeństwie osiągnięć nauk biologiczno-medycznych oraz psychologii w zakresie poznania chorób nowotworowych, przyznając nagrody i wyróżnienia oraz fundując stypendia za najwybitniejsze osiągnięcia w profilaktyce; diagnostyce i wdrażaniu nowoczesnych terapii w zakresie onkologii w Polsce. Celem Fundacji Onkologii Doświadczalnej i Klinicznej jest zbliżenie nauki z praktyką kliniczną, przyśpieszenie wdrażania nowych metod diagnostyki i leczenia nowotworów i rozwój oryginalnych polskich. Założona przez nas Fundacja jest wynikiem niecierpliwości, niecierpliwości chorych, lekarzy, naukowców oczekujących przełomu w onkologii, nie tylko zrozumienia istoty choroby, ale przede wszystkim przełamania bezsilności wobec jej niepohamowanego wzrostu. Wiemy również, iż świadomość potrzeby rozwoju nauk podstawowych dla potrzeb medycyny musi być zrozumiała i powszechna, gdyż to właśnie one decydują o postępie. Cezary Szczylik 6

7 SYMPOSIUM S PROGRAM / PROGRAM SYMPOZJUM Thursday / Czwartek r Registration of participants / Rejestracja uczestników Lunch / Obiad Session I: Molecular medicine for kidney cancer Sesja I: Medycyna molekularna raka nerki Session moderators / Moderatorzy sesji: Bożena Kamińska-Kaczmarek, Salem Chouaib Welcome of participants / Powitanie uczestników Cezary Szczylik The role of hypoxia in cancer development / Rola niedotlenienia w powstawaniu nowotworów złośliwych Claudine Kieda Genomic characterization of ccrcc towards biomarker discovery and clinical validation/charakterystyka genomowa raka nerki poszukiwanie nowych biomarkerów i ich kliniczna walidacja Joanna Wesoły Proteins regulated by mtor and new therapeutic implications / Białka regulowane przez mtor implikacje terapeutyczne Bożena Kamińska-Kaczmarek Tumor microenvironment as metastasis regulator / Rola podścieliska nowotworowego w powstawaniu przerzutów Katarzyna Kamińska Cancer stem cells facts and myths in ccrcc / Komórki macierzyste nowotworów złośliwych fakty i mity Damian Matak Disscusion / Dyskusja Coffee break / Przerwa kawowa Therapeutic modulation of multiple growth pathways as the novel strategy for therapeutic intervention in RCC current status and future perspectives / Modulacja terapeutyczna dróg przewodzenia sygnału jako nowa strategia interwencji terapeutycznej RCC aktualny stan i perspektywy Jerzy Pieczykolan Genomics, proteomics and metabolomics in ccrcc research / Zastosowanie genomiki, proteomiki i metabolomiki w badaniach nad rakiem jasnokomórkowym nerki Zofia Bielecka 7

8 The role of insulin-like growth factors system in RCC / Rola układu insulinopodobnych czynników wzrostu w raku nerki Wojciech Solarek The role of angiogenesis in pathophysiology and treatment of RCC / Rola angiogenezy w patofizjologii i leczeniu RCC Anna Czarnecka Disscusion / Dyskusja Gala dinner / Uroczysta kolacja Friday / Piątek Breakfast / Śniadanie Session II: Kidney cancer in 2013 Sesja II: Rak nerki w 2013 r. Session moderators / Moderatorzy sesji: Claudine Kieda, Anna Czarnecka Current recommendations of mrcc treatment based on III phase clinical trials / Współczesne zalecenia terapeutyczne na podstawie wyników badań klinicznych III fazy przerzutowego raka nerki Bernard Escudier Axitinib in the treatmtent of the second line of mrcc / Nowy lek w leczeniu II linii po progresji leczeniu inhibitorem kinaz tyrozynowych Axitinib Cezary Szczylik Axitinib in sequential therapy in metastatic renal cell carcinoma case report / Axitinib w terapii przerzutowego raka nerki studium przypadku Agata Kuchar mrcc treatment the role of sequencing therapy / Leczenie sekwencyjne przerzutowego raka nerki Camillo Porta Disscusion / Dyskusja Coffee break / Przerwa kawowa Immunohistochemistry of renal cell carcinoma clinical implications / Znaczenie badań immunohistochemicznych w diagnostyce raka nerki Marcin Ligaj Prognostic and predictive factors personalized treatment of patients with colorectal cancer, and these experiences can be extrapolated to renal cell carcinoma / Czynniki prognostyczne i predykcyjne personalizacja terapii chorych na raka jelita grubego, czy te doświadczenia można ekstrapolować na raka 8

9 nerkowokomórkowego Rafał Stec Epidemiology of renal cell carcinoma / Epidemiologia raka nerki Urszula Wojciechowska GSK SESSION / SESJA GSK Pazopanib as the front line in the treatment of metastatic renal cell carcinoma / Pazopanib jego rola w leczeniu I rzutu rozsianego raka nerki Cezary Szczylik How to choose proper TKI results of the PISCES clinical trial / PISCES badanie preferencji pacjentów w leczeniu inhibitorami kinaz tyrozynowych Piotr Tomczak Pazopanib vs. sunitinib in the front line of mrcc / Pazopanib vs. sunitynib w leczeniu I linii mrcc Przemysław Langiewicz Lunch / Obiad Session III: Immunology and Immunotherapy RCC Sesja III: Immunologia i immunoterapia RCC Session moderators / Moderatorzy sesji: Salem Chouaib, Piotr Wysocki Influence of hypoxic stress on anti-tumour response / Wpływ stresu hipoksyjnego na odpowiedź przeciw-nowotworową Salem Chouaib The role of IL-6 in RCC development and progression / Rola IL-6 w powstawaniu i progresji raka nerki Katarzyna Kamińska Immunotherapy with monoclonal antibodies in cancer management / Przeciwciała monoklonalne w leczeniu nowotworów to też immunoterapia Piotr Wysocki The role of IL-15 in ccrcc development and progression / Rola IL-15 w powstawaniu i progresji raka nerki Anna Czarnecka The role of CXCL chemokines in progression of clear cell renal cell carcinoma following Bevacizumab treatment / Rola chemokin typu CXCL w progresji raka nerki po leczeniu bewacyzumabem Gilles Pagès Disscusion / Dyskusja Coffee break / Przerwa kawowa 9

10 Session IV: The role of surgery in management of renal cell cancer Sesja IV: Leczenie operacyjne raka nerki Session moderators / Moderatorzy sesji: Rafał Stec, Piotr Tomczak Surgery of renal cell cancer when vena cava inferior is involved / Leczenie operacyjne raka nerki z uwzględnieniem nacieku i penetracji do żyły głównej dolnej Wojciech Rogowski Molecular basics of renal cell cancer drug resistance / Molekularne podstawy lekooporności raka nerki Zofia Bielecka The pros and cons of nephron-sparing surgery in renal cell cancer the latest data / Leczenie oszczędzające miąższ nerki co nowego? Piotr Radziszewski The results of RAPTOR study in papillary renal cell cancer treated with everolimus / Wyniki badania II fazy Afinitoru w leczeniu raka rozsianego papilarnego nerki (Raptor) Jakub Żołnierek The role m-tor inhibitores in the treatment of advanced renal cell carcinoma / Rola inhibitorów m-tor w leczeniu zaawansowanego raka nerki Rafał Stec Discussion / Dyskusja Gala dinner / Uroczysta kolacja Saturday / Sobota Breakfast / Śniadanie Session V: Surgery of renal cell cancer combined with systemic therapy Sesja V: Leczenie operacyjne i systemowe przerzutowej postaci raka nerki Session moderators / Moderatorzy sesji: Wojciech Rogowski, Cezary Szczylik NOVARTIS SESSION / SESJA NOVARTIS The biological fundamentals of sequential tergeted therapy of disseminated renal cell cancer / Biologiczne podstawy molekularnie ukierunkowanego leczenia sekwencyjnego przerzutowego raka nerki Gabriel Wcisło Sequential targeted therapy sunitibin-everolimus efficacy and toxicity profile in metastatic renal cell cancer / Ocena skuteczności i toksyczności leczenia sekwencyjnego Sunitib-Ewerolimus przerzutowego raka nerki. 10

11 Doświadczenia własne Przemysław Langiewicz The role of PI3K/ AKT/mTOR pathway as the potential prognostic and predicitive factors in renal cell cancer patients treated with everolimus in the second and subsequent lines / Ewerolimus znaczenie prognostyczne i predykcyjne ekspresji wybranych komponentów szlaku PI3K/ AKT/mTOR/ Lubomir Bodnar Renal cell cancer treatment with the use of TK and mtor inhibitors in Poland based upon data from the National Health Fund programs or registry / Ocena efektywności leczenia raka nerki inhibitorami kinaz i mtor w świetle danych NFZ Marcin Świerkowski Coffee break / Przerwa kawowa Surgery of pulmonary metastases in renal cell cancer / Leczenie operacyjne przerzutów do płuc raka nerki Tadeusz Orłowski Surgery and gemma-knife in the management of renal cell cancer metastases to the brain / Leczenie operacyjne przerzutów do mózgu raka nerki oraz zastosowanie gamma knife Mirosław Ząbek Surgery of bone metastasis in the course of renal cell cancer / Leczenie operacyjne przerzutów do kości raka nerki Wojciech Marczyński Disscusion / Dyskusja Coffee break / Przerwa kawowa Session VI: Systemic therapy of metastatic renal cell cancer Sesja VI: Leczenie systemowe przerzutowej postaci raka nerki Session moderators / Moderatorzy sesji: Gabriel Wcisło, Cezary Szczylik, Rafał Stec The role of sunitinib in the management of metastatic renal cell cancer / Sunitinib: pozycja tego inhibitora I generacji w leczeniu mcc-rcc Piotr Tomczak Bevacizumab plus Interferon the role of this combination in the treatment of the first-line metastatic renal cell carcinoma / Bewacyzumab plus Interferon rola tego skojarzenia w leczeniu I linii rozsianego raka nerki Rafał Stec Silesian experiences in the sequential treatment of mrcc / Leczenie sekwencyjne rozsianego raka nerki doświadczenia ośrodka śląskiego Wojciech Poborski 11

12 New potential drugs against disseminated renal cell cancer tivozanib and dovitinib / Nowe leki: Tivozanib i Dovitinib Cezary Szczylik Why 800 cgy? The role radiation therapy in management of bone metastasis in renal cell cancer patients / Dlaczego 800 cgy? Rola radioterapii w leczeniu przerzutów rozsianego raka nerki do układu kostnego Jacek Fijuth Disscusion / Dyskusja Attempt to make recommendations in renal cell cancer treatment by panelists / Okrągły stół zalecenia terapeutyczne w leczeniu rozsianego raka nerkowo komórkowego Cezary Szczylik, Rafał Stec, Jakub Żołnierek, Lubomir Bodnar, Wojciech Poborski Dinner / Obiad 12

13 Thursday / Czwartek r. Session I: Molecular medicine for kidney cancer Sesja I: Medycyna molekularna raka nerki Session moderators / Moderatorzy sesji: Bożena Kamińska-Kaczmarek, Salem Chouaib 13

14 The role of hypoxia in cancer development Rola niedotlenienia w powstawaniu nowotworów złośliwych Claudine Kieda Molecular Biophysics Centre, UPR 4301 CNRS, Orléans, France Oxygen partial pressure (po 2 ), is a key parameter of organ physiology, the balance O2 delivery/consumption of a tissue, characterized by its own normoxia called: physioxia. This is disturbed in cancer and decreased po 2 -associated pathologies. Hypoxia turns on the angiogenic process. O2 delivery remains impaired in tumours where vessels and chaotic and leaky. Thus tumour angiogenesis contributes to growth and metastasic spreading. Counteracting tumour hypoxia is the issue to control selection of aggressive and resistant cancer stem-like cells. Although The therapeutic approach has long been considered to be antiangiogenesis, this strategy is being revisited. Angiogenesis-related therapies now favor blood vessels normalization/maturation vs destruction. New strategies aim to tumour targeted genes expressed in a hypoxia-restricted manner to normalize tumour vasculature, restore efficient blood flow and reduce hypoxia. Tumour targeting using endothelial cells to incorporate the newly developing blood vessels can normalize angiogenesis. They are carriers of vectors toward the tumour. Controlled tumour vessels normalization can be also obtained by enhancing O2 delivery using allosteric effectors of hemoglobin and control PI3K/AKT/mTOR pathway that allows stabilization of tumour angiogenesis normalization. Thus tumour hypoxia compensation is the challenge for efficient radiotherapy and/or chemotherapy, reverting pathologic angiogenesis and blocking metastasis spreading. 14

15 Genomic characterization of ccrcc towards biomarker discovery and clinical validation Charakterystyka genomowa raka nerki poszukiwanie nowych biomarkerów i ich kliniczna walidacja Joanna Wesoly Laboratory of High Throughput Technologies, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland We provide a comprehensive summary of available clear cell renal cell carcinoma (ccrcc) microarray data in the form of meta-analysis of genes differentially regulated in tumours as compared to healthy tissue, using effect size to measure the strength of a relationship between the disease and gene expression. We identified 725 differentially regulated genes, with a number of interesting targets, such as TMEM 213, SMIM5 or ATPases: ATP6V0A4 and ATP6V1G3, of which limited or no information is available in terms of their function in ccrcc pathology. Transmembrane family of proteins TMEMs comprises of 1900 highly conserved between species membrane integral proteins of unclear function in ccrcc. We find a correlation between gene expression in tumours, tumour size and Furhman grade. Currently TMEM expression patterns in tumours and blood of ccrcc patients are investigated in order to assess the utility of TMEMs as markers of disease development and metastasis. 15

16 Proteins regulated by mtor and new therapeutic implications Białka regulowane przez mtor implikacje terapeutyczne Bożena Kamińska-Kaczmarek Laboratory of Molecular Neurobiology, Neurobiology Center, Nencki Institute of Experimental Biology, Poland Rapamycin (Sirolimus) binds the cytosolic immunophilin FKBP12 and such complex inhibits the mammalian target of rapamycin (mtor), a serine/threonine kinase that integrates signals from multiple pathways. mtor regulates numerous cellular functions, such as translation, transcription, protein turnover, cell growth, differentiation, cell survival, metabolism, energy balance, and stress response. Immune responses of macrophages and dendritic cells are regulated by mtor signaling that regulates the expression of various cytokines (interferons, interleukins IL-1beta, 2, 4, 12, and 10) in the innate immune cells. Because more than 80% of human cancers acquire hyperactivation of the mtor pathway, the combined use of rapamycin/derivatives alone or in combination with other anticancer agents are under investigation in several human cancers, such as brain, breast, and other solid tumours. Recently, the mtor inhibitor everolimus was shown to be effective in the treatment of subependymal giant cell astrocytomas (SEGA, a brain tumour) and renal AMLs (kidney tumours) in TSC patients. TSC1/2 are suppressors of mtor, their dysfunctions lead to hyperactivation of mtor. Several biomarkers have been developed to monitor the effects of mtor inhibitors, such as Western blot or immunohistochemistry of S6K and 4E-BP1 phosphorylation. Because these methods lack the required selectivity and sensitivity, there is a clear need for the identification and validation of new biomarkers to predict and monitor responses to mtor inhibitors. Novel mtor-regulated proteins: ANXA1, GPNMB, LTF, RND3, S100A11, SFRP4, and NPTX1 have been identified by gene expression profiling and immunohistochemistry in SEGA, and functional analysis indicates their involvement in tumorigenesis and nervous system development. Silencing of ANXA1, GPNMB, S100A11 expression in glioblastoma cells impaired tumour invasion and affected proteolytic activities of MMPs (metalloproteinases). In renal cell carcinoma (RCC) the expression of a negative mtor regulator PTEN was lower, while phosphorylated AKT, and mtor effectors phospho-s6 kinase and phospho-4ebp1 levels were higher than in normal kidney, that is consistent with dysregulation of mtor signaling. Dependence of RCC oncogenesis on the mtor pathway has led to clinical trials of an mtor inhibitor temsirolimus that has shown clinical efficacy in monotherapy of poor-risk RCC leading to an overall survival of 10.8 months in the phase III trial. Many adverse effects of mtor inhibitors consist of metabolic dysregulation (hyperlipemia, hyperglycemia), mucositis, rash and pneumonitis which need careful monitoring and management. 16

17 Tumour microenvironment as metastasis regulator Rola podścieliska nowotworowego w powstawaniu przerzutów Katarzyna Kamińska Laboratory of Molecular Oncology, Department of Oncology, Military Institute of Medicine, Warsaw, Poland Tumour microenvironment is defined as the normal cells, molecules, and blood vessels that surround and feed a tumour cell; a tumour can change its microenvironment, and the microenvironment can affect how a tumour grows. Studies indicate that the cell environment, as much as gene expression events, profoundly affects aspects of cancer development. Interactions between tumour microenvironment and the tumour cells regulates the metastatic potential of tumour. These interactions can be modified by the accumulation of genetic changes and by the transient alterations in gene expression induced by the local tumour microenvironment. Recent findings revealed that the crosstalk between neoplastic cells and tumour microenvironment is a key factor in metastasis. For instance, differential mirna expression in both the epithelial and stromal compartments of tumours compared with normal tissue suggests that mirnas are important drivers of metastasis. Further studies showed that not only cells but also their exosomes influence cancer progression and metastasis. Exosomes which contain also micrornas, mrnas, DNA fragments, and proteins are shuttled from a donor cell to recipient cells. Summarizing, in theme of tumour microenvironment impact on secondary tumour development we should consider it direct as well as indirect influence. This research was supported by Foundation for Polish Science TEAM project TEAM/2010-6/8. 17

18 Cancer stem cells facts and myths in ccrcc Komórki macierzyste nowotworów złośliwych fakty i mity Damian Matak Laboratory of Molecular Oncology, Department of Oncology, Military Institute of Medicine, Warsaw, Poland Cancer stem cells, or more precisely tumour-propagating cells were identified in human renal carcinomas using CD105 surface marker. Isolated and cloned CD105 population possess several properties: clonogenic activity, expression of stem cell markers and lack of differentiative markers, growth in spheroids, in vitro differentiation, in vivo generation of transplantable carcinomas1. Recently, intratumour heterogeneity was discovered using multiregion sequencing2, and this provides new approach to a patient samples analysis. Moreover, CD133+ population is probably responsible for supporting angiogenesis and renal tumour growth. Unlike, in other cancers CD133+ cells are not a tumour-propagating cells3. On the other hand, hypoxic conditions are natural microenviroment prevailing in tumours4. According to this data our study is basing on CD105+ and CD133+ populations from established renal cancer cell lines cultured under various the oxygen partial pressures. Detection of CD105+ and CD133+ populations with flow cytometry in various time lapses of cell culture were done. Proliferation rate and cell viability was measured. Colony formation assay and cell aggregation process was analyzed. 18

19 Therapeutic modulation of multiple growth pathways as the novel strategy for therapeutic intervention in RCC current status and future perspectives Modulacja terapeutyczna dróg przewodzenia sygnału jako nowa strategia interwencji terapeutycznej RCC aktualny stan i perspektywy Jerzy Pieczykolan Innovative Drug Discovery Department, Oncology Group, Adamed Ltd., Pieńków 149, Poland Tumour growth and development is tightly related to new vessels formation and tissue remodeling. Vascular endothelial growth factor (VEGF) is important for vascular development in physiological and pathological processes. Blockade of VEGF pathway has been shown to inhibit both pathological angiogenesis and tumour growth. RCC cancers are recognized to relay greatly on the number of growth signaling pathways what is exploited by a number of TKIs used in clinical practice. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) has been under intense scientific evaluation because of its remarkable ability to induce apoptosis in cancer cells while omitting normal cells. However, its activity was too low to become the effective single therapy agent. Here we present a novel fusion protein based TRAIL/Apo2L. The proposed new fusion protein consists of the recombinant variant of TRAIL fragment, which is linked to the repeated antiangiogenic effector peptide sequence and a motif recognized by tumour-specific proteases (MMP s, upa) in between. The AD-O51.4 is able to bind and sequester the VEGF receptors on malignant and endothelial cells but it is devoid of angiogenic activity. As a consequence, the peptide blocks the binding of VEGF ligand, preventing formation of new vessels. We postulate that due to the presence of VEGF receptors on cancer cells, they can be targeted by our VEGF receptorblocking peptide making them susceptible for TRAIL-induced apoptosis. We postulate that the use of this new class fusion molecules could be a potential new strategy of therapeutic intervention. This Work Was Supported by National Centre For Research And Development under the Framework Innovative Economy Operational Program supported by EU. 19

20 Genomics, proteomics and metabolomics in ccrcc research Genomika, proteomika i metabolomika w badaniach nad jasnokomórkowym rakiem nerki Zofia Bielecka Laboratory of Molecular Oncology, Department of Oncology, Military Institute of Medicine, Warsaw, Poland The advances in computer sciences and molecular biology have begun the OMICs era the complete sets of molecules (transcriptome, proteome or metabolome) measurement techniques. Changes on the genetic, protein and metabolite level are significant in cancer biology, also in clear-cell renal cell carcinoma (ccrcc). In genomics, either single gene transcripts or simultaneous measurements of thousands of gene transcripts are performed with the use of microarray analysis. Quantitative Real-time reverse transcriptase polymerase chain reaction (qrt-pcr) is often used for its confirmation. Human genome sequencing has provided a platform for applied molecular phenotyping and in this way microarrays are today a routine robust high-throughput measurement method on genome-wide transcriptome levels. This short presentation will shortly summarize some transcriptome profiling techniques and their impact in ccrcc research. A few most important current systematic investigations comprising proteomics and metabolomics will be also presented, together with chosen modified mass spectrometry separation techniques used in ccrcc research. Those will include combinations and modifications of: gas chromatography-mass spectrometry (GC-MS), liquid chromatographymass spectrometry (LC-MS), time-of-flight technique (TOF) and matrix-assisted laser desorption/ionization (MALDI). In general, genomics, proteomics and metabolomics overlap and all types of such highthroughput scientific studies may provide novel pathways in ccrcc as well as discover specific biomarkers. 20

21 The role of insulin-like growth factors system in RCC Rola układu insulinopodobnych czynników wzrostu w raku nerki Wojciech Solarek Laboratory of Molecular Oncology, Department of Oncology, Military Institute of Medicine, Warsaw, Poland Insulin is a peptide hormone and a crucial regulator of carbohydrate and fat metabolism, which is produced by beta cells in the pancreas. As insulin is normally linked with metabolism control, the insulin-like growth factors (IGFs), produced mainly in the liver, were identified as a proliferation regulators. This classical view, although in general correct regarding its basic premises, has become more complicated due to recent findings. The IGFs system was shown to play a critical role in cancer development and progression, including Renal Cell Carcinoma (RCC). Today there are convincing evidences of a positive association between overweight, obesity and risk of RCC. Indicated risk factors together with Type 2 diabetes are irreversibly connected with circulating insulin and IGFs levels. The interplay between this molecules, their receptors and IGF-binding proteins might be crucial for RCC cell biology and RCC progression. Given the potent activity IGF/IGF-1R inhibitors demonstrate against RCC in basic biology experiments, some type of combination therapy may prove to be beneficial clinically in the management of RCC. As IGF/IGF-1R inhibitors have entered clinical trials with various effects, their therapeutic potential in RCC should be considered. 21

22 The role of angiogenesis in pathophysiology and treatment of RCC Rola angiogenezy w patofizjologii i leczeniu RCC Anna Czarnecka Department of Oncology, Military Institute of Medicine, Warsaw, Poland The treatment of metastatic RCC has evolved rapidly over the last two decades. Major pathways that have been discovered to be involved in pathogenesis of ccrcc are vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mtor) pathways. The key signaling molecules that were shown to regulate proliferation and migration of endothelial cells are vascular endothelium growth factors (VEGF) and their receptors (VEGFR-1, -2 and -3). VEGFR-2, a receptor with higher VEGF affinity and high kinase activity, was shown as most important in the direct regulation of angiogenesis, mitogenic signaling, and permeability-enhancing effects in ccrcc. Advances in the understanding of VEGFs role in ccrcc growth and progression led to the development of new therapies including agents targeting VEGF and VEGF receptors: tyrosine kinase pathway, serine/threonine kinases, α 5 β 1-integrins, deacetylases, mammalian target of rapamycin (mtor), AKT, and phosphatidylinositol 3'-kinase (PI3K). Starting from sorafenib and sunitinib, several other targeted therapies have been approved for mrcc treatment. VEGF pathway activation is described with the recruitment, migration, and expansion of endothelial cells, and tumour formation. Finally molecular data behind development of new agents, including the kinase inhibitors axitinib, tivozanib, dovitinib and cediranib and VEGF-Trap monoclonal antibodies including velociximab are also discussed. 22

23 Friday / Piątek Session II: Kidney cancer in 2013 Sesja II: Rak nerki w 2013 r. Session moderators / Moderatorzy sesji: Claudine Kieda, Anna Czarnecka 23

24 Current recommendations of mrcc treatment based on III phase clinical trials Współczesne zalecenia terapeutyczne na podstawie wyników badań klinicznych III fazy przerzutowego raka nerki Institut Gustave Roussy, Villejuif, France Bernard Escudier Better understanding of the physiology of clear cell carcinoma has led in the past years to a new generation of drugs, aiming at targeting the VEGF/HIF pathway. Currently, many drugs have been approved for the treatment of RCC, in first, second and even third line: sorafenib, sunitinib, temsirolimus, bevacizumab, everolimus, pazopanib and more recently axitinib. Thus, it becomes urgent to try to define current strategies and future directions for RCC. Several phase III have been reported, and current guidelines based on phase III trials have been recently updated (ESMO 2012 guidelines), and more recent data presented after the guidelines have been written are still improving the current recommendations. The current algorithm for RCC is summarized on the table below. Histology and setting Risk group Standard Option Clear cell first line Good or intermediate Sunitinib Cytokines (including high risk Bevacizumab + IFN dose IL2) Pazopanib Poor risk Temsirolimus Sunitinib Another TKI Clear cell second line Post cytokines Sorafenib Sunitinib Pazopanib Axitinib Post TKIs Everolimus Sorafenib Axitinib Clear cell third line Post TKI/mTOR Sorafenib Rechallenge with same TKI Post 2 TKIs Everolimus Non clear cell histology Temsirolimus Sunitinib Sorafenib Everolimus *in the US only Although we have many drugs available, there are still a lot of questions and challenges: Is sequential therapy the best option for treatment in RCC? In sequential therapy, when should we switch from VEGF blockade to mtor inhibition? Is there still a role for immunotherapy, such as interferon? Is there any role for combination therapy? Which are the new expected drugs in RCC? With a lot of excitement for PD1/PDL1 inhibition as well as cmet inhibition. All these questions will be discussed. 24

25 Axitinib in the treatment in second line of metastatic renal cell cancer Nowy lek w leczeniu II linii po progresji leczeniu inhibitorem kinaz tyrozynowych Axitinib Cezary Szczylik Department of Oncology, Military Institute of Medicine, Warsaw, Poland In recent years, targeted therapies have changed the treatment capabilities for patients with diverse malignancies including metastatic renal clear cell cancer (mccrcc), leading to achieve better progression free survival and prolonging patients overall survival. In 2013 several such drugs have been registered for treatment of mccrcc and next novel targeted drugs are under investigation. My lecture will concentrate on one of newly approved molecules axitinib (Inlyta) in mccrcc treatment. Axitinib is a small molecule indazol derivative, potent multitargeted tyrosine kinase inhibitor, which selectively inhibits vascular endothelial growth factor receptors (VEGFR)-1, -2, -3 at subnanomolar concentrations. Its activity was confirmed in clinical phase II and III studies, showing its high activity in inhibiting mccrcc. In a first phase II study it showed clinical activity in patients with cytokine refractory mccrcc with median time to progression of 15.7 months and overall survival of 29, months. Next phase II study evaluated axitinib in patients who do not respond with advanced and refractory RCC. PFS was 7.4 months and OS was 13.6 months. Final phase III study (AGILE 1032, AXIS) in patients who failed one prior sunitinib, bevacizumab, temsirolimus or cytokine based therapy showed median PFS of 6.7 months for axitinib and 4.7 for sorafenib. Of great importance is fact that this trial confirms sequencing mode of mccrcc treatment as an optimal option in mccrcc therapy. 25

26 Axitinib in sequential therapy in metastatic renal cell carcinoma case report Axitinib w terapii przerzutowego raka nerki studium przypadku Agata Kuchar, Beata Hryciuk, Rafał Stec, Cezary Szczylik Department of Oncology, Military Institute of Medicine, Warsaw, Poland Introduction: Efficacy of new molecularly targeted drugs in the treatment of RCC, confirmed in clinical studies in relation to survival and prolongation of time to progression, has became a big chance for patients with metastatic renal cell cancer. Axitinib is a potent and selective receptor tyrosine kinase for vascular endothelial growth factor (VEGFR-1,2,3), platelet-derived growth factor (PDGRF-β) and c-kit. Methods: This is a case report of a 57-year old female patient with a history of left nephrectomy due to clear cell renal cell carcinoma. The patient had received three prior systemic treatments (interferon sorafenib everolimus) After consecutive progression the patient was qualified to 4 th line therapy axitinib at a dose of 5 mg twice daily. Partial response to treatment was achieved. After 6 months therapy was stopped due to the disease progression. The total time to progression was 37.5 months. The total survival time from the disease diagnosis was 45 months. Conclusions: Based on own experience we showed that sequential treatment RCC is associated with improved survival. In summary, axitinib may be an effective drug after failure of TKI therapy in previous lines of therapy. 26

27 Metastatic renal cell carcinoma (mrcc) treatment the role of sequencing therapy Leczenie sekwencyjne przerzutowego raka nerki Camillo Porta Medical Oncology, I.R.C.C.S. San Matteo University Hospital Foundation and Italian Nephro-Oncology Group (Gruppo Italiano di Oncologia Nefrologica, G.I.O.N.), Pavia, Italy Even though little is known on how many mrcc patients can receive second line of therapy (or even further lines) in a real world, and on how to predict those patients, the high antitumour activity of presently available first-line agents (in the range of 70 80%, irrespective of the drug used) makes quite common for patients to receive sequentially more than one line of therapy. Unfortunately, the randomized controlled trials (i.e., the cornerstone of Evidence-Based Medicine) performed so far in this setting are few and extremely heterogeneous. Indeed, the very first trial performed, the RECORD-1, allowed the enrollment of patients from different treatment lines, and used placebo as its control arm (vs Everolimus); the AXIS trial compared Axitinib with Sorafenib, but allowed the inclusion of patients pretreated with a number of different first-line agents, whilst the INTORSECT trial evaluated in a pure post-sunitinib second-line setting the mtor inhibitor Temsirolimus, which usually is neither indicated nor commonly used in this setting, vs Sorafenib. With all this caveats, and relying just on inter-trial comparisons (which are both questionable and biased), it appers that no huge differences are evident between the three above drugs, even though Axitinib seems to be the drug endowed by the greatest potential (but Sorafenib achieved an unexpected overall survival advantage over its competitor, not observed with the other two drugs). Primary refractory patients, as well as long-responders to first-line therapy then represents two completely different populations, with different features (also molecular?) and outcome. Since the lack of predictive biomarkers does not help us in making clinical decisions in a real life setting, our experience should guide us in identifying patient-, disease- and treatment-related characteristics which could be of some help, not to take into account the need for a correct management of treatment, which is key for it success. 27

28 Epidemiology of kidney cancer Epidemiologia raka nerki Urszula Wojciechowska Polish National Cancer Registry, The Maria Sklodowska-Curie Cancer Center and Institute of Oncology, Warsaw, Poland Kidney cancer accounted for an estimated incident cases (17000 M K), prevalent cases (5-years) and deaths in the world in the late 2010s. There are worldwide geographical variations of kidney cancers. The highest rate (agestandardized for the world population) was found for both sexes in the Czech Republic (35/10 5 in men and 15/10 5 in women). In men, the other regions with high incidence rates included Estonia (25/10 5 ), Lithuania (29/10 5 ), and Slovakia (25/10 5 ). Among females, the high incidence rates were found in Lithuania (12/10 5 ), Estonia (11/10 5 ), Slovakia (12/10 5 ), and Germany (11/10 5 ). In both sexes, the lowest rates were found in Africa and Asia. A sharp increase in the incidence of kidney cancer was observed in numerous cancer registries. Some of the greatest increases were observed in the Czech Republic and among the black population in the USA and also in Poland. These increasing trends are unlikely to be explained only by increased detection of presymptomatic tumours, and are instead likely to reflect real increases in the numbers of new cases. Cigarette smoking has been consistently observed to be a risk factor for kidney cancer, with increased risks as compared to never smokers (RR = ). Population attributable risk estimates indicate that cigarette smoking is responsible for approximately 20% of kidney cancer cases. 28

29 Immunohistochemistry of renal cell carcinoma clinical implications Znaczenie badań immunohistochemicznych w diagnostyce raka nerki Marcin Ligaj Department of pathology,maria Skłodowska-Curie Memorial Warsaw Cancer Center, Poland Immunohistochemistry (IHC) is a method of antigen detection based on an antigenantibody reaction. It can be used on formalin-fixed, paraffin-embedded tissue samples, which make it a great tool for routine histopathologic workup of tumours including renal cell carcinomas (RCC). IHC is useful for differential diagnosis of tumour subtypes enabling: 1) separation of benign from malignant tumours (e.g oncocytoma VS chromophobe RCC), 2) confirmation of metastatic dissemination of a renal primary, 3) identification of tumours amenable to treatment (clear cell RCC), 4) identification of a marginal group of unclassified RCC s showing mixed or divergent differentiation. Frequently used diagnostic immunostains include Cytokeratins, CD10, CD117, Vimentin, Pax 2, Pax 8. TFE3 and TFEB immunostains facilitate diagnosis of rare translocation RCC, especially in young patients. Immunohistochemical markers are studied as potentially prognostic and predictive RCC biomarkers, but none has been implemented in routine clinicopathologic practice. Antigens with identified prognostic value include p53, IMP3, CAIX. Studies of other markers, e.g. p400, CD44, CD133, KI67, are underway. This presentation is an overview of current immunohistochemical practice in RCC workup. 29

30 Prognostic and predictive factors personalized treatment of patients with colorectal cancer, and these experiences can be extrapolated to renal cell carcinoma Czynniki prognostyczne i predykcyjne personalizacja terapii chorych na raka jelita grubego, czy te doświadczenia można ekstrapolować na raka nerkowokomórkowego Rafał Stec Department of Oncology, Military Institute of Medicine, Warsaw, Poland Background: Predictive and personalized medicine (P&PM) approach aims to create personalized treatment algorithms tailored to the individual. Treatment on an individualized basis now involves analysis of a patient s and tumour s biomarker profile. Methods: A literature review was performed using the following medical databases: Medline and PubMed for articles published up to September Search was performed using the following keywords: renal cell carcinoma, molecular markers, prognostic and predictive factors, targeted therapy. Articles were selected according to the originality, actuality, number of patients included and the importance of clinical trials. Results: In CRC (colorectal cancer), the potential value of biomarkers for P&PM is strong, as predictors of anti-egfr therapy (Cetuximab and Panitumumab). At the moment, based on research, clearly predictive and prognostic value in colorectal cancer showed: gene KRAS, gene NRAS, gene BRAF. Potential predictive biomarkers in RCC (renal cell carcinoma) are different than in CRC, which is associated with other molecular disorders, and other molecular therapies. Patients treated with pazopanib who had high concentrations of interleukin 8, osteopontin, hepatocyte growth factor (HGF), and tissue inhibitor of metalloproteinases TIMP-1) had shorter PFS than did those with low concentrations. Also found 3 polymorphisms in IL-8 and HIF-1A showed significant association with PFS and 5 polymorphisms in HIF1A, NR1I2, and VEGFA showed significant association with RR in patients treated with pazopanib. Normal level of C-reactive protein is favorable predictor in patients with advanced RCC treated with sunitinib. Known activating KRAS/BRAF mutations are not responsible for the resistance of RCCs to anti-egfr targeted therapies. Otherwise TP53, KRAS and BRAF are not responsible for the development of renal cell carcinoma, even in absence of VHL mutation. Carbonic anhydrase IX and loss of PTEN are not an independent prognostic or predictive marker. Other potential candidate for biomarkers in RCC include: ribosomal protein S6, protein kinase B, survivin, vimentin A and fascin. Conclusions: Although some prognostic and predictive markers in mrcc were described, their role is very limited by retrospective analyses, and inconsistencies in researchbased assays. Due to different molecular abnormalities in colon cancer and kidney cancer, these experiences (personalized treatment of patients with colorectal cancer) can t be extrapolated to renal cell carcinoma. In summary, there are no predictive biomarkers that have been approved for standard use in mrcc. 30

31 GSK SESSION / SESJA GSK Pazopanib as the front line in the treatment of metastatic renal cell carcinoma Pazopanib jego rola w leczeniu I rzutu pacjentów z rozsianym rakiem jasnokomórkowym nerki. Cezary Szczylik Department of Oncology, Military Institute of Medicine, Warsaw, Poland Decision making proces in treatment of metastaic renal cell carcinoma stopped to be mechanistic e.g I line only X, II line only Y. In clinical practice as manu patients we see, we encounter different clinical situations and fortunatelly we can treat those patients with more delibarately chosen molecules.baased on randomized phase III clinical trial (VEGF105192) of pazopanib versus placebo in patients with advanced/metastatic renal cel carcinoma PFS for pazopanib was 9.2 vs placebo 4.2. Final overall survival was not statistically significant and was 22.9 vs 20.5 (0.224). Using independent alasses to adjust data to crossover suggest an OS benefit p=0.002) for patients treated with pazopanib. This treatment was quite well tolerated with few grade 3 and 4 side effects. Main side effects of grade 2 were diarrhea (52%), hypertension (40%), hair colour changes (38%), decreased apetite (24%) and fatuigue (20%). Data from phase II and III trials give strong evidence of pazopanib activity used as a first line treatment in metastic clear cell carcinoma. 31

32 GSK SESSION / SESJA GSK How to choose proper TKI results of the PISCES clinical trial PISCES badanie preferencji pacjentów w leczeniu inhibitorami kinaz tyrozynowych Poznan University of Medical Sciences Piotr Tomczak Pazopanib is an oral multitargeted tyrosin kinase inhibitor (TKI) of vascular endothelial growth factor receptor. In the randomized phase III trial (COMPARZ) pazopanib showed comparable activity to sunitinib and is now indicated in the first line treatment of metastatic renal cell cancer (mrcc). In this study the progression-free survival (PFS) on pazopanib treatment was 8.4 months, objective response rate (ORR) reached31% and treatment was associated with 28.4 months of overall survival (OS). The overall adverse event (AE) profiles for pazopanib were moderate and the most frequent clinical adverse events reported in COMPARZ study were diarrhea (63%), fatigue (55%), arterial hypertension (46%), nausea (48%), lost of appetite (37%), increase in transaminases levels (31%) and hand-foot syndrome (29%). The PISCES study was designed to find if the toxicity profile of pazopanib prefers pazopanib over sunitinib in the everyday practice. In the opinion both patients and physicians pazopanib treatment was found to be better tolerated and combined with superior quality of live. Respectively 70% of patients and 61% of physicians choosed pazopanib as the treatment to be continued in the further therapy. The PISCES trial indicates that quality of live during molecular targeted therapy is, at least, as important as the efficacy of treatment and may influence on patients preferences. 32

33 GSK SESSION / SESJA GSK Pazopanib vs. sunitinib in the front line of mrcc Pazopanib vs. sunitynib w leczeniu I linii mrcc Przemysław Langiewicz Department of Oncology, Military Institute of Medicine, Warsaw, Poland Background: Efficacy and safety sunitinib and pazopanib as first line TKI therapy of mrcc. Phase 3, randomized, open-label, multicentre clinical trial was analyzed (COMPARZ STUDY). Method: From August 2008 to September 2011, a total of 1100 patients with metastatic clear-cell renal carcinoma were enrolled. Were randomly 1:1 to pazopanib (800mg once daily 557 patients) or sunitinib (50mg daily for 4 weeks and 2 weeks break 553 patients). Exclusion criteria were important cardiovascular events, uncontrolled hypertension, poor condition and brain metastases. Primary end point was progression-free survival as assessed per RECIST criteria. Secondary end points included response rate, overall survival, safety and quality of life evaluate. Results: Median PFS for pazopanib was 8.4 months ( mos, CI 95%) and was similar as for sunitinib 9.5 months ( mos) in independent analysis. In investigator review median PFS was 10.5 months for pazopanib and 10.2 month for sunitinib group. Complete response was observed for 1 patient in pazopanib arm and 3 for sunitinib group. Objective response rate was similar in both group: 33% for pazopanib and 28 for sunitinib. Median overall survival was 28.4 months for pazopanib arm and 29.3 months for sunitinib arm, and was similar (p = 0.28). Patients in sunitinib group had higher risk of hematologic abnormality but in pazopanib group patients had higher risk of transaminase and bilirubin level increase. Conclusion: COMPARZ study showed that pazopanib and sunitinib had similar efficacy and tolerability but overall safety profile favor pazopanib especially for patients with renal failure. 33