Finding new treatments for cancer
Developing effective and specific drug treatments for cancer and related diseases is a major challenge. In MCCB, researchers utilize animal and cell disease models developed through their basic research endeavors as platforms for both chemical and genetic screens to identify new therapeutic compounds or targets. These efforts have led to the identification of new small molecules that have the potential to treat patients with a particular type of leukemia. Chemical screens have also been used to identify specific anti-fungal agents that may protect patients from common hospital pathogens. Unique whole organism-based chemical screens using zebrafish disease models are also ongoing. These efforts are supported by a Small Molecule Screening facility that provides access to chemical libraries, liquid handling and informatics resources, as well as a High-throughput Imaging facility located within MCCB. At the same time, MCCB labs are using both cell- and organism-based genetic screens to identify genes that are essential for cancer initiation or progression, or for related processes such as angiogenesis. In these efforts, MCCB researchers benefit from the RNAi Core facility, which is located within the department and provides genome-wide mouse and human RNAi or CRISPR libraries for cell-based screening.
Click below for more details on chemical and genetic screening efforts in MCCB:
The Bergmann Lab has developed genetic screening methods in Drosophila which were initially designed to identify genes that confer resistance of cancer cells to cell death, a hallmark of cancer. Interestingly, these screens also led to the identification of genes involved in tumor growth and tumor suppression suggesting that genes involved in cell death are intimately linked to cell proliferation and tumor suppression. Characterizing and understanding the function of these genes may ultimately lead to the identification of new drug targets for treatment of cancer.
- Herz et al. (2010). The H3K27me3-demethylase dUTX is a suppressor of Notch- and Rb-dependent tumors in Drosophila. Molecular and Cellular Biology 30, 2485-2497.
- Fan et al. (2010). Dual roles of Drosophila p53 in cell death and cell differentiation. Cell Death & Differentiation 17, 912-921.
- Bergmann A and Steller H (2010). Apoptosis, stem cells and tissue regeneration. Science Signaling. 3, re8.
- Pérez et al. (2015). Autophagy regulates tissue overgrowth in a context-dependent manner. Oncogene. 34(26):3369-3376
The Cantor lab performs mechanistic studies to uncover how the hereditary breast cancer genes protect the genome and suppress cancer. Through biochemical protein purifcation strategies and genome-wide RNA interference (RNAi) screens, the lab seeks to identify novel genes and pathways that function with the hereditary breast cancer genes in DNA repair and tumors suppression. Importantly, these approaches have provided insight towards the regulation of DNA repair pathways, how this regulation is altered in cancer, and how cancer cells evade therapies.
- Cantor, SB, Bell, D, Ganesan, S, Kass, E, Drapkin, R, Grossman, S, Wahrer, D, Sgroi, D, Lane, W, Haber, D, Livingston, D. BACH1, a novel helicase–like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell. 2001; 105:149.
- Litman, R, Peng, M, Jin, Z, Zhang, F, Zhang, J, Powell, S, Andreassen, PR, Cantor, SB. BACH1 is critical for homologous recombination and appears to be the Fanconi anemia gene product FANCJ. Cancer Cell. 2005; 8:255–265.
- Min Peng, Jenny Xie, Anna Ucher, Janet Stavnezer & Cantor SB, Crosstalk between BRCA-Fanconi anemia and mismatch repair pathways prevents MSH2-dependent aberrant DNA damage responses. EMBO J. 2014 June 25: 10.15252/embj.201387530.
- Guillemette S, Serra R, Peng M, Hayes JA, Konstantinopoulos PA, Green MR, and. Cantor SB, Resistance to therapy in BRCA2 mutant cells due to loss of the nucleosome-remodeling factor CHD4, Genes and Development, 2015 Mar 1;29(5):489-94.
The Green lab has performed a series of genome-wide RNA interference (RNAi) screens to identify novel factors involved in various aspects of cancer biology, including oncogene-induced epigenetic silencing, oncogene-induced senescence, transcriptional regulation of tumor suppressor genes and the induction of apoptosis by chemotherapeutic agents. Importantly, the pathways and components revealed by these screens have provided potential new targets for therapeutic intervention.
- Wajapeyee et al. (2008) Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell, 132(3):363-74.
- Wajapeyee et al. (2009) Efficacy of IGFBP7 for treatment of metastatic melanoma and other cancers in mouse models and human cell lines. Mol Cancer Ther, 8(11):3009-14.
- Sheng Z et al. (2010) A genome-wide RNA interference screen reveals an essential CREB3L2-ATF5-MCL1 survival pathway in malignant glioma with therapeutic implications.Nat Med, 16(6):671-7.
- Ma L et al. (2014) A therapeutically targetable mechanism of BCR-ABL-independent imatinib resistance in chronic myeloid leukemia. Sci Transl Med, 6(252):252ra121.
The goal of the Kim lab is to understand how changes in metabolic pathways support cancer cells and their survival within the tumor environment, and to exploit these changes for therapeutic purposes. Cancer cells are dependent on metabolic pathways which involve the formation of toxic metabolites. The lab aims to understand the role of these pathways, and to target these pathways to poison cancer cells with their own metabolites.
- Kim et al. SHMT2 drives glioma cell survivalin ischaemia but imposes a dependence on glycine clearance. (2015) Nature, 520(7547):363-367
The lymphatic system, which normally provides a conduit for fluid drainage in parallel to the circulatory system, can be co-opted as a passageway for metastasizing cancer cells. At the same time, components of the lymphatic system (e.g. lymph nodes) are often removed in the course of surgical treatment for cancer. Thus, both inhibition and stimulation of lymphatic growth is relevant to cancer. The Lawson Lab uses the zebrafish as a model to identify signals important for lymphatic development. In addition to genetic approaches, more recent efforts include using zebrafish lymphatic mutants as a platform for small molecule screens to identify therapeutic compounds that may be used to modulate lymphatic growth in disease settings.
- Villefranc et al. (2013) A truncation allele in vascular endothelial growth factor c reveals distinct modes of signaling during lymphatic and vascular development. Development, 140(7):1497-506