Even if discovered at stage I and surgically removed, lung adenocarcinomas can relapse within months, spreading to lymph nodes, the contra-lateral lung, brain, bones, and the adrenal glands. The genetic determinants and molecular mechanisms involved in lung adenocarcinoma metastasis are obscure. During the previous grant period, the Massague group (RP1) began to clarify these issues. The work revealed a link between WNT and pulmonary tumor progression, identified a lung WNT gene signature (LWS) that predicts distant relapse in lung adenocarcinoma tumors ofany stage, provided tractable experimental models for bone and brain metastasis by lung adenocarcinoma cells, and uncovered H0XB9 as a WNT target gene that enhances tumor re-initiation in brain and bone marrow. Based on this progress.
Aims 1 and 2 RPl in this competing renewal will seek to identify genes and pathways that support the viability of lung adenocarcinoma micrometastases, with the goal of providing information to target such pathways in the adjuvant setting after resection in order to prevent metastasis.
Aim 3 in RP1 will build on this lab's recent progress in brain metastasis by focusing on the role of Serpins in this process, in particular Neuroserpin, a brain-specific member ofthis family of secreted protease inhibitors. RPI's preliminary data demonstrate that lung adenocarcinoma cells express Neuroserpin as a mediator of brain colonization, and that Neuroserpin is highly expressed in at least one-half of the human lung adenocarcinoma brain metastases that have so far been examined by immunohistochemistry. Other data from the Massague lab has recently shown that S100A8/9 are mediators of metastasis-linked chemoresistance in nfiouse models, and that S100A8 is amplified and highly expressed in human lung adenocarcinoma samples.
Aim 4 in RPl proposes to investigate the role of S100A8/9 in lung adenocarcinoma metastasis and response to chemotherapy, with the goal of uncovering new ways to augment the efficacy of targeted and conventional chemotherapies in lung cancers.

Public Health Relevance

Lung cancers are America's leading cancer killers, responsible for 158,000 deaths this year. This project addresses the two critical roadblocks to improving the care and curability of persons with lung adenocarcinomas: (1) understanding how adenocarcinomas spread to the brain (metastasis) and (2) the lack of highly effective medicines to prevent spread or to eradicate cancers that have spread from the lung

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA129243-06
Application #
8391906
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (M1))
Project Start
2007-07-23
Project End
2017-08-31
Budget Start
2012-09-12
Budget End
2013-08-31
Support Year
6
Fiscal Year
2012
Total Cost
$259,338
Indirect Cost
$93,721
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Gao, Yijun; Chang, Matthew T; McKay, Daniel et al. (2018) Allele-Specific Mechanisms of Activation of MEK1 Mutants Determine Their Properties. Cancer Discov 8:648-661
Arbour, Kathryn C; Jordan, Emmett; Kim, Hyunjae Ryan et al. (2018) Effects of Co-occurring Genomic Alterations on Outcomes in Patients with KRAS-Mutant Non-Small Cell Lung Cancer. Clin Cancer Res 24:334-340
Gallant, Jean-Nicolas; Lovly, Christine M (2018) Established, emerging and elusive molecular targets in the treatment of lung cancer. J Pathol 244:565-577
Hellmann, Matthew D; Nathanson, Tavi; Rizvi, Hira et al. (2018) Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer. Cancer Cell 33:843-852.e4
Yao, Zhan; Gao, Yijun; Su, Wenjing et al. (2018) RAF inhibitor PLX8394 selectively disrupts BRAF dimers and RAS-independent BRAF-mutant-driven signaling. Nat Med :
Suzawa, Ken; Offin, Michael; Lu, Daniel et al. (2018) Activation of KRAS Mediates Resistance to Targeted Therapy in MET Exon 14-mutant Non-small Cell Lung Cancer. Clin Cancer Res :
Yu, Helena A; Planchard, David; Lovly, Christine M (2018) Sequencing Therapy for Genetically Defined Subgroups of Non-Small Cell Lung Cancer. Am Soc Clin Oncol Educ Book :726-739
Yuan, Tina L; Amzallag, Arnaud; Bagni, Rachel et al. (2018) Differential Effector Engagement by Oncogenic KRAS. Cell Rep 22:1889-1902
Ruscetti, Marcus; Leibold, Josef; Bott, Matthew J et al. (2018) NK cell-mediated cytotoxicity contributes to tumor control by a cytostatic drug combination. Science 362:1416-1422
Du, Zhenfang; Lovly, Christine M (2018) Mechanisms of receptor tyrosine kinase activation in cancer. Mol Cancer 17:58

Showing the most recent 10 out of 188 publications