Notch und p53 - welchen Einfluss haben sie auf die Lungenkrebstumorigenese?
Zusammenfassung der Projektergebnisse
Highly predictive animal-based translational cancer research is needed to meet the urgent need for more effective anticancer treatments in the clinic. In the present work, we have developed a new platform to predict therapeutic responses to radiotherapy by mimicking human non-small cell lung cancer much closer than previously possible. - We present a novel technique allowing, for the first time, the formation of a single lung tumor nodule in genetically engineered mice, thereby being the first and to our knowledge only available lung cancer model to mimic solitary autochthonous tumor initiation and growth as seen in human disease. - This novel technique enabled us to perform three-dimensional conformal radiotherapy planning and state-of-the-art image-guided radiotherapy delivery as performed in humans. - We employed these techniques to three highly relevant genetically engineered mouse models of non-small cell lung cancer carrying activating mutations in Kras, and deletion of either tumor suppressor gene Lkb1 or p53. We and others previously showed that these models closely recapitulate human treatment responses. - We then compared the treatment efficacy of two radiotherapy regimens that are used in patients in three different genetically engineered mouse models of primary lung adenocarcinoma, and found genotype-dependent differences in treatment response. Together, these findings suggest that loss of Lkb1 or p53 in Kras-driven lung adenocarcinomas are more resistant to ionizing radiation and that the addition of other anticancer agents are likely required to treat this aggressive cancer. - Additionally, we found that the combination of radiation and immune checkpoint blockade is highly effective against Kras-driven lung adenocarcinomas in mice. These findings are of immediate and broad interest to the medical and scientific communities and of clinical relevance for several reasons. First, non-small cell lung cancer is one of the most deadliest cancers in the western world, and numerous academic as well as industrial research laboratories are investigating treatment options and are dependent on predictive in vivo models for most efficient bench-to-bedside drug development. Second, despite the common application of radiotherapy to patients with non-small cell lung cancer, we are still lacking profound knowledge on genotype-dependent outcome. Therefore, our novel platform will allow investigators to perform studies to develop novel therapeutic combinations to enhance the response to radiotherapy as well as to identify biomarkers for patient stratification. We expected that our Kras,Lkb1-mutant model would respond similarly as Kras-mutant tumors after radiotherapy due to functional DNA damage response pathway. However, we observed the opposite and are curious to investigate the underlying biologic mechanisms. Furthermore, we were surprised about the treatment effects of combined radiation and immune checkpoint blockade in Kras-mutant tumors as most drugs only have transient antitumor efficacy.
Projektbezogene Publikationen (Auswahl)
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Activating mutations in ERBB2 and their impact on diagnostics and treatment. Front Oncol. 2013; 3:86
Herter-Sprie GS, Greulich H, Wong KK
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Mouse models of cancer – how to optimize their predictive value in cancer drug development. Experimental Biology (2013), Boston, USA - FASEB J April 9, 2013 27:1088.17
Herter-Sprie GS, Wong KK
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New cast for a new era: preclinical cancer drug development revisited. J Clin Invest. 2013; 123(9):3639-45
Herter-Sprie GS, Kung AL, Wong KK
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Image-guided radiotherapy platform using single nodule conditional lung cancer mouse models. Nat Commun. 2014 Dec 18;5:5870
Herter-Sprie GS, Korideck H, Christensen CL, Herter JM, Rhee K, Berbeco RI, Bennett DG, Akbay EA, Kozono D, Mak RH, Makrigiorgos GM, Kimmelman AC, Wong KK
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Intratracheal delivery of gold nanoparticles for radiation therapy in murine lung adenocarcinoma. ASTRO (2014), San Francisco, USA - Int J Rad Oncol Biol Phys September 1, 2014 90(1):S942-S943
Korideck H, Kumar R, Herter-Sprie G, Wong K, Srinivas S, Kozono D, Berbeco R, Makrigiorgos M, Ngwa W
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Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor. Cancer Cell. 2014. 8;26(6):909-22
Christensen CL, Kwiatkowski N, Abraham BJ, Carretero J, Al-Shahrour F, Zhang T, Chipumuro E, Herter-Sprie GS, Akbay EA, Altabef A, Zhang J, Shimamura T, Capelletti M, Reibel JB, Cananaugh JD, Gao P, Liu Y, Michaelsen SR, Poulsen HS, Aref AR, Barbie DA, Bradner JE, George RE, Gray NS, Young RA, Wong KK
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AKAP9 regulates activation-induced retention of T lymphocytes at sites of inflammation. Nat Commun, volume 6, Article number: 10182 (2015), 14 S.
Herter JM, Grabie N, Cullere X, Azcutia V, Rosetti F, Bennett P, Herter-Sprie GS, Elyaman W, Luscinskas FW, Lichtman AH, Mayadas TN
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Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nature Communications volume 7, Article number: 10501 (2016)
Koyama S, Akbay EA, Li Y, Herter-Sprie GS, Buczkowski KA, William G. Richards, Gandhi L, Redig A, Rodig SJ, Asahina H, Jones RE, Kulkarni MM, Mari Kuraguchi, Sangeetha Palakurthi, Fecci PE, Johnson BE, Janne PA, Engelman J, Gangadharan SP, Costa DB, Freem
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STK11/LKB1 Deficiency Promotes Neutrophil Recruitment and Proinflammatory Cytokine Production to Suppress T-cell Activity in the Lung Tumor Microenvironment. Cancer Research, 6(5) March 1, 2016. 11 S.
Shohei Koyama, Esra A. Akbay, Yvonne Y. Li, Amir R. Aref, Ferdinandos Skoulidis, Grit S. Herter-Sprie, Kevin A. Buczkowski, Yan Liu, Mark M. Awad, Warren L. Denning, Lixia Diao, Jing Wang, Edwin R. Parra-Cuentas, Ignacio I. Wistuba, Margaret Soucheray, Tr
