Metastatic breast cancer (MBC) is a devastating disease that accounts for over 90% of breast cancer mortality and for which there are no current effective treatments. With over 230,000 new breast cancer cases diagnosed annually and accounting for more than 40,000 deaths every year in the United States alone, developing safe and effective treatments for MBC is an utmost priority. Our research program proposes to address this important disease by combining basic and pre-clinical studies that can translate into meaningful clinical outcomes for patients with MBC. Prompted by an increasing understanding of the molecular mechanisms underlying oncogenic dependence and resistance to therapy, the advent of targeted therapies, and, most recently, of immunotherapy, has revolutionized our approach to modern cancer treatment. These advances, together with improved models and novel technologies, open the door to tackling some of the hardest challenges in cancer treatment. We will capitalize on our expertise on signal transduction and pharmacology, as well as on our previous findings on targeted drug resistance and sensitivity, to design safe and effective targeted therapies against MBC. Specifically, we will investigate the role of PTEN and specific PI3K isoforms in metastatic spread using multiple genetically-engineered mouse models (GEMMs) and patient-derived xenografts (PDXs). We will also evaluate the use of combined immunotherapy and targeted PI3K isoform- specific inhibition on syngeneic mouse models of MBC. In addition, we will thoroughly research two recently discovered and promising novel targets, Maternal Embryonic Leucine-zipper Kinase (MELK) and CDK7, which proved to be essential in basal-like or triple negative breast cancer, but dispensable in normal cells, for their role in normal cell physiology and cancer pathogenesis, and for potential targeting in MBC. Importantly, we will invest considerable efforts into researching breast cancer brain metastasis (BCBM), a disease that has been largely neglected due to a lack of clinically relevant models and the difficulty to explore new treatment approaches. To this end, we will use novel orthotopic PDX models of BCBM that faithfully recapitulate genetic and phenotypic characteristics of the original patient samples, to investigate targeted drug combination therapies and resistance. There is a yet unmet need to develop safe targeted therapies against MBC, to thoroughly investigate combined immunotherapy and targeted therapies in breast cancer, and to discover effective treatments against BCBM. We have the experience, expertise and support to carry out these studies, and we are confident that we can make a significant contribution to the field of metastatic breast cancer, and to the many patients and families afflicted by this disease.

Public Health Relevance

Patients suffering from metastatic breast cancer (MBC) frequently face a dismal prognosis, with only limited and often ineffective treatment strategies available to them. In this project, we will aim to deliver on the promise of precision medicine by developing novel targeted therapies against specific molecular abnormalities found in MBC. If successful, the results from this study have the potential to dramatically affect the lives of many patients suffering from MBC by providing effective and safer therapeutic options.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
1R35CA210057-01
Application #
9186720
Study Section
Special Emphasis Panel (ZCA1-GRB-S (M1))
Program Officer
Kondapaka, Sudhir B
Project Start
2016-09-01
Project End
2023-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
1
Fiscal Year
2016
Total Cost
$775,816
Indirect Cost
$313,669
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Kabraji, Sheheryar; Ni, Jing; Lin, Nancy U et al. (2018) Drug Resistance in HER2-Positive Breast Cancer Brain Metastases: Blame the Barrier or the Brain? Clin Cancer Res 24:1795-1804
Bian, X; Gao, J; Luo, F et al. (2018) PTEN deficiency sensitizes endometrioid endometrial cancer to compound PARP-PI3K inhibition but not PARP inhibition as monotherapy. Oncogene 37:341-351
Wang, Yubao; Li, Ben B; Li, Jing et al. (2018) A Conditional Dependency on MELK for the Proliferation of Triple-Negative Breast Cancer Cells. iScience 9:149-160
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Li, Ben B; Qian, Changli; Gameiro, Paulo A et al. (2018) Targeted profiling of RNA translation reveals mTOR-4EBP1/2-independent translation regulation of mRNAs encoding ribosomal proteins. Proc Natl Acad Sci U S A 115:E9325-E9332
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Thorpe, Lauren M; Spangle, Jennifer M; Ohlson, Carolynn E et al. (2017) PI3K-p110? mediates the oncogenic activity induced by loss of the novel tumor suppressor PI3K-p85?. Proc Natl Acad Sci U S A 114:7095-7100
Zhang, Jing; Gao, Xueliang; Schmit, Fabienne et al. (2017) CRKL Mediates p110?-Dependent PI3K Signaling in PTEN-Deficient Cancer Cells. Cell Rep 20:549-557

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