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| 1. | Lahde, M; Heino, S; Hogstrom, J; Kaijalainen, S; Anisimov, A; Flanagan, D; Kallio, P; Leppanen, VM; Ristimaki, A; Ritvos, O; Wu, K; Tammela, T; Hodder, M; Sansom, OJ; Alitalo, K In: Gastroenterology, 160 (1), pp. 245–259, 2021, ISSN: 0016-5085. Abstract | Links | iCAN PI: Alitalo, Kari @article{0db55647733d47b0803df5676e91b48e, title = {Expression of R-Spondin 1 in Apc(Min/+) Mice Suppresses Growth of Intestinal Adenomas by Altering Wnt and Transforming Growth Factor Beta Signaling}, author = {Lahde, M; Heino, S; Hogstrom, J; Kaijalainen, S; Anisimov, A; Flanagan, D; Kallio, P; Leppanen, VM; Ristimaki, A; Ritvos, O; Wu, K; Tammela, T; Hodder, M; Sansom, OJ; Alitalo, K}, editor = {Alitalo, Kari}, doi = {10.1053/j.gastro.2020.09.011}, issn = {0016-5085}, year = {2021}, date = {2021-01-01}, journal = {Gastroenterology}, volume = {160}, number = {1}, pages = {245--259}, publisher = {W B SAUNDERS CO-ELSEVIER INC}, abstract = {BACKGROUND & AIMS: Mutations in the APC gene and other genes in the Wnt signaling pathway contribute to development of colorectal carcinomas. R-spondins (RSPOs) are secreted proteins that amplify Wnt signaling in intestinal stem cells. Alterations in RSPO genes have been identified in human colorectal tumors. We studied the effects of RSPO1 overexpression in ApcMin/thorn mutant mice. METHODS: An adeno associated viral vector encoding RSPO1-Fc fusion protein, or control vector, was injected into ApcMin/thornmice. Their intestinal crypts were isolated and cultured as organoids. which were incubated with or without RSPO1-Fc and an inhibitor of transforming growth factor beta receptor (TGFBR). Livers were collected from mice and analyzed by immunohistochemistry. Organoids and adenomas were analyzed by quantitative reverse-transcription PCR, single cell RNA sequencing, and immunohistochemistry. RESULTS: Intestines from Apcthorn/thorn mice injected with the vector encoding RSPO1-Fc had significantly deeper crypts, longer villi, with increased EdU labeling, indicating increased proliferation of epithelial cells, in comparison to mice given control vector. AAV-RSPO1-Fctransduced ApcMin/thorn mice also developed fewer and smaller intestinal tumors and had significantly longer survival times. Adenomas of ApcMin/thorn mice injected with the RSPO1-Fc vector showed a rapid increase in apoptosis and in the expression of Wnt target genes, followed by reduced expression of messenger RNAs and proteins regulated by the Wnt pathway, reduced cell proliferation, and less crypt branching than adenomas of mice given the control vector. Addition of RSPO1 reduced the number of adenoma organoids derived from ApcMin/thorn mice and suppressed expression of Wnt target genes but increased phosphorylation of SMAD2 and transcription of genes regulated by SMAD. Inhibition of TGFBR signaling in organoids stimulated with RSPO1-Fc restored organoid formation and expression of genes regulated by Wnt. The TGFBR inhibitor restored apoptosis in adenomas from ApcMin/thorn mice expressing RSPO1Fc back to the same level as in the adenomas from mice given the control vector. CONCLUSIONS: Expression of RSPO1 in ApcMin/thorn mice increases apoptosis and reduces proliferation and Wnt signaling in adenoma cells, resulting in development of fewer and smaller intestinal tumors and longer mouse survival. Addition of RSPO1 to organoids derived from adenomas inhibits their growth and promotes proliferation of intestinal stem cells that retain the APC protein; these effects are reversed by TGFB inhibitor. Strategies to increase the expression of RSPO1 might be developed for the treatment of intestinal adenomas.}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND & AIMS: Mutations in the APC gene and other genes in the Wnt signaling pathway contribute to development of colorectal carcinomas. R-spondins (RSPOs) are secreted proteins that amplify Wnt signaling in intestinal stem cells. Alterations in RSPO genes have been identified in human colorectal tumors. We studied the effects of RSPO1 overexpression in ApcMin/thorn mutant mice. METHODS: An adeno associated viral vector encoding RSPO1-Fc fusion protein, or control vector, was injected into ApcMin/thornmice. Their intestinal crypts were isolated and cultured as organoids. which were incubated with or without RSPO1-Fc and an inhibitor of transforming growth factor beta receptor (TGFBR). Livers were collected from mice and analyzed by immunohistochemistry. Organoids and adenomas were analyzed by quantitative reverse-transcription PCR, single cell RNA sequencing, and immunohistochemistry. RESULTS: Intestines from Apcthorn/thorn mice injected with the vector encoding RSPO1-Fc had significantly deeper crypts, longer villi, with increased EdU labeling, indicating increased proliferation of epithelial cells, in comparison to mice given control vector. AAV-RSPO1-Fctransduced ApcMin/thorn mice also developed fewer and smaller intestinal tumors and had significantly longer survival times. Adenomas of ApcMin/thorn mice injected with the RSPO1-Fc vector showed a rapid increase in apoptosis and in the expression of Wnt target genes, followed by reduced expression of messenger RNAs and proteins regulated by the Wnt pathway, reduced cell proliferation, and less crypt branching than adenomas of mice given the control vector. Addition of RSPO1 reduced the number of adenoma organoids derived from ApcMin/thorn mice and suppressed expression of Wnt target genes but increased phosphorylation of SMAD2 and transcription of genes regulated by SMAD. Inhibition of TGFBR signaling in organoids stimulated with RSPO1-Fc restored organoid formation and expression of genes regulated by Wnt. The TGFBR inhibitor restored apoptosis in adenomas from ApcMin/thorn mice expressing RSPO1Fc back to the same level as in the adenomas from mice given the control vector. CONCLUSIONS: Expression of RSPO1 in ApcMin/thorn mice increases apoptosis and reduces proliferation and Wnt signaling in adenoma cells, resulting in development of fewer and smaller intestinal tumors and longer mouse survival. Addition of RSPO1 to organoids derived from adenomas inhibits their growth and promotes proliferation of intestinal stem cells that retain the APC protein; these effects are reversed by TGFB inhibitor. Strategies to increase the expression of RSPO1 might be developed for the treatment of intestinal adenomas. |
| 2. | Feurstein, S; Churpek, JE; Walsh, T; Keel, S; Hakkarainen, M; Schroeder, T; Germing, U; Geyh, S; Heuser, M; Thol, F; Pohlkamp, C; Haferlach, T; Gao, JH; Owen, C; Goehring, G; Schlegelberger, B; Verma, D; Krause, DS; Gao, GM; Cronin, T; Gulsuner, S; Lee, M; Pritchard, CC; Subramanian, HP; del Gaudio, D; Li, ZJ; Das, S; Kilpivaara, O; Wartiovaara-Kautto, U; Wang, EIS; Griffiths, EA; Dohner, K; Dohner, H; King, MC; Godley, LA Germline variants drive myelodysplastic syndrome in young adults Journal Article In: Leukemia, 2021, ISSN: 0887-6924. Links | iCAN PI: Kilpivaara, Outi @article{82abc0ae11304a5d8f3640fcaeba76b2, title = {Germline variants drive myelodysplastic syndrome in young adults}, author = {Feurstein, S; Churpek, JE; Walsh, T; Keel, S; Hakkarainen, M; Schroeder, T; Germing, U; Geyh, S; Heuser, M; Thol, F; Pohlkamp, C; Haferlach, T; Gao, JH; Owen, C; Goehring, G; Schlegelberger, B; Verma, D; Krause, DS; Gao, GM; Cronin, T; Gulsuner, S; Lee, M; Pritchard, CC; Subramanian, HP; del Gaudio, D; Li, ZJ; Das, S; Kilpivaara, O; Wartiovaara-Kautto, U; Wang, EIS; Griffiths, EA; Dohner, K; Dohner, H; King, MC; Godley, LA}, editor = {Kilpivaara, Outi}, doi = {10.1038/s41375-021-01137-0}, issn = {0887-6924}, year = {2021}, date = {2021-01-01}, journal = {Leukemia}, publisher = {Nature Publishing Group}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
| 3. | Ianevski, A; Lahtela, J; Javarappa, KK; Sergeev, P; Ghimire, BR; Gautam, P; Vaha-Koskela, M; Turunen, L; Linnavirta, N; Kuusanmaki, H; Kontro, M; Porkka, K; Heckman, CA; Mattila, P; Wennerberg, K; Giri, AK; Aittokallio, T Patient-tailored design for selective co-inhibition of leukemic cell subpopulations Journal Article In: Science Advances, 7 (8), 2021, ISSN: 2375-2548. Links | iCAN PI: Aittokallio, Tero @article{110fda106946406abd71f4caff020446, title = {Patient-tailored design for selective co-inhibition of leukemic cell subpopulations}, author = {Ianevski, A; Lahtela, J; Javarappa, KK; Sergeev, P; Ghimire, BR; Gautam, P; Vaha-Koskela, M; Turunen, L; Linnavirta, N; Kuusanmaki, H; Kontro, M; Porkka, K; Heckman, CA; Mattila, P; Wennerberg, K; Giri, AK; Aittokallio, T}, editor = {Aittokallio, Tero}, doi = {10.1126/sciadv.abe4038}, issn = {2375-2548}, year = {2021}, date = {2021-01-01}, journal = {Science Advances}, volume = {7}, number = {8}, publisher = {American Association for the Advancement of Science (AAAS)}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
| 4. | Dustin J. Flanagan, Nalle Pentinmikko, Kalle Luopajärvi, Nicky J. Willis, Kathryn Gilroy, Alexander P. Raven, Lynn Mcgarry, Johanna I. Englund, Anna T. Webb, Sandra Scharaw, Nadia Nasreddin, Michael C. Hodder, Rachel A. Ridgway, Emma Minnee, Nathalie Sphyris, Ella Gilchrist, Arafath K. Najumudeen, Beatrice Romagnolo, Christine Perret, Ann C. Williams, Hans Clevers, Pirjo Nummela, Marianne Lähde, Kari Alitalo, Ville Hietakangas, Ann Hedley, William Clark, Colin Nixon, Kristina Kirschner, E. Yvonne Jones, Ari Ristimäki, Simon J. Leedham, Paul V. Fish, Jean-Paul Vincent, Pekka Katajisto & Owen J. NOTUM from Apc-mutant cells biases clonal competition to initiate cancer Journal Article In: Nature, 594 (7863), pp. 430–+, 2021, ISSN: 0028-0836. Links | iCAN PI: Katajisto, Pekka @article{0d60f233972d476cb6db817ae967b4bb, title = {NOTUM from Apc-mutant cells biases clonal competition to initiate cancer}, author = {Dustin J. Flanagan, Nalle Pentinmikko, Kalle Luopajärvi, Nicky J. Willis, Kathryn Gilroy, Alexander P. Raven, Lynn Mcgarry, Johanna I. Englund, Anna T. Webb, Sandra Scharaw, Nadia Nasreddin, Michael C. Hodder, Rachel A. Ridgway, Emma Minnee, Nathalie Sphyris, Ella Gilchrist, Arafath K. Najumudeen, Beatrice Romagnolo, Christine Perret, Ann C. Williams, Hans Clevers, Pirjo Nummela, Marianne Lähde, Kari Alitalo, Ville Hietakangas, Ann Hedley, William Clark, Colin Nixon, Kristina Kirschner, E. Yvonne Jones, Ari Ristimäki, Simon J. Leedham, Paul V. Fish, Jean-Paul Vincent, Pekka Katajisto & Owen J. }, editor = {Katajisto, Pekka}, doi = {10.1038/s41586-021-03525-z}, issn = {0028-0836}, year = {2021}, date = {2021-01-01}, journal = {Nature}, volume = {594}, number = {7863}, pages = {430--+}, publisher = {Nature Publishing Group}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
| 5. | Autio, M; Leivonen, SK; Bruck, O; Mustjoki, S; Jorgensen, JM; Karjalainen-Lindsberg, ML; Beiske, K; Holte, H; Pellinen, T; Leppa, S Immune cell constitution in the tumor microenvironment predicts the outcome in diffuse large B-cell lymphoma Journal Article In: Haematologica, 106 (3), pp. 718–729, 2021, ISSN: 0390-6078. @article{6f8b0913bbf24fa79139653fc146826e, title = {Immune cell constitution in the tumor microenvironment predicts the outcome in diffuse large B-cell lymphoma}, author = {Autio, M; Leivonen, SK; Bruck, O; Mustjoki, S; Jorgensen, JM; Karjalainen-Lindsberg, ML; Beiske, K; Holte, H; Pellinen, T; Leppa, S}, editor = {Leppä, Sirpa}, doi = {10.3324/haematol.2019.243626}, issn = {0390-6078}, year = {2021}, date = {2021-01-01}, journal = {Haematologica}, volume = {106}, number = {3}, pages = {718--729}, publisher = {FERRATA STORTI FOUNDATION}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
| 6. | Stenman, S; Bychkov, D; Kucukel, H; Linder, N; Haglund, C; Arola, J; Lundin, J Antibody Supervised Training of a Deep Learning Based Algorithm for Leukocyte Segmentation in Papillary Thyroid Carcinoma Journal Article In: IEEE Journal of Biomedical and Health Informatics, 25 (2), pp. 422 – 428, 2021, ISSN: 2168-2194. Links | iCAN PI: Lundin, Johan @article{0a412396319d43369d2af532d2e247c9, title = {Antibody Supervised Training of a Deep Learning Based Algorithm for Leukocyte Segmentation in Papillary Thyroid Carcinoma}, author = {Stenman, S; Bychkov, D; Kucukel, H; Linder, N; Haglund, C; Arola, J; Lundin, J}, editor = {Lundin, Johan}, doi = {10.1109/JBHI.2020.2994970}, issn = {2168-2194}, year = {2021}, date = {2021-01-01}, journal = {IEEE Journal of Biomedical and Health Informatics}, volume = {25}, number = {2}, pages = {422 -- 428}, publisher = {IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
| 7. | Satu Mustjoki, M.D., and Neal S. Young, M.D. Somatic Mutations in “Benign” Disease Journal Article In: NEJM, in press , 2021. @article{Mustjoki2021, title = {Somatic Mutations in “Benign” Disease}, author = {Satu Mustjoki, M.D., and Neal S. Young, M.D. }, editor = {Mustjoki}, url = {https://www.nejm.org/doi/full/10.1056/NEJMra2101920?query=featured_home}, year = {2021}, date = {2021-05-27}, journal = {NEJM, in press }, keywords = {}, pubstate = {published}, tppubtype = {article} } |
| 8. | Mikaela Grönholm, Michaela Feodoroff, Gabriella Antignani, Beatriz Martins, Firas Hamdan, Vincenzo Cerullo Patient-Derived Organoids for Precision Cancer Immunotherapy Journal Article In: Cancer Research, 81 (12), pp. 3149–3155, 2021, ISSN: 0008-5472. Links | iCAN PI: Cerullo, Vincenzo @article{c4c6d8c4c1a348b69caaad6110a62f98, title = {Patient-Derived Organoids for Precision Cancer Immunotherapy}, author = {Mikaela Grönholm, Michaela Feodoroff, Gabriella Antignani, Beatriz Martins, Firas Hamdan, Vincenzo Cerullo}, editor = {Cerullo, Vincenzo}, doi = {10.1158/0008-5472.CAN-20-4026}, issn = {0008-5472}, year = {2021}, date = {2021-01-01}, journal = {Cancer Research}, volume = {81}, number = {12}, pages = {3149--3155}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
| 9. | Zhou J, Gelot C, Pantelidou C, Li A, Yücel A, E. Davis RE, Färkkilä A, Kochupurakkal B, Aleem Syed, Shapiro GI, Tainer JA, Blagg BSJ, Ceccaldi R, and D’Andrea AD A first-in-class polymerase theta inhibitor selectively targets homologous-recombination-deficient tumors Journal Article In: Nature Cancer, 2 (6), pp. 598–610, 2021. Links | iCAN PI: Färkkilä, Anniiina @article{Zhou2021, title = {A first-in-class polymerase theta inhibitor selectively targets homologous-recombination-deficient tumors}, author = {Zhou J, Gelot C, Pantelidou C, Li A, Yücel A, E. Davis RE, Färkkilä A, Kochupurakkal B, Aleem Syed, Shapiro GI, Tainer JA, Blagg BSJ, Ceccaldi R, and D’Andrea AD}, editor = {Färkkilä, Anniiina}, url = {https://doi.org/10.1038/s43018-021-00203-x}, doi = {10.1038/s43018-021-00203-x}, year = {2021}, date = {2021-01-01}, journal = {Nature Cancer}, volume = {2}, number = {6}, pages = {598--610}, publisher = {Springer Science and Business Media LLC}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
| 10. | Oikkonen, J; Zhang, KY; Salminen, L; Schulman, I; Lavikka, K; Andersson, N; Ojanpera, E; Hietanen, S; Grenman, S; Lehtonen, R; Huhtinen, K; Carpen, O; Hynninen, J; Farkkila, A; Hautaniemi, S Prospective Longitudinal ctDNA Workflow Reveals Clinically Actionable Alterations in Ovarian Cancer Journal Article In: JCO Precision Oncology, 3 (3), pp. 1–12, 2019, ISSN: 2473-4284. Links | iCAN PI: Hautaniemi, Sampsa @article{76c3a171f4cb400bae3a6b744e7b3667, title = {Prospective Longitudinal ctDNA Workflow Reveals Clinically Actionable Alterations in Ovarian Cancer}, author = {Oikkonen, J; Zhang, KY; Salminen, L; Schulman, I; Lavikka, K; Andersson, N; Ojanpera, E; Hietanen, S; Grenman, S; Lehtonen, R; Huhtinen, K; Carpen, O; Hynninen, J; Farkkila, A; Hautaniemi, S}, editor = {Hautaniemi, Sampsa}, doi = {10.1200/PO.18.00343}, issn = {2473-4284}, year = {2019}, date = {2019-01-01}, journal = {JCO Precision Oncology}, volume = {3}, number = {3}, pages = {1--12}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
| 11. | Haikala, HM; Anttila, JM; Marques, E; Raatikainen, T; Ilander, M; Hakanen, H; Ala-Hongisto, H; Savelius, M; Balboa, D; Von Eyss, B; Eskelinen, V; Munne, P; Nieminen, AI; Otonkoski, T; Schuler, J; Laajala, TD; Aittokallio, T; Sihto, H; Mattson, J; Heikkila, P; Leidenius, M; Joensuu, H; Mustjoki, S; Kovanen, P; Eilers, M; Leverson, JD; Klefstrom, J Pharmacological reactivation of MYC-dependent apoptosis induces susceptibility to anti-PD-1 immunotherapy Journal Article In: Nature Communications, 10 , 2019, ISSN: 2041-1723. Links | iCAN PI: Klefstrom, Juha @article{8a475917513b45d5bcfdf32c4654305d, title = {Pharmacological reactivation of MYC-dependent apoptosis induces susceptibility to anti-PD-1 immunotherapy}, author = {Haikala, HM; Anttila, JM; Marques, E; Raatikainen, T; Ilander, M; Hakanen, H; Ala-Hongisto, H; Savelius, M; Balboa, D; Von Eyss, B; Eskelinen, V; Munne, P; Nieminen, AI; Otonkoski, T; Schuler, J; Laajala, TD; Aittokallio, T; Sihto, H; Mattson, J; Heikkila, P; Leidenius, M; Joensuu, H; Mustjoki, S; Kovanen, P; Eilers, M; Leverson, JD; Klefstrom, J}, editor = {Klefstrom, Juha}, doi = {10.1038/s41467-019-08541-2}, issn = {2041-1723}, year = {2019}, date = {2019-01-01}, journal = {Nature Communications}, volume = {10}, publisher = {Nature Publishing Group}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
| 12. | Konstantinopoulos, PA; Waggoner, S; Vidal, GA; Mita, M; Moroney, JW; Holloway, R; Van Le, L; Sachdev, JC; Chapman-Davis, E; Colon-Otero, G; Penson, RT; Matulonis, UA; Kim, YB; Moore, KN; Swisher, EM; Farkkila, A; D'Andrea, A; Stringer-Reasor, E; Wang, J; Buerstatte, N; Arora, S; Graham, JR; Bobilev, D; Dezube, BJ; Munster, P Single-Arm Phases 1 and 2 Trial of Niraparib in Combination With Pembrolizumab in Patients With Recurrent Platinum-Resistant Ovarian Carcinoma Journal Article In: JAMA Oncology, 5 (8), pp. 1141-1149, 2019, ISSN: 2374-2437. Abstract | Links | iCAN PI: Färkkilä, Anniiina @article{10.1001/jamaoncol.2019.1048, title = {Single-Arm Phases 1 and 2 Trial of Niraparib in Combination With Pembrolizumab in Patients With Recurrent Platinum-Resistant Ovarian Carcinoma}, author = {Konstantinopoulos, PA; Waggoner, S; Vidal, GA; Mita, M; Moroney, JW; Holloway, R; Van Le, L; Sachdev, JC; Chapman-Davis, E; Colon-Otero, G; Penson, RT; Matulonis, UA; Kim, YB; Moore, KN; Swisher, EM; Farkkila, A; D'Andrea, A; Stringer-Reasor, E; Wang, J; Buerstatte, N; Arora, S; Graham, JR; Bobilev, D; Dezube, BJ; Munster, P}, editor = {Färkkilä, Anniiina}, url = {https://doi.org/10.1001/jamaoncol.2019.1048}, doi = {10.1001/jamaoncol.2019.1048}, issn = {2374-2437}, year = {2019}, date = {2019-01-01}, journal = {JAMA Oncology}, volume = {5}, number = {8}, pages = {1141-1149}, abstract = {Patients with recurrent ovarian carcinoma frequently develop resistance to platinum-based chemotherapy, at which time treatment options become limited.To evaluate the poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitor niraparib combined with pembrolizumab in patients with recurrent ovarian carcinoma.The TOPACIO/KEYNOTE-162 (Niraparib in Combination With Pembrolizumab in Patients With Triple-Negative Breast Cancer or Ovarian Cancer) trial, an open-label, single-arm phases 1 and 2 study enrolled women with advanced or metastatic triple-negative breast cancer (TNBC) or recurrent ovarian carcinoma, irrespective of BRCA mutation status. Median follow-up was 12.4 months (range, 1.2 to ≥23.0 months). Data were collected from April 15, 2016, through September 4, 2018, with September 4, 2018, as a data cutoff, and analyzed from September 4, 2018, through January 30, 2019.The recommended phase 2 dose (RP2D) was 200 mg of oral niraparib once daily and 200 mg of intravenous pembrolizumab on day 1 of each 21-day cycle.The primary objectives of phase 1 were to evaluate dose-limiting toxic effects and establish the RP2D and dosing schedule. The primary objective of phase 2 was to assess objective response rate (ORR; complete plus partial responses). Results from the phase 1 ovarian carcinoma and TNBC cohorts and phase 2 ovarian carcinoma cohort are reported. Because of the similarity in the phase 1 and 2 ovarian carcinoma populations, the data were pooled to perform an integrated efficacy analysis.Fourteen patients (9 with ovarian carcinoma and 5 with TNBC) in phase 1 and 53 patients with ovarian carcinoma in phase 2 were enrolled, for a pooled ovarian carcinoma cohort of 62 patients (median age, 60 years [range, 46-83 years]). In the integrated efficacy phases 1 and 2 ovarian carcinoma population (60 of 62 evaluable patients), ORR was 18% (90% CI, 11%-29%), with a disease control rate of 65% (90% CI, 54%-75%), including 3 (5%) with confirmed complete responses, 8 (13%) with confirmed partial responses, 28 (47%) with stable disease, and 20 (33%) with progressive disease. The ORRs were consistent across subgroups based on platinum-based chemotherapy sensitivity, previous bevacizumab treatment, or tumor BRCA or homologous recombination deficiency (HRD) biomarker status. Median duration of response was not reached (range, 4.2 to ≥14.5 months). At data cutoff, 2 patients with a response and 1 patient with stable disease continued to receive treatment.Niraparib in combination with pembrolizumab is tolerable, with promising antitumor activity for patients with ovarian carcinoma who have limited treatment options regardless of platinum status, biomarker status, or prior treatment with bevacizumab. Responses in patients without tumor BRCA mutations or non-HRD cancers were higher than expected with either agent as monotherapy.ClinicalTrials.gov identifier: NCT02657889}, keywords = {}, pubstate = {published}, tppubtype = {article} } Patients with recurrent ovarian carcinoma frequently develop resistance to platinum-based chemotherapy, at which time treatment options become limited.To evaluate the poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitor niraparib combined with pembrolizumab in patients with recurrent ovarian carcinoma.The TOPACIO/KEYNOTE-162 (Niraparib in Combination With Pembrolizumab in Patients With Triple-Negative Breast Cancer or Ovarian Cancer) trial, an open-label, single-arm phases 1 and 2 study enrolled women with advanced or metastatic triple-negative breast cancer (TNBC) or recurrent ovarian carcinoma, irrespective of BRCA mutation status. Median follow-up was 12.4 months (range, 1.2 to ≥23.0 months). Data were collected from April 15, 2016, through September 4, 2018, with September 4, 2018, as a data cutoff, and analyzed from September 4, 2018, through January 30, 2019.The recommended phase 2 dose (RP2D) was 200 mg of oral niraparib once daily and 200 mg of intravenous pembrolizumab on day 1 of each 21-day cycle.The primary objectives of phase 1 were to evaluate dose-limiting toxic effects and establish the RP2D and dosing schedule. The primary objective of phase 2 was to assess objective response rate (ORR; complete plus partial responses). Results from the phase 1 ovarian carcinoma and TNBC cohorts and phase 2 ovarian carcinoma cohort are reported. Because of the similarity in the phase 1 and 2 ovarian carcinoma populations, the data were pooled to perform an integrated efficacy analysis.Fourteen patients (9 with ovarian carcinoma and 5 with TNBC) in phase 1 and 53 patients with ovarian carcinoma in phase 2 were enrolled, for a pooled ovarian carcinoma cohort of 62 patients (median age, 60 years [range, 46-83 years]). In the integrated efficacy phases 1 and 2 ovarian carcinoma population (60 of 62 evaluable patients), ORR was 18% (90% CI, 11%-29%), with a disease control rate of 65% (90% CI, 54%-75%), including 3 (5%) with confirmed complete responses, 8 (13%) with confirmed partial responses, 28 (47%) with stable disease, and 20 (33%) with progressive disease. The ORRs were consistent across subgroups based on platinum-based chemotherapy sensitivity, previous bevacizumab treatment, or tumor BRCA or homologous recombination deficiency (HRD) biomarker status. Median duration of response was not reached (range, 4.2 to ≥14.5 months). At data cutoff, 2 patients with a response and 1 patient with stable disease continued to receive treatment.Niraparib in combination with pembrolizumab is tolerable, with promising antitumor activity for patients with ovarian carcinoma who have limited treatment options regardless of platinum status, biomarker status, or prior treatment with bevacizumab. Responses in patients without tumor BRCA mutations or non-HRD cancers were higher than expected with either agent as monotherapy.ClinicalTrials.gov identifier: NCT02657889 |
| 13. | Pentinmikko, N; Iqbal, S; Mana, M; Andersson, S; Cognetta, AB; Suciu, RM; Roper, J; Luopajarvi, K; Markelin, E; Gopalakrishnan, S; Smolander, OP; Naranjo, S; Saarinen, T; Juuti, A; Pietilainen, K; Auvinen, P; Ristimaki, A; Gupta, N; Tammela, T; Jacks, T; Sabatini, DM; Cravatt, BF; Yilmaz, OH; Katajisto, P Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium Journal Article In: Nature, 571 (7765), pp. 398–+, 2019, ISSN: 0028-0836. Links | iCAN PI: Katajisto, Pekka @article{e1104302b1a04e4580816fe665c92659, title = {Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium}, author = {Pentinmikko, N; Iqbal, S; Mana, M; Andersson, S; Cognetta, AB; Suciu, RM; Roper, J; Luopajarvi, K; Markelin, E; Gopalakrishnan, S; Smolander, OP; Naranjo, S; Saarinen, T; Juuti, A; Pietilainen, K; Auvinen, P; Ristimaki, A; Gupta, N; Tammela, T; Jacks, T; Sabatini, DM; Cravatt, BF; Yilmaz, OH; Katajisto, P}, editor = {Katajisto, Pekka}, doi = {10.1038/s41586-019-1383-0}, issn = {0028-0836}, year = {2019}, date = {2019-01-01}, journal = {Nature}, volume = {571}, number = {7765}, pages = {398--+}, publisher = {Nature Publishing Group}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
| 14. | Fusciello, M; Fontana, F; Tahtinen, S; Capasso, C; Feola, S; Martins, B; Chiaro, J; Peltonen, K; Ylosmaki, L; Ylosmaki, E; Hamdan, F; Kari, OK; Ndika, J; Alenius, H; Urtti, A; Hirvonen, JT; Santos, HA; Cerullo, V Artificially cloaked viral nanovaccine for cancer immunotherapy Journal Article In: Nature Communications, 10 , 2019, ISSN: 2041-1723. Abstract | Links | iCAN PI: Cerullo, Vincenzo @article{a47d935604ba48d3bc82680520378026, title = {Artificially cloaked viral nanovaccine for cancer immunotherapy}, author = {Fusciello, M; Fontana, F; Tahtinen, S; Capasso, C; Feola, S; Martins, B; Chiaro, J; Peltonen, K; Ylosmaki, L; Ylosmaki, E; Hamdan, F; Kari, OK; Ndika, J; Alenius, H; Urtti, A; Hirvonen, JT; Santos, HA; Cerullo, V}, editor = {Cerullo, Vincenzo}, doi = {10.1038/s41467-019-13744-8}, issn = {2041-1723}, year = {2019}, date = {2019-01-01}, journal = {Nature Communications}, volume = {10}, publisher = {Nature Publishing Group}, abstract = {Virus-based cancer vaccines are nowadays considered an interesting approach in the field of cancer immunotherapy, despite the observation that the majority of the immune responses they elicit are against the virus and not against the tumor. In contrast, targeting tumor associated antigens is effective, however the identification of these antigens remains challenging. Here, we describe ExtraCRAd, a multi-vaccination strategy focused on an oncolytic virus artificially wrapped with tumor cancer membranes carrying tumor antigens. We demonstrate that ExtraCRAd displays increased infectivity and oncolytic effect in vitro and in vivo. We show that this nanoparticle platform controls the growth of aggressive melanoma and lung tumors in vivo both in preventive and therapeutic setting, creating a highly specific anti-cancer immune response. In conclusion, ExtraCRAd might serve as the next generation of personalized cancer vaccines with enhanced features over standard vaccination regimens, representing an alternative way to target cancer.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Virus-based cancer vaccines are nowadays considered an interesting approach in the field of cancer immunotherapy, despite the observation that the majority of the immune responses they elicit are against the virus and not against the tumor. In contrast, targeting tumor associated antigens is effective, however the identification of these antigens remains challenging. Here, we describe ExtraCRAd, a multi-vaccination strategy focused on an oncolytic virus artificially wrapped with tumor cancer membranes carrying tumor antigens. We demonstrate that ExtraCRAd displays increased infectivity and oncolytic effect in vitro and in vivo. We show that this nanoparticle platform controls the growth of aggressive melanoma and lung tumors in vivo both in preventive and therapeutic setting, creating a highly specific anti-cancer immune response. In conclusion, ExtraCRAd might serve as the next generation of personalized cancer vaccines with enhanced features over standard vaccination regimens, representing an alternative way to target cancer. |
| 15. | Song, E; Mao, TY; Dong, HP; Boisserand, LSB; Antila, S; Bosenberg, M; Alitalo, K; Thomas, JL; Iwasaki, A VEGF-C-driven lymphatic drainage enables immunosurveillance of brain tumours Journal Article In: Nature, 577 (7792), pp. 629–630, 2020, ISSN: 0028-0836. Links | iCAN PI: Alitalo, Kari @article{c24592c65fb04d64a702c52e4025a5d7, title = {VEGF-C-driven lymphatic drainage enables immunosurveillance of brain tumours}, author = {Song, E; Mao, TY; Dong, HP; Boisserand, LSB; Antila, S; Bosenberg, M; Alitalo, K; Thomas, JL; Iwasaki, A}, editor = {Alitalo, Kari}, doi = {10.1038/s41586-019-1912-x}, issn = {0028-0836}, year = {2020}, date = {2020-01-01}, journal = {Nature}, volume = {577}, number = {7792}, pages = {629--630}, publisher = {Nature Publishing Group}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
| 16. | Dufva O, Koski J, Maliniemi P, Ianevski A, Klievink J, Leitner J, Polonen P, Hohtari H, Saeed K, Hannunen T, Ellonen P, Steinberger P, Kankainen M, Aittokallio T, Keranen MAI, Korhonen M, Mustjoki S. Integrated drug profiling and CRISPR screening identify essential pathways for CAR T-cell cytotoxicity Journal Article In: Blood, 135 (9), pp. 597–609, 2020, ISSN: 0006-4971. Links | iCAN PI: Mustjoki, Satu @article{11ac593d06bb4167b203a5f5caef0205, title = {Integrated drug profiling and CRISPR screening identify essential pathways for CAR T-cell cytotoxicity}, author = {Dufva O, Koski J, Maliniemi P, Ianevski A, Klievink J, Leitner J, Polonen P, Hohtari H, Saeed K, Hannunen T, Ellonen P, Steinberger P, Kankainen M, Aittokallio T, Keranen MAI, Korhonen M, Mustjoki S. }, editor = {Mustjoki, Satu}, doi = {10.1182/blood.2019002121}, issn = {0006-4971}, year = {2020}, date = {2020-01-01}, journal = {Blood}, volume = {135}, number = {9}, pages = {597--609}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
| 17. | Kuusanmaki, H; Leppa, AM; Polonen, P; Kontro, M; Dufva, O; Deb, D; Yadav, B; Bruck, O; Kumar, A; Everaus, H; Gjertsen, BT; Heinaniemi, M; Porkka, K; Mustjoki, S; Heckman, CA Phenotype-based drug screening reveals association between venetoclax response and differentiation stage in acute myeloid leukemia Journal Article In: Haematologica, 105 (3), pp. 708–720, 2020, ISSN: 0390-6078. Abstract | Links | iCAN PI: Heckman, Caroline A. @article{0f37bf2f1d96467abe481fda0d2de22c, title = {Phenotype-based drug screening reveals association between venetoclax response and differentiation stage in acute myeloid leukemia}, author = {Kuusanmaki, H; Leppa, AM; Polonen, P; Kontro, M; Dufva, O; Deb, D; Yadav, B; Bruck, O; Kumar, A; Everaus, H; Gjertsen, BT; Heinaniemi, M; Porkka, K; Mustjoki, S; Heckman, CA}, editor = {Heckman, Caroline A.}, doi = {10.3324/haematol.2018.214882}, issn = {0390-6078}, year = {2020}, date = {2020-01-01}, journal = {Haematologica}, volume = {105}, number = {3}, pages = {708--720}, publisher = {FERRATA STORTI FOUNDATION}, abstract = {Ex vivo drug testing is a promising approach to identify novel treatment strategies for acute myeloid leukemia (AML). However, accurate blast- specific drug responses cannot be measured with homogeneous "add-mix-measure" cell viability assays. In this study, we implemented a flow cytometry-based approach to simultaneously evaluate the ex vivo sensitivity of different cell populations in 34 primary AML samples to seven drugs and 27 rational drug combinations. Our data demonstrate that different cell populations present in AML samples have distinct sensitivity to targeted therapies. Particularly, blast cells of FAB M0/1 AML showed high sensitivity to venetoclax. In contrast, differentiated monocytic cells abundantly present in M4/5 subtypes showed resistance to Bcl-2 inhibition, whereas immature blasts in the same samples were sensitive, highlighting the importance of blast-specific readouts. Accordingly, in the total mononuclear cell fraction the highest BCL2/MCL1 gene expression ratio was observed in M0/1 and the lowest in M4/5 AML. Of the seven tested drugs, venetoclax had the highest blast-specific toxicity, and combining venetoclax with either MEK inhibitor trametinib or JAK inhibitor ruxolitinib effectively targeted all venetoclax-resistant blasts. In conclusion, we show that ex vivo efficacy of targeted agents and particularly Bcl-2 inhibitor venetoclax is influenced by the cell type, and accurate blast-specific drug responses can be assessed with a flow cytometry-based approach.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Ex vivo drug testing is a promising approach to identify novel treatment strategies for acute myeloid leukemia (AML). However, accurate blast- specific drug responses cannot be measured with homogeneous "add-mix-measure" cell viability assays. In this study, we implemented a flow cytometry-based approach to simultaneously evaluate the ex vivo sensitivity of different cell populations in 34 primary AML samples to seven drugs and 27 rational drug combinations. Our data demonstrate that different cell populations present in AML samples have distinct sensitivity to targeted therapies. Particularly, blast cells of FAB M0/1 AML showed high sensitivity to venetoclax. In contrast, differentiated monocytic cells abundantly present in M4/5 subtypes showed resistance to Bcl-2 inhibition, whereas immature blasts in the same samples were sensitive, highlighting the importance of blast-specific readouts. Accordingly, in the total mononuclear cell fraction the highest BCL2/MCL1 gene expression ratio was observed in M0/1 and the lowest in M4/5 AML. Of the seven tested drugs, venetoclax had the highest blast-specific toxicity, and combining venetoclax with either MEK inhibitor trametinib or JAK inhibitor ruxolitinib effectively targeted all venetoclax-resistant blasts. In conclusion, we show that ex vivo efficacy of targeted agents and particularly Bcl-2 inhibitor venetoclax is influenced by the cell type, and accurate blast-specific drug responses can be assessed with a flow cytometry-based approach. |
| 18. | Farkkila, A; Gulhan, DC; Casado, J; Jacobson, CA; Nguyen, H; Kochupurakkal, B; Maliga, Z; Yapp, C; Chen, YA; Schapiro, D; Zhou, YH; Graham, JR; Dezube, BJ; Munster, P; Santagata, S; Garcia, E; Rodig, S; Lako, A; Chowdhury, D; Shapiro, GI; Matulonis, UA; Park, PJ; Hautaniemi, S; Sorger, PK; Swisher, EM; D'Andrea, AD; Konstantinopoulos , PA Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer Journal Article In: Nature Communications, 11 (1), 2020. Links | iCAN PI: Färkkilä, Anniiina @article{Frkkil2020, title = {Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer}, author = {Farkkila, A; Gulhan, DC; Casado, J; Jacobson, CA; Nguyen, H; Kochupurakkal, B; Maliga, Z; Yapp, C; Chen, YA; Schapiro, D; Zhou, YH; Graham, JR; Dezube, BJ; Munster, P; Santagata, S; Garcia, E; Rodig, S; Lako, A; Chowdhury, D; Shapiro, GI; Matulonis, UA; Park, PJ; Hautaniemi, S; Sorger, PK; Swisher, EM; D'Andrea, AD; Konstantinopoulos , PA}, editor = {Färkkilä, Anniiina}, doi = {10.1038/s41467-020-15315-8}, year = {2020}, date = {2020-01-01}, journal = {Nature Communications}, volume = {11}, number = {1}, publisher = {Springer Science and Business Media LLC}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
| 19. | Gao, YJ; Yan, Y; Tripathi, S; Pentinmikko, N; Amaral, A; Paivinen, P; Domenech-Moreno, E; Andersson, S; Wong, IPL; Clevers, H; Katajisto, P; Makela, TP LKB1 Represses ATOH1 via PDK4 and Energy Metabolism and Regulates Intestinal Stem Cell Fate Journal Article In: Gastroenterology, 158 (5), pp. 1389–+, 2020, ISSN: 0016-5085. Abstract | Links | iCAN PI: Makela, Tomi @article{6397cb8b55254f7dab3e41cdfe5b0e9a, title = {LKB1 Represses ATOH1 via PDK4 and Energy Metabolism and Regulates Intestinal Stem Cell Fate}, author = {Gao, YJ; Yan, Y; Tripathi, S; Pentinmikko, N; Amaral, A; Paivinen, P; Domenech-Moreno, E; Andersson, S; Wong, IPL; Clevers, H; Katajisto, P; Makela, TP}, editor = {Makela, Tomi}, doi = {10.1053/j.gastro.2019.12.033}, issn = {0016-5085}, year = {2020}, date = {2020-01-01}, journal = {Gastroenterology}, volume = {158}, number = {5}, pages = {1389--+}, publisher = {W B SAUNDERS CO-ELSEVIER INC}, abstract = {BACKGROUND & AIMS: In addition to the Notch and Wnt signaling pathways, energy metabolism also regulates intestinal stem cell (ISC) function. Tumor suppressor and kinase STK11 (also called LKB1) regulates stem cells and cell metabolism. We investigated whether loss of LKB1 alters ISC homeostasis in mice. METHODS: We deleted LKB1 from ISCs in mice using Lgr5-regulated CRE-ERT2 (Lkb1(Lgr5-KO) mice) and the traced lineages by using a CRE-dependent TdTomato reporter. Intestinal tissues were collected and analyzed by immunohistochemical and immunofluorescence analyses. We purified ISCs and intestinal progenitors using flow cytometry and performed RNA-sequencing analysis. We measured organoid-forming capacity and ISC percentages using intestinal tissues from Lkb1(Lgr5-KO) mice. We analyzed human Ls174t cells with knockdown of LKB1 or other proteins by immunoblotting, real-time quantitative polymerase chain reaction, and the Seahorse live-cell metabolic assay. RESULTS: Some intestinal crypts from Lkb1(Lgr5-KO) mice lost ISCs compared with crypts from control mice. However, most crypts from Lkb1(Lgr5-KO) mice contained functional ISCs that expressed increased levels of Atoh1 messenger RNA (mRNA), acquired a gene expression signature associated with secretory cells, and generated more cells in the secretory lineage compared with control mice. Knockdown of LKB1 in Ls174t cells induced expression of Atoh1 mRNA and a phenotype of increased mucin production; knockdown of ATOH1 prevented induction of this phenotype. The increased expression of Atoh1 mRNA after LKB1 loss from ISCs or Ls174t cells did not involve Notch or Wnt signaling. Knockdown of pyruvate dehydrogenase kinase 4 (PDK4) or inhibition with dichloroacetate reduced the up-regulation of Atoh1 mRNA after LKB1 knockdown in Ls174t cells. Cells with LKB1 knockdown had a reduced rate of oxygen consumption, which was partially restored by PDK4 inhibition with dichloroacetate. ISCs with knockout of LKB1 increased the expression of PDK4 and had an altered metabolic profile. CONCLUSIONS: LKB1 represses transcription of ATOH1, via PDK4, in ISCs, restricting their differentiation into secretory lineages. These findings provide a connection between metabolism and the fate determination of ISCs.}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND & AIMS: In addition to the Notch and Wnt signaling pathways, energy metabolism also regulates intestinal stem cell (ISC) function. Tumor suppressor and kinase STK11 (also called LKB1) regulates stem cells and cell metabolism. We investigated whether loss of LKB1 alters ISC homeostasis in mice. METHODS: We deleted LKB1 from ISCs in mice using Lgr5-regulated CRE-ERT2 (Lkb1(Lgr5-KO) mice) and the traced lineages by using a CRE-dependent TdTomato reporter. Intestinal tissues were collected and analyzed by immunohistochemical and immunofluorescence analyses. We purified ISCs and intestinal progenitors using flow cytometry and performed RNA-sequencing analysis. We measured organoid-forming capacity and ISC percentages using intestinal tissues from Lkb1(Lgr5-KO) mice. We analyzed human Ls174t cells with knockdown of LKB1 or other proteins by immunoblotting, real-time quantitative polymerase chain reaction, and the Seahorse live-cell metabolic assay. RESULTS: Some intestinal crypts from Lkb1(Lgr5-KO) mice lost ISCs compared with crypts from control mice. However, most crypts from Lkb1(Lgr5-KO) mice contained functional ISCs that expressed increased levels of Atoh1 messenger RNA (mRNA), acquired a gene expression signature associated with secretory cells, and generated more cells in the secretory lineage compared with control mice. Knockdown of LKB1 in Ls174t cells induced expression of Atoh1 mRNA and a phenotype of increased mucin production; knockdown of ATOH1 prevented induction of this phenotype. The increased expression of Atoh1 mRNA after LKB1 loss from ISCs or Ls174t cells did not involve Notch or Wnt signaling. Knockdown of pyruvate dehydrogenase kinase 4 (PDK4) or inhibition with dichloroacetate reduced the up-regulation of Atoh1 mRNA after LKB1 knockdown in Ls174t cells. Cells with LKB1 knockdown had a reduced rate of oxygen consumption, which was partially restored by PDK4 inhibition with dichloroacetate. ISCs with knockout of LKB1 increased the expression of PDK4 and had an altered metabolic profile. CONCLUSIONS: LKB1 represses transcription of ATOH1, via PDK4, in ISCs, restricting their differentiation into secretory lineages. These findings provide a connection between metabolism and the fate determination of ISCs. |
| 20. | Nava, MM; Miroshnikova, YA; Biggs, LC; Whitefield, DB; Metge, F; Boucas, J; Vihinen, H; Jokitalo, E; Li, XP; Arcos, JMG; Hoffmann, B; Merkel, R; Niessen, CM; Dahl, KN; Wickstrom, SA Heterochromatin-Driven Nuclear Softening Protects the Genome against Mechanical Stress-Induced Damage Journal Article In: Cell, 181 (4), pp. 800–+, 2020, ISSN: 0092-8674. Links | iCAN PI: Wickström, Sara @article{965085d96b3541d0aefd872f96e63801, title = {Heterochromatin-Driven Nuclear Softening Protects the Genome against Mechanical Stress-Induced Damage}, author = {Nava, MM; Miroshnikova, YA; Biggs, LC; Whitefield, DB; Metge, F; Boucas, J; Vihinen, H; Jokitalo, E; Li, XP; Arcos, JMG; Hoffmann, B; Merkel, R; Niessen, CM; Dahl, KN; Wickstrom, SA}, editor = {Wickström, Sara}, doi = {10.1016/j.cell.2020.03.052}, issn = {0092-8674}, year = {2020}, date = {2020-01-01}, journal = {Cell}, volume = {181}, number = {4}, pages = {800--+}, publisher = {Cell Press}, keywords = {}, pubstate = {published}, tppubtype = {article} } |