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 #
5P01CA129243-07
Application #
8563894
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
7
Fiscal Year
2013
Total Cost
$238,055
Indirect Cost
$82,375
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Yu, Helena A; Perez, Leslie; Chang, Qing et al. (2017) A Phase 1/2 Trial of Ruxolitinib and Erlotinib in Patients with EGFR-Mutant Lung Adenocarcinomas with Acquired Resistance to Erlotinib. J Thorac Oncol 12:102-109
Ichihara, Eiki; Westover, David; Meador, Catherine B et al. (2017) SFK/FAK Signaling Attenuates Osimertinib Efficacy in Both Drug-Sensitive and Drug-Resistant Models of EGFR-Mutant Lung Cancer. Cancer Res 77:2990-3000
Yaeger, Rona; Yao, Zhan; Hyman, David M et al. (2017) Mechanisms of Acquired Resistance to BRAF V600E Inhibition in Colon Cancers Converge on RAF Dimerization and Are Sensitive to Its Inhibition. Cancer Res 77:6513-6523
Weigelt, Britta; Comino-Méndez, Iñaki; de Bruijn, Ino et al. (2017) Diverse BRCA1 and BRCA2 Reversion Mutations in Circulating Cell-Free DNA of Therapy-Resistant Breast or Ovarian Cancer. Clin Cancer Res 23:6708-6720
Pal, Debjani; Pertot, Anja; Shirole, Nitin H et al. (2017) TGF-? reduces DNA ds-break repair mechanisms to heighten genetic diversity and adaptability of CD44+/CD24- cancer cells. Elife 6:
Yu, H A; Sima, C; Feldman, D et al. (2017) Phase 1 study of twice weekly pulse dose and daily low-dose erlotinib as initial treatment for patients with EGFR-mutant lung cancers. Ann Oncol 28:278-284
Boire, Adrienne; Zou, Yilong; Shieh, Jason et al. (2017) Complement Component 3 Adapts the Cerebrospinal Fluid for Leptomeningeal Metastasis. Cell 168:1101-1113.e13
Nieto, Patricia; Ambrogio, Chiara; Esteban-Burgos, Laura et al. (2017) A Braf kinase-inactive mutant induces lung adenocarcinoma. Nature 548:239-243
Yao, Zhan; Yaeger, Rona; Rodrik-Outmezguine, Vanessa S et al. (2017) Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS. Nature 548:234-238
Drilon, Alexander; Somwar, Romel; Wagner, Jacob P et al. (2016) A Novel Crizotinib-Resistant Solvent-Front Mutation Responsive to Cabozantinib Therapy in a Patient with ROS1-Rearranged Lung Cancer. Clin Cancer Res 22:2351-8

Showing the most recent 10 out of 168 publications