E. Robert McDonald III, PhD
Cambridge, Massachusetts, United States
Recent cancer genome sequencing efforts (e.g., TCGA) have provided an unprecedented amount of genomic data to help decipher the molecular underpinnings of cancer. However, these large scale projects have failed to reveal novel, recurrently mutated oncogenes that are clinically actionable. Instead, the large majority of newly-identified genetic lesions constitute tumor suppressors. Given that tumor suppressors cannot be targeted directly with current therapeutic strategies, we are focusing our efforts on the application of functional genomic screens towards the systematic identification of synthetic lethal cancer vulnerabilities. For these screens, we apply large scale pharmacological and RNA interference approaches across the Cancer Cell line Encyclopedia, which represents a thoroughly annotated collection of 1000 cancer cell lines. The extensive molecular characterization of the CCLE provides a powerful tool for the identification of novel associations uncovered by these loss-of-function screens.
Based on the current landscape of cancer, a re-dedication to classical oncogenes, such as Ras, is in order, as therapeutic options for these patients still remain limited. The lab focuses on indications that harbor frequent MAPK pathway alterations (e.g., colon, lung, skin, and pancreas) in order to study tissue-specific signaling and feedback mechanisms. All four of these indications are replete with cell line models (>50) that are representative of primary disease, based on expression, mutation, and CN profiles. The lab offers a unique opportunity to employ functional genomic screens to study basic signaling questions, but also those with therapeutic impact, including mechanisms of resistance to targeted agents.
Global chromatin profiling reveals NSD2 mutations in pediatric acute lymphoblastic leukemia
Jaffe JD, Wang Y, Chan HM, Zhang J, Huether R, Kryukov GV, Bhnag HE, Taylor JE, Hu M, Englund, NP, Yan F, Wang Z, McDonald ER 3rd, Wei L, Ma J, Easton J, Yu Z, deBeaumont R, Gibaja V, Venkatesan K, Schlegel R, Sellers WR, Keen N, Caponigro G, Barretina J, Cooke VG, Mullighan C, Carr SA, Downing JR, Garraway LA, Stegmeier F
Nature Genetics 2013 Nov; 45(11):1386-91
A DNA damage response screen identifies RHINO, a 9-1-1 and TopBP1 interacting protein required for ATR signaling
Cotta-Ramusino C*, McDonald ER 3rd*, Hurov K, Sowa ME, Harper JW, Elledge SJ
Science 2011 Jun; 332(6035):1313-7. (*co-first authors)
Suppression of caspase-8 and -10-associated RING proteins results in sensitization to death ligands and inhibition of tumor cell growth
McDonald ER 3rd, El-Deiry WS
PNAS 2004 Apr; 101(16):6170-5.
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