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PBX binding, is highly cytotoxic to prostate and breast cancer cells
Poster Session – Molecular targeted agents II, Thursday 1 December 2016 a robust reduction in tumor growth in a mouse models. These CPABs represent the best-in-class cell penetrating protein therapeutics opening unprecedented opportunities to tackle intracellular PPI critical to diseases with unmet medical need. No conflict of interest. 405 Poster (Board P084) HTL001, a novel inhibitor of HOX/PBX binding, is highly cytotoxic to prostate and breast cancer cells M. Primon1 , E. Hoffman1 , H.S. Pandha2 , R. Morgan1 . 1 University of Bradford, Institute of Cancer Therapeutics, Bradford, United Kingdom; 2 University of Surrey, Faculty of Health and Medical Sciences, Guildford, United Kingdom Background: The HOX genes are a family of homeodomain-containing transcription factors that determine cellular identity during development and which are dys-regulated in most cancers. In this study we examined the efficacy of a novel inhibitor of HOX function, HTL001, which blocks the interaction between HOX and PBX proteins, in breast and prostate cancer. Methods: We tested the sensitivity of prostate and breast cancer-derived lines to HTL001, a novel peptide antagonist of HOX protein binding to its PBX co-factor. Apoptosis was measured using a FACS-based assay with Annexin, and changes in the expression of previously identified HOX/PBX target genes were measured using RT-QPCR on RNA extracted from cell lines. The in vivo efficacy of HTL001 was tested in a mouse PC3 flank tumor xenograft model. Results: Targeting HOX genes with HTL001 caused apoptotic cell death in all of the cell lines, and prevented the growth of prostate tumors in a mouse xenograft model. Furthermore, HTL001 was significantly more effective than the previously described inhibitor of HOX/PBX interactions, HXR9, both in vivo and in vitro. We show that HTL001 causes a very rapid increase in the expression of 2 genes previously identified as targets of HXR9, cFos and DUSP1, and that the latter could act as a marker of tumor response. Conclusion: HTL001 is a significantly more effective inhibitor of the interaction between HOX and PBX proteins than the previously described antagonist, HXR9, and is highly cytotoxic to both prostate and breast cancer cells in vitro and in vivo. No conflict of interest. 406 Poster (Board P085) Preliminary biomarker and pharmacokinetic analysis from the completed dose escalation part of the first-in-human Phase I study evaluating MP0250, a multi-DARPin® blocking HGF and VEGF-A, in patients with advanced solid tumors K. Dawson1 , D. Feurstein1 , U. Fiedler2 , K. Kuster1 , M. Bez1 , S. Schreiner3 , D. Turner3 , K. Tadjalli Mehr3 , M. Stumpp3 , A. Harstrick3 , R. Baird4 , A. Omlin5 , M. Middleton6 , J. Rodon7 , C. Zitt8 . 1 Molecular Partners, Operations, Zurich-Schlieren, ¨ Switzerland; 2 Molecular Partners, Oncology, Zurich-Schlieren, ¨ Switzerland; 3 Molecular Partners, Clinical, Zurich-Schlieren, ¨ Switzerland; 4 Addenbrooke’s Hospital, Breast cancer ¨ unit, Cambridge, United Kingdom; 5 Kantonsspital St. Gallen, Klinik fur ¨ Onkologie und Hamatologie, St. Gallen, Switzerland; 6 Churchill Hospital, 7 Cancer and Haematology Centre, Oxford, United Kingdom; Vall d’Hebron Institute of Oncology, Oncology, Barcelona, Spain; 8 Molecular Partners, Biology, Zurich-Schlieren, ¨ Switzerland Background: The VEGF/VEGFR and HGF/cMet pathways are implicated in tumor survival, growth, angiogenesis, invasion and metastasis. DARPins® (designed ankyrin repeat proteins) are small proteins that can be engineered to bind to specific targets with high specificity and affinity. MP0250 is a first-in-class, tri-specific multi-DARPin® neutralizing VEGF-A and HGF as well as binding to human serum albumin to increase plasma half-life and potentially enhance tumor penetration. As specific dual blockade of VEGF-A and HGF is new, a broad panel of potential plasma biomarkers was analysed. Methods: A phase I, open-label, multi-center study with completed dose escalation. Eligibility: Patients with advanced solid tumors. Design: 3+3 dose escalation cohorts receiving intravenous MP0250 every 2 weeks. Primary objectives: Safety, tolerability and PK. Secondary objective: ADA, explore potential biomarkers to assess target binding in circulation and changes in cytokine profiles. Plasma concentrations of MP0250, VEGF, HGF and cytokines were measured by immunoassays (ELISA/Luminex). PK parameters were derived using non-compartmental analysis. Results: 24 patients were enrolled in 5 cohorts: 0.5 (n = 3), 1.5 (n = 3), 4 (n = 6), 8 (n = 7), or 12 mg/kg (n = 5) MP0250. The maximum tolerated dose was determined to be 8 mg/kg when MP0250 was given every two weeks. Adverse events, mainly consistent with VEGF inhibition, and signs of clinical activity, have been reported elsewhere (ESMO 2016, submitted abstract). Sustained exposure was observed over multiple dosing cycles of up to 1 year, indicating the absence of neutralizing or clearing ADAs. MP0250 trough plasma levels for doses 0.5 mg/kg were above those
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associated with activity in preclinical models. There were no treatmentrelated effects on the levels of a range of exploratory biomarkers (VEGF-C, angiopoietin-2, endoglin, FGF-2, IL-6, IL-8, TNF-a, IL-10, sVEGFR2 and MMP-2). However, MP0250 reduced VEGF-A levels to undetectable for the duration of treatment. Plasma levels of total HGF increased over time, most likely as a result of MP0250 binding, since a similar increase of MP0250HGF complexes was observed. Conclusions: In a phase I study, MP0250 was found to be well tolerated and to show signs of clinical activity. MP0250 showed a favorable PK profile and sustained exposure over treatment periods. MP0250 had a strong impact on plasma levels of VEGF-A and HGF, but no other biomarkers were identified. Conflict of interest: Ownership: Dawson, Feurstein, Zitt, Fiedler, Kuster, Bez, Schreiner, Turner, Tadjalli Mehr, Stumpp, Harstrick are employees of Molecular Partners and have shares or share options in the company. Corporate-sponsored Research: Baird, Omlin, Middleton, Rodon receive funding from Molecular Partners for providing clinical services to the phase 1 trial. 407 Poster (Board P086) Galunisertib combined with sorafenib affects in vivo tumor growth and immune landscape in hepatocellular carcinoma (HCC) A. Tijeras-Raballand1 , M.A. Le Bitoux2 , A. Maillard3 , M. Albuquerque4 , N. Colnot4 , M. Barral5 , A. Dohan5 , P. Bonnin5 , M. Pocard6 , K. Benhadji7 , V. Paradis4 , E. Raymond8 , A. Harari2 , S. Faivre9 , A. De Gramont10 . 1 AFR Oncology, Preclinical and Translational Department, Paris, France; 2 Immune Monitoring Core, CHUV, Oncology Department, Lausanne, Switzerland; 3 New drugs evaluation laboratory, Center of experimental Therapeutics, CHUV, Oncology Department, Lausanne, Switzerland; 4 Insert U773, Beaujon Hospital, Pathology Department, Clichy, France; 5 Inserm U965, Lariboisiere Hospital, Vascular and Visceral Radiology Department, Paris, France; 6 Inserm U965, Lariboisiere Hospital, Gastroenterology Surgery Department, Paris, France; 7 Eli Lillly and Company, Oncology Early Phase Clinical Research, Bridgewater, USA; 8 Saint-Joseph Hospital, Medical Oncology Department, Paris, France; 9 Beaujon Hospital, Medical Oncology Department, Clichy, France; 10 AFR Oncology and New drugs Evaluation Laboratory, Center of Experimental Therapeutics, Oncology Department, Lausanne, Switzerland Introduction: The TGF-b pathway that has been associated with hepatocellular carcinoma (HCC) progression, can be targeted by galunisertib, a selective ATP-mimetic TGF-b receptor (TbR)-I inhibitor currently under clinical investigation in HCC patients. Our study aimed to investigate the anti-tumoral effects of galunisertib with or without sorafenib in a transgenic mice model of HCC. Methods: Transgenic mice developing stage-defined HCC were treated for 8 weeks (W) from W8 to W16 with either vehicle, sorafenib (30 mg/kg), galunisertib (100 mg/kg) or sorafenib plus galunisertib. Tumor growth was evaluated by ultrasound (liver size) and by the number of macronodules at sacrifice. Angiogenesis was evaluated by doppler (blood flow in the coeliac trunk) and by CD31 staining, and immune landscape by flow cytometry analysis. Results: Liver size and the number of liver tumor macronodules were significantly lower in all treatment arms compared to control placebo at both the W12 intermediary sacrifice and W16 final sacrifice; the combination of galunisertib and sorafenib showing potentiation effects (14.2±3.7 macronodules at W16 in the combination arm vs 28.6±6.7, 26.3±7.2, 83±17.6 in the sorafenib, galunisertib and placebo arms respectively). Angiogenesis (CD31 staining) was decreased in all treatment arms and the combination of galunisertib and sorafenib was better than sorafenib and galunisertib monotherapies, reducing both the number of vessels and the vessel lumen area. These effects on angiogenesis were confirmed by Doppler, measuring the mean blood flow in the coeliac trunk (TCm). TCm was decreased in all treatment arm compared to placebo. At W16, we observed a potentiation in the combination arm, compared to the monotherapy (a decrease of 29%, 18% and 39% of the TCm compared to placebo in the sorafenib, galunisertib and combination arms respectively). The combination treatment was significantly associated with an increased number of monocytes and a decreased number of neutrophils and Kuppfer cells. It was also associated with increased NK cells and decreased NKT cells. Dendritic cells as well as B and T cells population did not show particular modulation with the exception of CD4+CD25+ T cells that were strongly decreased in mice treated with sorafenib alone. Conclusion: The combination of galunisertib and sorafenib in animal studies showed promising anti-tumor activities that were associated with decreased angiogenesis and inflammation. Conflict of interest: Corporate-sponsored Research: Pr V. Paradis, Pr S. Faivre, Pr E. Raymond, Dr A. de Gramont, Dr A. Tijeras-Raballand. Other Substantive Relationships: Karim Benhadji is an employee of Eli Lilly, who sponsored this study.
Poster abstracts S133
associated with activity in preclinical models. There were no treatmentrelated effects on the levels of a range of exploratory biomarkers (VEGF-C, angiopoietin-2, endoglin, FGF-2, IL-6, IL-8, TNF-a, IL-10, sVEGFR2 and MMP-2). However, MP0250 reduced VEGF-A levels to undetectable for the duration of treatment. Plasma levels of total HGF increased over time, most likely as a result of MP0250 binding, since a similar increase of MP0250HGF complexes was observed. Conclusions: In a phase I study, MP0250 was found to be well tolerated and to show signs of clinical activity. MP0250 showed a favorable PK profile and sustained exposure over treatment periods. MP0250 had a strong impact on plasma levels of VEGF-A and HGF, but no other biomarkers were identified. Conflict of interest: Ownership: Dawson, Feurstein, Zitt, Fiedler, Kuster, Bez, Schreiner, Turner, Tadjalli Mehr, Stumpp, Harstrick are employees of Molecular Partners and have shares or share options in the company. Corporate-sponsored Research: Baird, Omlin, Middleton, Rodon receive funding from Molecular Partners for providing clinical services to the phase 1 trial. 407 Poster (Board P086) Galunisertib combined with sorafenib affects in vivo tumor growth and immune landscape in hepatocellular carcinoma (HCC) A. Tijeras-Raballand1 , M.A. Le Bitoux2 , A. Maillard3 , M. Albuquerque4 , N. Colnot4 , M. Barral5 , A. Dohan5 , P. Bonnin5 , M. Pocard6 , K. Benhadji7 , V. Paradis4 , E. Raymond8 , A. Harari2 , S. Faivre9 , A. De Gramont10 . 1 AFR Oncology, Preclinical and Translational Department, Paris, France; 2 Immune Monitoring Core, CHUV, Oncology Department, Lausanne, Switzerland; 3 New drugs evaluation laboratory, Center of experimental Therapeutics, CHUV, Oncology Department, Lausanne, Switzerland; 4 Insert U773, Beaujon Hospital, Pathology Department, Clichy, France; 5 Inserm U965, Lariboisiere Hospital, Vascular and Visceral Radiology Department, Paris, France; 6 Inserm U965, Lariboisiere Hospital, Gastroenterology Surgery Department, Paris, France; 7 Eli Lillly and Company, Oncology Early Phase Clinical Research, Bridgewater, USA; 8 Saint-Joseph Hospital, Medical Oncology Department, Paris, France; 9 Beaujon Hospital, Medical Oncology Department, Clichy, France; 10 AFR Oncology and New drugs Evaluation Laboratory, Center of Experimental Therapeutics, Oncology Department, Lausanne, Switzerland Introduction: The TGF-b pathway that has been associated with hepatocellular carcinoma (HCC) progression, can be targeted by galunisertib, a selective ATP-mimetic TGF-b receptor (TbR)-I inhibitor currently under clinical investigation in HCC patients. Our study aimed to investigate the anti-tumoral effects of galunisertib with or without sorafenib in a transgenic mice model of HCC. Methods: Transgenic mice developing stage-defined HCC were treated for 8 weeks (W) from W8 to W16 with either vehicle, sorafenib (30 mg/kg), galunisertib (100 mg/kg) or sorafenib plus galunisertib. Tumor growth was evaluated by ultrasound (liver size) and by the number of macronodules at sacrifice. Angiogenesis was evaluated by doppler (blood flow in the coeliac trunk) and by CD31 staining, and immune landscape by flow cytometry analysis. Results: Liver size and the number of liver tumor macronodules were significantly lower in all treatment arms compared to control placebo at both the W12 intermediary sacrifice and W16 final sacrifice; the combination of galunisertib and sorafenib showing potentiation effects (14.2±3.7 macronodules at W16 in the combination arm vs 28.6±6.7, 26.3±7.2, 83±17.6 in the sorafenib, galunisertib and placebo arms respectively). Angiogenesis (CD31 staining) was decreased in all treatment arms and the combination of galunisertib and sorafenib was better than sorafenib and galunisertib monotherapies, reducing both the number of vessels and the vessel lumen area. These effects on angiogenesis were confirmed by Doppler, measuring the mean blood flow in the coeliac trunk (TCm). TCm was decreased in all treatment arm compared to placebo. At W16, we observed a potentiation in the combination arm, compared to the monotherapy (a decrease of 29%, 18% and 39% of the TCm compared to placebo in the sorafenib, galunisertib and combination arms respectively). The combination treatment was significantly associated with an increased number of monocytes and a decreased number of neutrophils and Kuppfer cells. It was also associated with increased NK cells and decreased NKT cells. Dendritic cells as well as B and T cells population did not show particular modulation with the exception of CD4+CD25+ T cells that were strongly decreased in mice treated with sorafenib alone. Conclusion: The combination of galunisertib and sorafenib in animal studies showed promising anti-tumor activities that were associated with decreased angiogenesis and inflammation. Conflict of interest: Corporate-sponsored Research: Pr V. Paradis, Pr S. Faivre, Pr E. Raymond, Dr A. de Gramont, Dr A. Tijeras-Raballand. Other Substantive Relationships: Karim Benhadji is an employee of Eli Lilly, who sponsored this study.