Research Interest
Cancer Radiobiology and Radiosensitization in Radioligand Therapy
Radioligand therapy (RLT) delivers cytotoxic radiation to cancer lesions but is often limited by radioresistance, insufficient radioligand delivery, or toxicity to healthy tissues. Strategies to enhance radiosensitization or tumor-specific radiopharmaceutical uptake hold promise for improving RLT efficacy and safety. My research focuses on understanding the molecular mechanisms of cancer responses to RLT via signaling networks, and biology of targeted receptor to develop more effective treatments. Using drug library screens, proteomics, and phosphoproteomics, we investigate radiobiology across different particle radiations to identify radiosensitization targets for combinatorial therapies.
Our recent phosphoproteomics studies in medullary thyroid cancer (MTC) models identified key signaling alterations following treatment with minigastrin analogue PP-F11N radiolabeled with actinium-225 (α-particles) [Qin et al. 2023, J Nucl Med] and lutetium-177 (β-particles), compared to external beam radiotherapy [Grzmil et al. 2022, J Hematol Oncol]. This research identified radiosensitizing targets and evaluated small-molecule inhibitors in enhancing efficacy of [177Lu]Lu-PP-F11N and [225Ac]Ac-PP-F11N therapy in MTC models. Furthermore, drug library screens revealed that pharmacological inhibition of mammalian target of rapamycin complex 1 (mTORC1) signaling augments tumor-specific uptake of [177Lu]Lu-PP-F11N, providing a clinically feasible strategy to enhance RLT efficacy and nuclear imaging [Grzmil et al. 2020, Theranostics].
Publications (since 2020)
-
Pekeč T, Venkatachalapathy S, Shim AR, Paysan D, Grzmil M, Schibli R, et al.
Detecting radio- and chemoresistant cells in 3D cancer co-cultures using chromatin biomarkers
Scientific Reports. 2023; 13(1): 20662 (14 pp.). https://doi.org/10.1038/s41598-023-47287-2
DORA PSI -
Qin Y, Imobersteg S, Frank S, Blanc A, Chiorazzo T, Berger P, et al.
Signaling network response to α-particle–targeted therapy with the 225Ac-labeled minigastrin analog 225Ac-PP-F11N reveals the radiosensitizing potential of histone deacetylase inhibitors
Journal of Nuclear Medicine. 2023; 64(6): 873-879. https://doi.org/10.2967/jnumed.122.264597
DORA PSI -
Grzmil M, Wiesmann F, Schibli R, Behe M
Targeting mTORC1 activity to improve efficacy of radioligand therapy in cancer
Cancers. 2023; 15(1): 17 (12 pp.). https://doi.org/10.3390/cancers15010017
DORA PSI -
Grzmil M, Boersema P, Sharma A, Blanc A, Imobersteg S, Pruschy M, et al.
Comparative analysis of cancer cell responses to targeted radionuclide therapy (TRT) and external beam radiotherapy (EBRT)
Journal of Hematology & Oncology. 2022; 15(1): 123 (5 pp.). https://doi.org/10.1186/s13045-022-01343-y
DORA PSI -
Grzmil M, Imobersteg S, Blanc A, Frank S, Schibli R, Béhé MP
Therapeutic response of CCKBR-positive tumors to combinatory treatment with everolimus and the radiolabeled minigastrin analogue [177Lu]Lu-PP-F11N
Pharmaceutics. 2021; 13(12): 2156 (8 pp.). https://doi.org/10.3390/pharmaceutics13122156
DORA PSI -
Grzmil M, Qin Y, Schleuniger C, Frank S, Imobersteg S, Blanc A, et al.
Pharmacological inhibition of mTORC1 increases CCKBR-specific tumor uptake of radiolabeled minigastrin analogue [177Lu]Lu-PP-F11N
Theranostics. 2020; 10(24): 10861-10873. https://doi.org/10.7150/thno.45440
DORA PSI -
Qin Y, Imobersteg S, Blanc A, Frank S, Schibli R, Béhé MP, et al.
Evaluation of actinium-225 labeled minigastrin analogue [225Ac]Ac-DOTA-PP-F11N for targeted alpha particle therapy
Pharmaceutics. 2020; 12(11): 1088 (12 pp.). https://doi.org/10.3390/pharmaceutics12111088
DORA PSI
Book chapter
-
Grzmil M, Meisel A, Behé M, Schibli R
An overview of targeted radiotherapy
In: Lewis JS, Windhorst AD, Zeglis BM, eds. Radiopharmaceutical chemistry. Cham: Springer; 2019:85-100. https://doi.org/10.1007/978-3-319-98947-1_5
DORA PSI
Publications (2010-2019)
Moncayo G, Grzmil M, Smirnova T, Zmarz P, Huber RM, Hynx D, Kohler H, Wang Y, Hotz HR, Hynes NE, Keller G, Frank S, Merlo A, Hemmings BA. (2018) SYK inhibition blocks proliferation and migration of glioma cells and modifies the tumor microenvironment. Neuro Oncol. 20:621-631.
Grzmil M, Seebacher J, Hess D, Behe M, Schibli R, Moncayo G, Frank S, Hemmings BA. (2016) Inhibition of MNK pathways enhances cancer cell response to chemotherapy with temozolomide and targeted radionuclide therapy. Cell Signal. Jun 8;28(9):1412-1421.
Tang F, Gill J, Ficht X, Barthlott T, Cornils H, Schmitz-Rohmer D, Hynx D, Zhou D, Zhang L, Xue G, Grzmil M, Yang Z, Hergovich A, Hollaender GA, Stein JV, Hemmings BA, Matthias P. (2015). The kinases NDR1/2 act downstream of the Hippo homolog MST1 to mediate both egress of thymocytes from the thymus and lymphocyte motility. Sci Signal. 8:ra100.
Grzmil M, Huber RM, Hess D, Frank S, Hynx D, Moncayo G, Klein D, Merlo A, Hemmings BA. (2014). MNK1 pathway activity maintains protein synthesis in rapalog-treated gliomas. J Clin Invest 124:742-54.
Grzmil M, Hemmings BA. (2013). Overcoming resistance to rapalogs in gliomas by combinatory therapies. Biochim Biophys Acta 1834:1371-80.
Grzmil M, Hemmings BA. (2012). Translation Regulation as a Therapeutic Target in Cancer. Cancer Res 72:3891-900.
Tchorz JS, CloettaD, Tome M, Sivasankaran B, Grzmil M, Huber RM, Schatzmann F, Kirchhoff F, Schaeren-WiemersN, Gassmann N, Hemmings BA, Merlo A, Bernhard B. (2012). Notch2 Signaling in Neural Stem Cells Promotes Features of Glioma Stem Cells. Cell Death Dis 21;3:e325.
Wang Y, Moncayo G, Morin P, Xue G, Grzmil M, Lino MM, Clément V, Frank S, Merlo A, Hemmings BA. (2012). Mer receptor tyrosine kinase promotes invasion and survival in glioblastoma multiforme. Oncogene 14;32(7):872-82.
Grzmil M, Mori P, Lino MM, Merlo A, Frank S, Wang Y, Moncayo G, and. Hemmings BA. (2011). MAP kinase-interacting kinase 1 (MNK1) regulates SMAD2-dependent TGF-β signalling pathway in human glioblastoma. Cancer Res 71:2392-402.
Grzmil M, Rzymski T, Milani M, Harris AL, Capper RG, Saunders NJ, Salhan A, Ragoussis J, Norbury CJ. (2010). An oncogenic role of eIF3e/INT6 in human breast cancer. Oncogene 29:4080-9.
Grzmil M, Hemmings BA. (2010). Deregulated signalling networks in human brain tumours. Biochim Biophys Acta 1804:476-83.