A major challenge in the development of novel cancer therapies has been a lack of genetic alterations whose altered protein products are easily druggable. Entire classes of cancer driver alterations such as transcription factor amplification or tumor suppressor gene mutation have failed to produce targeting therapeutics, despite decades of effort. Due to genomic instability, cancer cells frequently delete one copy of large segment of DNA containing essential genes. In fact, a median 10% of the genome is hemizygously deleted in cancer cells. We hypothesize that hemizygous loss of essential genes in cancer cells may cause selective vulnerabilities to their further suppression. These vulnerabilities are not shared by diploid cells composing normal tissues and may therefore form the basis of a therapeutic window. We have integrated genomic copy number data with the results of a genome-wide shRNA screen across 216 cancer cell lines to find 170 genes whose hemizygous deletion sensitizes cells to its further suppression with RNAi. One of the top hits in our analysis is the recently recognized oncogene, SF3B1 whose role in cancer remains unknown. SF3B1 is hemizygously deleted in approximately 21% of breast cancers. Our preliminary data support the hypothesis that hemizygous loss of SF3B1 (SF3B1loss) uniquely sensitizes cells to its further suppression.
In Aim 1 we propose to further test the hypothesis that SF3B1 suppression selectively decreases the proliferation of SF3B1loss cancer cells using gene-editing technology and mouse models. We will test whether existing SF3b-targeting compounds can mimic the effects of RNAi to selectively kill SF3B1loss cells.
In Aim 2, we will test the hypothesis that SF3B1 suppression causes apoptosis through splicing alterations in SF3B1loss cells. We will assess whether SF3B1loss cancer cells undergo alterations in cell cycle progression and apoptosis after SF3B1 suppression. We will use RNA-sequencing experiments to determine whether SF3B1loss cells undergo more dramatic alterations in pre-mRNA splicing upon knockdown of SF3B1 than cells with normal SF3B1 genomic copy number.
In Aim 3, we will test the hypothesis that specific buffers account for the relative resistance o cells with normal SF3B1 genomic copy number to suppression of SF3B1. We will perform experiments to determine whether an excess of SF3B1 mRNA, protein or transcriptional reserve form the basis for the buffer that distinguishes cells with normal SF3B1 genomic copy number from cells with hemizygous loss in the face of SF3B1 suppression. The possibility that hemizygous deletion of essential genes represents a novel therapeutic window may enable the development of a large number of new cancer therapies. Our proposed study will form the basis for this effort and has the potential to extend targeted cancer therapy to many more cancer types and patients.

Public Health Relevance

Cancers genomes undergo widespread structural alteration and commonly delete one copy of many essential genes. We propose to determine whether further suppression of these hemizygously deleted essential genes can kill cancer cells while leaving normal cells with two copies unharmed.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
1F30CA192725-01
Application #
8833549
Study Section
Special Emphasis Panel (ZRG1-F09A-L (20))
Program Officer
Damico, Mark W
Project Start
2015-03-30
Project End
2017-05-29
Budget Start
2015-03-30
Budget End
2016-03-29
Support Year
1
Fiscal Year
2015
Total Cost
$48,120
Indirect Cost
Name
Harvard Medical School
Department
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Bi, Wenya Linda; Horowitz, Peleg; Greenwald, Noah F et al. (2017) Landscape of Genomic Alterations in Pituitary Adenomas. Clin Cancer Res 23:1841-1851
Paolella, Brenton R; Gibson, William J; Urbanski, Laura M et al. (2017) Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability. Elife 6:
Gibson, William J; Ruan, Daniel T; Paulson, Vera A et al. (2017) Genomic Heterogeneity and Exceptional Response to Dual Pathway Inhibition in Anaplastic Thyroid Cancer. Clin Cancer Res 23:2367-2373
Gibson, William J; Hoivik, Erling A; Halle, Mari K et al. (2016) The genomic landscape and evolution of endometrial carcinoma progression and abdominopelvic metastasis. Nat Genet 48:848-55
Bandopadhayay, Pratiti; Ramkissoon, Lori A; Jain, Payal et al. (2016) MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. Nat Genet 48:273-82
Ceccarelli, Michele; Barthel, Floris P; Malta, Tathiane M et al. (2016) Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma. Cell 164:550-63
Holst, Frederik; Hoivik, Erling A; Gibson, William J et al. (2016) Recurrent hormone-binding domain truncated ESR1 amplifications in primary endometrial cancers suggest their implication in hormone independent growth. Sci Rep 6:25521
Olenchock, Benjamin A; Moslehi, Javid; Baik, Alan H et al. (2016) EGLN1 Inhibition and Rerouting of ?-Ketoglutarate Suffice for Remote Ischemic Protection. Cell 164:884-95
Berg, Anna; Hoivik, Erling A; Mjøs, Siv et al. (2015) Molecular profiling of endometrial carcinoma precursor, primary and metastatic lesions suggests different targets for treatment in obese compared to non-obese patients. Oncotarget 6:1327-39
Ciriello, Giovanni; Gatza, Michael L; Beck, Andrew H et al. (2015) Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer. Cell 163:506-19

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