作者: Oezen, Iris ; Alansary, Dalia ; Bozza, Matthias ; Dorsch, Marion ; Marsh, Kelly ; Green, Edward ; Schrimpf, Daniel ; Cahill, Daniel P ; Kilian, Michael ; Bunse, Lukas ; Zhu, Dongwei ; Hänggi, Daniel ; Platten, Michael ; Ratliff, Miriam ; Sanghvi, Khwab ; Herold-Mende, Christel ; Al-Ali, Ruslan ; Kramer, Magdalena ; Harter, Patrick N ; Bieback, Karen ; Nicolay, Brandon ; Wick, Wolfgang ; Benner, Axel ; Uhlig, Stefanie ; Bunse, Theresa ; Meyer, Jochen ; Friedrich, Mirco ; Preusser, Matthias ; Wiestler, Benedikt ; Poschet, Gernot ; Deumelandt, Katrin ; von Landenberg, Anna ; Burger, Michael C ; Kaulfuss, Stefan ; Nadji-Ohl, Minou ; Steadman, Mya ; Plate, Karl H ; Neftel, Cyril ; Weller, Michael ; Hess-Stumpp, Holger ; Thon, Niklas ; Habel, Antje ; Niemeyer, Barbara A ; Harbottle, Richard ; Sonner, Jana K ; Okun, Jürgen ; Turcan, Sevin ; Pusch, Stefan ; Berghoff, Anna S ; Breckwoldt, Michael O ; Sahm, Felix ; Kessler, Tobias ; Suvà, Mario L ; Karcher-Bausch, Simone ; Eisel, Jessica ; von Deimling, Andreas

The oncometabolite (R)-2-hydroxyglutarate (R-2-HG) produced by isocitrate dehydrogenase (IDH) mutations promotes gliomagenesis via DNA and histone methylation. Here, we identify an additional activity of R-2-HG: tumor cell-derived R-2-HG is taken up by T cells where it induces a perturbation of nuclear factor of activated T cells transcriptional activity and polyamine biosynthesis, resulting in suppression of T cell activity. IDH1-mutant gliomas display reduced T cell abundance and altered calcium signaling. Antitumor immunity to experimental syngeneic IDH1-mutant tumors induced by IDH1-specific vaccine or checkpoint inhibition is improved by inhibition of the neomorphic enzymatic function of mutant IDH1. These data attribute a novel, non-tumor cell-autonomous role to an oncometabolite in shaping the tumor immune microenvironment.

Blood and Lymphatic Cancer: Targets and Therapy

<p>IDH1-mutated relapsed or refractory AML: current challenges and future prospects</p>

Review

作者: Megías-Vericat, Juan Eduardo ; Montesinos, Pau ; Ballesta-López, Octavio ; Barragán, Eva

The prognosis of patients with relapsed or refractory acute myeloid leukemia (R/R AML) is discouraging with salvage standard approaches. Mutations of isocitrate dehydrogenase 1 (IDH1 ^mut ), present in 7-14% of AML patients, have been discovered recently, opening the door to targeted agents aiming to improve the outcomes in this setting. Several oral selective IDH1 ^mut inhibitors are under investigation, ivosidenib being the first approved for R/R AML. We performed a systematic review to analyze the clinical outcomes and safety reported with IDH1 ^mut inhibitors and other agents in adult patients with IDH1 ^mut R/R AML. Ivosidenib in monotherapy achieved complete remission (CR) of 24%, overall response of 42%, and median overall survival of 9 months in R/R AML, and promising outcomes were reported with IDH305 and FT-2102. IDH1 ^mut inhibitors were generally well tolerated, but some therapy-related toxicities should be monitored, including IDH-differentiation syndrome, prolongation of the QT interval, and leukocytosis, all manageable and reversible. Also, venetoclax, CB-839, PARP inhibitors, and IDH1 peptide vaccine are being studied in IDH1^mut AML. The results of the ongoing and upcoming clinical trials will bring new evidence to establish the role of IDH1 ^mut inhibitors in therapeutic strategies of AML.

项与 IDH1 peptide vaccine(Deutsches Krebsforschungszentrum, Dkfz) 相关的新闻（医药）

2023-05-04

·BioSpace

Bicycle Therapeutics Announces Collaboration With the German Cancer Research Center, to Discover and Develop Wholly Owned Bicycle® Radio Conjugates for a Range of Oncology Targets

CAMBRIDGE, England, & BOSTON--(BUSINESS WIRE)-- Bicycle Therapeutics plc (NASDAQ: BCYC), a biotechnology company pioneering a new and differentiated class of therapeutics based on its proprietary bicyclic peptide (Bicycle®) technology, today announced that it has entered into a collaboration with the German Cancer Research Center (DKFZ), to develop and discover Bicycle® radio conjugates (BRCs) for a range of oncology targets. Founded in 1964, DKFZ is the largest biomedical research institution in Germany. It is a premier radioligand therapy organization that has a proven track record of supporting the development of such therapies and, together with the University of Heidelberg, was vital to the early development of Pluvicto™. Bicycle and DKFZ have been collaborating on tumor targeting BRCs which in preclinical studies, have shown superior tumor uptake compared to antibody-based approaches. Results from the preclinical study were published in Cancer Research in February 2019 and can be accessed here. With this new alliance, the relationship has expanded to include a more continuous and purpose-driven commitment towards advancing candidates towards the clinic. Professor Matthias Eder commented that he and his colleagues at DKFZ were excited to work with Bicycle to develop novel radiopharmaceutical therapies. “We have experience working with Bicycle scientists on radiochemistry projects and believe that the physicochemical properties of Bicycle’s constrained bi-cyclic peptides make them ideal ligands for targeted radioisotope delivery.” “We believe the advancement of BRCs is a promising application of the Bicycle platform and represents the third leg within our core oncology focus. Building on the recent announcement of our collaboration with Novartis, we are excited to deepen our relationship with DKFZ, a leading radioligand research organization, to seek to accelerate the development of our wholly owned BRCs,” said Kevin Lee, Ph.D., Chief Executive Officer of Bicycle Therapeutics. “The goal of the collaboration is to develop a pipeline of wholly owned BRC compounds with the potential to become new treatment options for patients living with cancer.” Dr. Lee continued, “We are thrilled to have now announced multiple collaborations in the radiopharmaceutical space this year, which we believe provides further validation of the Bicycle platform. Likewise, we remain encouraged by data generated to date from our wholly owned pipeline of Bicycle Toxin Conjugates® (BTCs) and Bicycle tumor-targeted immune cell agonists (Bicycle TICAs) which we believe demonstrates differentiation compared to antibody-based approaches and other modalities. We look forward to providing multiple updates this year as we advance BT8009, BT5528 and BT7480 in the clinic. In addition, we intend to commence initial testing of our own BRCs in patients by the end of 2024.” About Bicycle Therapeutics Bicycle Therapeutics (NASDAQ: BCYC) is a clinical-stage biopharmaceutical company developing a novel class of medicines, referred to as Bicycles, for diseases that are underserved by existing therapeutics. Bicycles are fully synthetic short peptides constrained with small molecule scaffolds to form two loops that stabilize their structural geometry. This constraint facilitates target binding with high affinity and selectivity, making Bicycles attractive candidates for drug development. Bicycle is evaluating BT5528, a second-generation Bicycle Toxin Conjugate (BTC™) targeting EphA2; BT8009, a second-generation BTC targeting Nectin-4, a well-validated tumor antigen; and BT7480, a Bicycle TICA™ targeting Nectin-4 and agonizing CD137, in company-sponsored Phase I/II trials. In addition, BT1718, a BTC that targets MT1-MMP, is being investigated in an ongoing Phase I/IIa clinical trial sponsored by the Cancer Research UK Centre for Drug Development. Bicycle is headquartered in Cambridge, UK, with many key functions and members of its leadership team located in Cambridge, MA. For more information, visit bicycletherapeutics.com. About DKFZ The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institution in Germany. More than 1,300 scientists at the DKFZ investigate how cancer develops, identify cancer risk factors and search for new strategies to prevent people from developing cancer. They are developing new methods to diagnose tumors more precisely and treat cancer patients more successfully. The DKFZ's Cancer Information Service (KID) provides patients, interested citizens and experts with individual answers to all questions on cancer. Forward Looking Statements This press release may contain forward-looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements may be identified by words such as “aims,” “anticipates,” “believes,” “could,” “estimates,” “expects,” “forecasts,” “goal,” “intends,” “may,” “plans,” “possible,” “potential,” “seeks,” “will” and variations of these words or similar expressions that are intended to identify forward-looking statements, although not all forward-looking statements contain these words. Forward-looking statements in this press release include, but are not limited to, statements regarding Bicycle’s collaboration with DKFZ; the discovery and development of potential product candidates using Bicycle’s technology and under the collaboration agreement; the therapeutic potential for Bicycles in oncology; the provision of updates in relation to the clinical development of BT8009, BT5528 and BT7480; and the intention to commence initial testing of BRCs in patients by the end of 2024. Bicycle may not actually achieve the plans, intentions or expectations disclosed in these forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in these forward-looking statements as a result of various factors, including: the risk that Bicycle may not realize the intended benefits of its technology or of the collaboration agreement with DKFZ, including that Bicycle and DKFZ may not successfully identify and develop additional product candidates; the risk that Bicycle may not be able to maintain its collaboration with DKFZ and realize the benefits thereof; and other important factors, any of which could cause Bicycle’s actual results to differ from those contained in the forward-looking statements and which are described in greater detail in the section entitled “Risk Factors” in Bicycle’s Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC) on February 28, 2023, as well as in other filings Bicycle may make with the SEC in the future. Any forward-looking statements contained in this press release speak only as of the date hereof, and Bicycle expressly disclaims any obligation to update any forward-looking statements contained herein, whether because of any new information, future events, changed circumstances or otherwise, except as otherwise required by law. View source version on businesswire.com: Contacts Investors: David Borah, CFA SVP, Capital Markets & Corporate Communications david.borah@bicycletx.com 617-203-8300 Media: Argot Partners Sarah Sutton bicycle@argotpartners.com 212-600-1902 Source: Bicycle Therapeutics plc View this news release online at:

临床研究

2022-10-26

·Science Daily

How tumors suppress the development of metastases

Why do metastases often only appear after the original tumor has been surgically removed? Scientists have now published an explanation for this phenomenon. They were able to identify a messenger substance of the cancer cells that locally promotes the growth of the primary tumor. In the blood, the messenger is split into two fragments, one of which suppresses metastasis. Tumor-bearing mice treated with the metastasis-inhibiting fragment survived cancer longer than untreated animals. Why do metastases often only appear after the original tumor has been surgically removed? Scientists from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) and the Mannheim Medical Faculty of Heidelberg University have now published an explanation for this phenomenon. They were able to identify a messenger substance of the cancer cells that locally promotes the growth of the primary tumor. In the blood, the messenger is split into two fragments, one of which suppresses metastasis. Tumor-bearing mice treated with the metastasis-inhibiting fragment survived cancer longer than untreated animals. Cancer doctors are familiar with the observation: in many of their patients, the usually life-threatening metastases only appear after the original tumor has been surgically removed. This phenomenon is particularly common in breast cancer and black skin cancer. Physicians have derived the concept of "concomitant tumor resistance" from this observation. It states that the original cancer focus, also called the primary tumor, can suppress the growth of the daughter tumors known as metastases. The causes of this phenomenon are as yet poorly understood. Experts assume that the immune system plays a role, together with so-called angiogenic factors, which influence the connection of the metastases to the blood vessel system. From a size of about one millimeter, the daughter tumors depend on being supplied by blood vessels. Researchers were able to show several years ago that, depending on the tissue environment, tumors either release messenger substances that promote the formation of new blood vessels or factors that suppress the sprouting of new veins. Scientists led by Hellmut Augustin and Moritz Felcht of the German Cancer Research Center and the Mannheim Medical School of Heidelberg University have now taken a closer look at the messenger angiopoietin-like 4 (ANGPLT4). "We became aware of ANGPLT4 because there are many contradictory publications on this factor," Augustin said. "While ANGPLT4 was initially described as promoting the formation of new blood vessels and thus also promoting cancer, other studies were able to prove the exact opposite and show that ANGPLT4 inhibits the development of metastases." In comprehensive series of experiments on human and mouse tumors, the Heidelberg-Mannheim team elucidated a surprising mechanism. Among 38 different messenger substances that act on vascularization and possibly on concomitant tumor resistance, ANGPLT4 was found to be one of the molecules most strongly correlated with progressive tumor growth ANGPLT4 is produced by cells of the primary tumor and locally promotes its growth. However, if the messenger substance is released into the bloodstream, it is cleaved. The two cleavage products are called nANGPLT4 and cANGPLT4. For reasons not yet fully understood, the n fragment (nANGPLT4) is found almost exclusively in serum. nANGPLT4, however, binds to a different receptor than either the intact molecule or the c fragment. This receptor switch leads to the suppression of vessel growth and thus also the outgrowth of macrometastases. The researchers demonstrated this in numerous experimental approaches: Tumors transferred to mice formed fewer metastases after treatment with the n-fragment, and the animals survived longer. "Of course, surgical removal of the primary tumors remains the gold standard in the treatment of most cancers," says Moritz Fecht. "But we now understand that this simultaneously dries up the source of the metastasis-suppressing n fragment. If nANGPLT4 is missing, individual dormant metastatic tumor cells can become active and grow into a dangerous macrometastasis," says Moritz Felcht. "By cleaving the protein in the body and the resulting opposite functions in tumor metastasis, we can now explain the contradictory results of previous studies." "Many cancer patients could benefit from drugs that effectively suppress metastatic outgrowth. However, some of these agents have already failed in clinical trials. But in view of the enormous gain that such a drug could mean for those affected, it is worthwhile to continue researching ANGPLT4 preclinically and then clinically," Hellmut Augustin sums up. Corinne Hübers, Ashik Ahmed Abdul Pari, Denise Grieshober, Martin Petkov, Alexander Schmidt, Tatjana Messmer, Christian Moritz Heyer, Sebastian Scholch, Stephanie Kapel, Nicolas Gengenbacher, Mahak Singhal, Benjamin Schieb, Claudine Fricke, Rainer Will, Kim Remans, Jochen Sven Utikal, Christoph Reissfelder, Matthias Schlesner, Kairbaan M. Hodivala-Dilke, Sander Kersten, Sergij Goerdt, Hellmut G. Augustin and Moritz Felcht: Primary tumor-derived systemic nANGPTL4 inhibits metastasis. Journal of Experimental Medicine 2022, DOI: The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institution in Germany. More than 1,300 scientists at the DKFZ investigate how cancer develops, identify cancer risk factors and search for new strategies to prevent people from developing cancer. They are developing new methods to diagnose tumors more precisely and treat cancer patients more successfully. The DKFZ's Cancer Information Service (KID) provides patients, interested citizens and experts with individual answers to all questions on cancer. Jointly with partners from the university hospitals, the DKFZ operates the National Center for Tumor Diseases (NCT) in Heidelberg and Dresden, and the Hopp Children's Cancer Center KiTZ in Heidelberg. In the German Consortium for Translational Cancer Research (DKTK), one of the six German Centers for Health Research, the DKFZ maintains translational centers at seven university partner locations. NCT and DKTK sites combine excellent university medicine with the high-pro of the DKFZ. They contribute to the endeavor of transferring promising approaches from cancer research to the clinic and thus improving the chances of cancer patients. The DKFZ is 90 percent financed by the Federal Ministry of Education and Research and 10 percent by the state of Baden-Württemberg. The DKFZ is a member of the Helmholtz Association of German Research Centers. Contact:

100 项与 IDH1 peptide vaccine(Deutsches Krebsforschungszentrum, Dkfz) 相关的药物交易

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