RESEARCH

Contributions to Science (Selected publications):

1: Repetitive element heterochromatinization by tumor suppressor proteins.
My research provides the first evidence to demonstrate that heterochromatinization and silencing of repetitive elements is an unappreciated facet of pRB-mediated tumor suppression that occurs independent of cell cycle control.

a.    Marshall AE, Ishak CA*, Dick FA. An RB-Condensin II Complex Mediates Long- Range Chromosome Interactions and Influences Expression at Divergently Paired Genes. Mol Cell Biol. 2020 Jan 3;40(2):e00452-19. doi: 10.1128/MCB.00452-19. PMID: 31685548; PMCID: PMC6944469.
                                               i.    Highlighted in: Molecular and Cellular Biology ‘Spotlight articles’

b.    Ishak CA*, Marshall AE, Passos DT, White CR, Kim SJ, Cecchini MJ, Ferwati S, MacDonald WA, Howlett CJ, Welch ID, Rubin SM, Mann MRW, Dick FA. An RB-EZH2 Complex Mediates Silencing of Repetitive DNA Sequences. Molecular Cell. 2016 Dec 15;64(6):1074-1087. doi: 10.1016/j.molcel.2016.10.021. Epub 2016 Nov 23. PMID: 27889452; PMCID: PMC5340194.

i) Highlighted in:
Mol Cell. 2016 Dec 15;64(6):1015-1017. doi: 10.1016/j.molcel.2016.11.035.
Cancer Discovery. 2017;7(1):13. https://doi.org/10.1158/2159-8290.CD-RW2016-228
Mobile DNA ‘Editor’s Picks’ https://mobilednajournal.biomedcentral.com/editors-picks
ii.     Press coverage: CTV News, Rogers News, LHRI
iii.     Awards: Lucille & Norton Wolf Publication Award: Epigenetics, LHRI

c.     Ishak CA*, Dick FA. Conditional haploinsufficiency of the retinoblastoma tumor suppressor gene. Mol Cell Oncol. 2014 Oct 30;2(1):e968069. doi: 10.4161/23723548.2014.968069. PMID: 27308386; PMCID: PMC4905237.

2. Contributions of repetitive DNA towards cancer initiation, immune evasion, and therapy resistance. My work demonstrates that loss of chromatin at repetitive DNA promotes replication stress, mitotic errors, and genome instability that precedes lymphomagenesis upon perturbed pRB function. Similar observations with other tumor suppressors are expanded upon our invited reviews.

a.    Ishak CA*, De Carvalho DD. Reactivation of Endogenous Retroelements in Cancer Development and Therapy. Annual Review of Cancer Research. 2020 Mar4(4):159-176. https://doi.org/10.1146/annurev-cancerbio-030419-033525.
                                               i.     Highlighted in: Annual Reviews ‘Shot of Science’.

b.    Ishak CA*, Coschi CH, Roes MV, Dick FA. Disruption of CDK-resistant chromatin association by pRB causes DNA damage, mitotic errors, and reduces Condensin II recruitment. Cell Cycle. 2017 Aug 3;16(15):1430-1439. doi: 10.1080/15384101.2017.1338984. Epub 2017 Jul 19. PMID: 28723239; PMCID: PMC5553398.
Highlighted in:
New insights into the pRB/ Condensin II interaction. Cell Cycle. 2017;16(20):1859-1860. doi:10.1080/15384101.2017.1360658

c.     Coschi CH, Ishak CA*, Gallo D, Marshall A, Talluri S, Wang J, Cecchini MJ, Martens AL, Percy V, Welch I, Boutros PC, Brown GW, Dick FA. Haploinsufficiency of an RB-E2F1-Condensin II complex leads to aberrant replication and aneuploidy. Cancer Discovery. 2014 Jul;4(7):840-53. doi: 10.1158/2159-8290.CD-14-0215. Epub 2014 Apr 16. PMID: 24740996.

i. Highlighted in:
Cancer Discovery. 2017;7(1):13. https://doi.org/10.1158/2159-8290.CD-RW2016-228
ii. Awards: Dr. Joseph Gilbert Research Contribution of the Year Award, LHRI

3. Approaches to leverage repeat RNA and protein to augment cancer immunotherapies and detection. Cancer-specific epigenetic changes extend beyond the 1-2% of coding sequence in the genome into the 50% comprised of repetitive sequences. This body of work demonstrates that cancer-specific DNA methylation gains / losses at repetitive can be leveraged towards epigenetic therapy selection and DNA methylation-based liquid biopsies.

a.    Ishak CA*, De Carvalho DD. DNA methylation profiling of premalignant lesions as a path to ovarian cancer early detection. Clin Cancer Res. 2020 Sep 28:clincanres.3331.2020. doi: 10.1158/1078-0432.CCR-20-3331. Epub ahead of print. PMID: 32988966.

b.    Taylor K, Loo Yau H, Chakravarthy A, Wang B, Shen SY, Ettayebi I, Ishak CA*, Bedard PL, Abdul Razak A, R Hansen A, Spreafico A, Cescon D, Butler MO, Oza AM, Lheureux S, Stjepanovic N, Van As B, Boross-Harmer S, Wang L, Pugh TJ, Ohashi PS, Siu LL, De Carvalho DD. An open-label, phase II multicohort study of an oral hypomethylating agent CC-486 and durvalumab in advanced solid tumors. J Immunother Cancer. 2020 Aug;8(2):e000883. doi: 10.1136/jitc-2020-000883. PMID: 32753546; PMCID: PMC7406114.

c.     Ishak CA*, Lheureux S, De Carvalho DD. DNA Methylation as a Robust Classifier of Epithelial Ovarian Cancer. Clin Cancer Res. 2019 Oct 1;25(19):5729-5731. doi: 10.1158/1078-0432.CCR-19-1797. Epub 2019 Jul 23. PMID: 31337645.

d.    Ishak CA*, Classon M, De Carvalho DD. Deregulation of Retroelements as an Emerging Therapeutic Opportunity in Cancer. Trends in Cancer. 2018 Aug;4(8):583-597. doi: 10.1016/j.trecan.2018.05.008. Epub 2018 Jun 19. PMID: 30064665.

e.    Cecchini MJ, Ishak CA*, Passos DT, Warner A, Palma DA, Howlett CJ, Driman DK, Dick FA. Loss of the retinoblastoma tumor suppressor correlates with improved outcome in patients with lung adenocarcinoma treated with surgery and chemotherapy. Hum Pathol. 2015 Dec;46(12):1922-34. doi: 10.1016/j.humpath.2015.08.010. Epub 2015 Sep 11. PMID: 26475095.