Mutation of the BRAF oncogene is a common event in colorectal cancer (CRC). These mutations are associated with adverse outcome and insensitivity to epidermal growth factor receptor (EGFR) based therapy. Whereas RAF inhibitors have been succesful in the treatment of BRAF-mutant malignant melanoma, response rates in BRAF-mutant CRC are surprisingly low. The basis for these disparate treatment outcomes remains incompletely understod. Preliminary studies from our groups found that suppression of the MAPK pathway by PLX4720 is incomplete in CRC lines. In some cases, this may be due to augmented EGFR-dependent signaling, but this does not explain all resistance in this setting. Our objective is to identify mechanisms operant in BRAF-mutant colorectal cancer that confer de novo resistance to RAF inhibitors, in hopes of enabling more efficacious therapeutics. First, differentially expressed genes linked to BRAF-mutant CRC will be identified by analysis of the TCGA dataset;these genes will be Integrated with those that modify response to MAPK pathway inhibitors based on ongoing systematic functional screens. Top-ranking genes will be subjected to mechanistic studies to elucidate the molecular basis by which they confer resistance, in parallel, ongoing functional screens will be expanded to Identify genes that are synthetic lethal with RAF inhibition in BRAF-mutant colorectal cells. Here, validation of leading candidates will be prioritized for genes that are potentially druggable-several candidates have already been nominated. Rational combinations of targeted agents with RAF inhibitors will be explored in cell culture and in xenograft models. Finally, clinical trials of combined RAF and MEK inhibitors will be performed at DF/HCC in an attempt to improve efficacy by enhancing suppression of the MAPK pathway and possibly prevent the emergence of drug-resistance. Tumor biopsies will be collected pre-treatment, on-treatment and post-progression, and whole exome and transcriptome sequencing will be used to identify genomic alterations that may drive resistance. Altogether, this work should provide a rigorous analysis of resistance to MAPK inhibitors and new therapeutic approaches to overcome them.

Public Health Relevance

The survival colorectal cancer patients whose tumors harbor BRAF mutations is dramatically worse than those with wildtype BRAF;the benefit of certain chemotherapy drugs is similarly poor. Therefore, It Is essential that novel therapeutic approaches are developed to address this unmet medical need. We will utilize state of the art technologies and experimental approaches together with a rational clinical trial to forge a new treatment framework for this lethal subtype of colorectal cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA127003-07
Application #
8933242
Study Section
Special Emphasis Panel (ZCA1-RPRB-M (J1))
Program Officer
Agarwal, Rajeev K
Project Start
2007-04-01
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
7
Fiscal Year
2014
Total Cost
$239,495
Indirect Cost
$60,788
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Russo, Mariangela; Siravegna, Giulia; Blaszkowsky, Lawrence S et al. (2016) Tumor Heterogeneity and Lesion-Specific Response to Targeted Therapy in Colorectal Cancer. Cancer Discov 6:147-53
Kugel, Sita; Sebastián, Carlos; Fitamant, Julien et al. (2016) SIRT6 Suppresses Pancreatic Cancer through Control of Lin28b. Cell 165:1401-15
Kim, Sun A; Inamura, Kentaro; Yamauchi, Mai et al. (2016) Loss of CDH1 (E-cadherin) expression is associated with infiltrative tumour growth and lymph node metastasis. Br J Cancer 114:199-206
Delaney, Susan K; Hultner, Michael L; Jacob, Howard J et al. (2016) Toward clinical genomics in everyday medicine: perspectives and recommendations. Expert Rev Mol Diagn 16:521-32
Mima, Kosuke; Cao, Yin; Chan, Andrew T et al. (2016) Fusobacterium nucleatum in Colorectal Carcinoma Tissue According to Tumor Location. Clin Transl Gastroenterol 7:e200
Whitley, Melodi Javid; Cardona, Diana M; Lazarides, Alexander L et al. (2016) A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer. Sci Transl Med 8:320ra4
Ahronian, Leanne G; Corcoran, Ryan B (2016) Effective MAPK Inhibition is critical for therapeutic responses in colorectal cancer with BRAF mutations. Mol Cell Oncol 3:e1048405
Saha, Supriya K; Zhu, Andrew X; Fuchs, Charles S et al. (2016) Forty-Year Trends in Cholangiocarcinoma Incidence in the U.S.: Intrahepatic Disease on the Rise. Oncologist 21:594-9
Ou, Wen-Bin; Lu, Minmin; Eilers, Grant et al. (2016) Co-targeting of FAK and MDM2 triggers additive anti-proliferative effects in mesothelioma via a coordinated reactivation of p53. Br J Cancer 115:1253-1263
Lazarides, Alexander L; Whitley, Melodi J; Strasfeld, David B et al. (2016) A Fluorescence-Guided Laser Ablation System for Removal of Residual Cancer in a Mouse Model of Soft Tissue Sarcoma. Theranostics 6:155-66

Showing the most recent 10 out of 481 publications