Gene Regulation and Cell Proliferation Program Program Leader: David L. Spector Program Co-leader: Christopher R. Vakoc Project Summary Alterations in the regulation of gene expression and promiscuous entry into the cell cycle are defining characteristics of human cancer cells. The Gene Regulation and Cell Proliferation Program (GR) represents an interdisciplinary program with the central aim focused on understanding the regulation of gene expression and cell proliferation in cancer cells. The program has three main focus areas: (1) RNA Biology, (2) Cancer Epigenetics, and (3) Cell Proliferation. Research in this Program over the past five years has produced major advances in our understanding of cancer promoting pathways and has led to the discovery of novel therapeutic strategies now under investigation in, or moving toward, human clinical trials. In the area of RNA biology, researchers in the GR Program have shown that machineries that regulate alternative pre-mRNA splicing reactions include a major class of oncoproteins in human breast and skin cancers. In addition, long non-coding RNAs have been causally linked to the differentiation and metastatic programs in breast cancer, thus motivating the evaluation of anti-sense oligonucleotide (ASO)-based therapeutics in pre-clinical models and in human clinical trials. Researchers investigating small RNA pathways have obtained insight into how cancer cells communicate with their microenvironment using exosomes and evade sensitivity to kinase-targeted therapeutics. An epigenetics focus of this program has led to the discovery that hematological malignancies exploit bromodomain-containing proteins to sustain oncogenic enhancer landscapes. This has led to a rationale to target specific bromodomains in cancer, an approach that is now under investigation in ealy stage clinical trials. Epigenomic profiling of mammary gland cell types is also revealing how a woman's risk for developing breast cancer can be modulated by transient signaling events during pregnancy. Studies in the area of DNA replication are focused on the mechanisms of origin recognition proteins and replicative DNA helicases, including those utilized by tumor-causing papillomaviruses. Technology development continues to be a major focus of the GR program. A novel CRISPR-based functional genomics strategy is revealing core gene regulatory circuitries that sustain the cancer cell state and is also identifying strategies to bolster blood stem cell self-renewal. High throughput screening of ASOs targeting long non-coding RNAs is leading to the identification of targetable vulnerabilites in breast cancers. A continued effort that balances basic research into molecular mechanisms with therapeutic development will lead to continued synergies among members of the Program that is fostered by the Cancer Center. Since 9/1/10, the GR Program published 126 cancer-related research articles, 30 (24%) involved multiple Cancer Center members; 11 (9%) from intra-programmatic collaborations and 25 (20%) from inter-programmatic collaborations. As of 8/1/15, scientists in the GR Program held $3.6 million of direct costs secured from NCI, other peer reviewed and non-peer reviewed, cancer-related research support. Of this, $3.2 million was from NCI and other peer reviewed cancer-related funding sources.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Center Core Grants (P30)
Project #
5P30CA045508-32
Application #
9773910
Study Section
Subcommittee I - Transistion to Independence (NCI)
Project Start
Project End
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
32
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Cold Spring Harbor Laboratory
Department
Type
DUNS #
065968786
City
Cold Spring Harbor
State
NY
Country
United States
Zip Code
11724
Aberle, M R; Burkhart, R A; Tiriac, H et al. (2018) Patient-derived organoid models help define personalized management of gastrointestinal cancer. Br J Surg 105:e48-e60
Bhagwat, Anand S; Lu, Bin; Vakoc, Christopher R (2018) Enhancer dysfunction in leukemia. Blood 131:1795-1804
Khan, Jalal A; Maki, Robert G; Ravi, Vinod (2018) Pathologic Angiogenesis of Malignant Vascular Sarcomas: Implications for Treatment. J Clin Oncol 36:194-201
Chen, Wei-Chia; Tareen, Ammar; Kinney, Justin B (2018) Density Estimation on Small Data Sets. Phys Rev Lett 121:160605
Cheng, Derek; Tuveson, David (2018) Kras in Organoids. Cold Spring Harb Perspect Med 8:
Albrengues, Jean; Shields, Mario A; Ng, David et al. (2018) Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice. Science 361:
Cook, Natalie; Basu, Bristi; Smith, Donna-Michelle et al. (2018) A phase I trial of the ?-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma. Br J Cancer 118:793-801
Melnikov, Sergey V; Rivera, Keith D; Ostapenko, Denis et al. (2018) Error-prone protein synthesis in parasites with the smallest eukaryotic genome. Proc Natl Acad Sci U S A 115:E6245-E6253
Krishnan, Navasona; Bonham, Christopher A; Rus, Ioana A et al. (2018) Harnessing insulin- and leptin-induced oxidation of PTP1B for therapeutic development. Nat Commun 9:283
Pommier, Arnaud; Anaparthy, Naishitha; Memos, Nicoletta et al. (2018) Unresolved endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases. Science 360:

Showing the most recent 10 out of 380 publications