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Research Collaborate Lab Bench
Thomas McFall, PhD

Thomas McFall, PhD

Assistant Professor

Locations

  • TBRC C4970

Contact Information

General Interests

I am interested in experimental-systems approaches that enable mechanism-based inference in genomic medicine and can help identify patients for selective therapeutic strategies.

Education

Postdoctoral Training, The Salk Institute for Biological Studies, 2017-2020
PhD, Oncology & Cancer Biology, Wayne State University School of Medicine, Karmanos Cancer Institute, 2017
MS, Northern Michigan University, 2012
MBA, Donald W. Main School of Business, Davenport University, 2012
BS, Northern Michigan University, 2008

Biography

My primary research interests focus on longstanding problems and controversies in observed clinical scenarios which cannot not be explained in mechanistic detail. Often times evidence-based medicine can determine optimal treatment regimens for “response” vs “non-response”, yet these clinical guidelines are a result of an evolution of clinical practices and remain absent of the mechanistic underpinnings. My graduate years were focused on the role of progesterone utilizing the progesterone receptor isoform PR-A to promote invasion and metastasis. My discoveries lead to a growing field of progesterone mediated metastasis by regulating multiple pathways, not limited to but including, estrogen receptor signaling and non-coding RNA regulation. Furthermore, I addressed a longstanding controversy in the RAS signaling field, the observation that colorectal cancers harboring a G13D mutation are sensitive to EGFR inhibitors. Utilizing systems biology to explore all the known biochemical parameters of the RAS Pathway, and by employing both computational and experimental methods, I found KRAS-G13D tumors should respond to EGFR inhibition as observed in the clinic. Currently I am building a research program combining my knowledge in Systems biology, MAPK signaling, and nuclear receptor signaling to address ongoing clinical cases of extraordinary responders to better treatment strategies. Furthermore, I have formal training and experience in business strategy development, non-profit 501(c)3 business law, foundation development, and non-profit matched/for-profit collaborations.

Research Interests

Synthetic Lethality

Cancer therapy has entered a new realm where systems pharmacology is leveraged to exploit selective dependencies in tumor cells. Utilizing my training in systems pharmacology and functional screening methods, I have provided biological expertise and leadership to identify novel pharmacological inhibitors of Werner syndrome helicase (WRN) at Ideaya Biosciences as a senior scientist and biology lead. Inhibition of WRN in cancer cells that are microsatellite instability-high (MSI-H), leads to cell cycle arrest and death. Moreover, cells that are microsatellite stable (Healthy cells) are insensitive to WRN inhibition, reducing unwanted toxicity and off target effects. Creating a pharmacological inhibition of WRN helicase function represents a valuable target for cancer therapy, as 10-15 percent of cancers are MSI-H.

RAS signaling

I have focused on resolving a controversy surrounding RAS mutants conferring resistance to EGFR inhibitors. Under current guidelines, patients with an activating RAS mutation are not eligible for EGFR inhibitor therapy. In a retrospective study of clinical trial data, investigators found patients harboring a G13D mutation were sensitive to the EGFR inhibitor Cetuximab. This work has been recapitulated in both cell line and mouse models, however, absent of a detailed mechanism, the medical community has been resistant to implementing this change. We used a systems biology approach paired with experimental models to elucidate the mechanism by which G13D mutations are sensitive to EGFR inhibition. We recently published our findings in Science Signaling, Cell Communication and Signaling, Molecular & Cellular Oncology and Cell Reports. Moreover, have expanded these studies and identified 10 more RAS mutants that show sensitivity to EGFR inhibition.

MAPK signaling cross talk with apo-estrogen receptor
I have investigated a unique scenario where a patient with estrogen receptor positive (ER) ovarian cancer harboring a mutant-KRAS was resistant to MEK inhibitor and Tamoxifen, however when treatment strategy was changed to MEK inhibitor and aromatase inhibitor the patient responded with near complete ablation of the tumor. A mechanism for this finding is unknown. I have worked up a mechanism by which this phenomenon is consistent to what is observed in the basic science setting. We found phosphorylated ER is what is driving growth and is dependent upon both MAPK activation, and the estradiol-dependent ER-GPCR for signaling. This was recently accepted in The Oncologist.

Publications

  • (McFall T, Stites EC.) Cell Rep. 2021 Dec 14;37(11):110096 PMID: 34910921 PMCID: PMC8867612 SCOPUS ID: 2-s2.0-85121146579 12/16/2021

  • (Kato S, McFall T, Takahashi K, Bamel K, Ikeda S, Eskander RN, Plaxe S, Parker B, Stites E, Kurzrock R.) Oncologist. 2021 Apr;26(4):e530-e536 PMID: 33528846 PMCID: PMC8018312 SCOPUS ID: 2-s2.0-85101866994 02/03/2021

  • (McFall T, Schomburg NK, Rossman KL, Stites EC.) Cell Commun Signal. 2020 Nov 05;18(1):179 PMID: 33153459 PMCID: PMC7643456 SCOPUS ID: 2-s2.0-85095115047 11/07/2020

  • (McFall T, Stites EC.) Mol Cell Oncol. 2020;7(2):1701914 PMID: 32158916 PMCID: PMC7051129 03/12/2020

  • (McFall T, Diedrich JK, Mengistu M, Littlechild SL, Paskvan KV, Sisk-Hackworth L, Moresco JJ, Shaw AS, Stites EC.) Sci Signal. 2019 Sep 24;12(600) PMID: 31551296 PMCID: PMC6864030 SCOPUS ID: 2-s2.0-85072619385 09/26/2019

  • (Rosati R, Polin L, Ducker C, Li J, Bao X, Selvakumar D, Kim S, Xhabija B, Larsen M, McFall T, Huang Y, Kidder BL, Fribley A, Saxton J, Kakuta H, Shaw P, Ratnam M.) Clin Cancer Res. 2018 Dec 15;24(24):6509-6522 PMID: 30185422 PMCID: PMC6295231 SCOPUS ID: 2-s2.0-85058440559 09/07/2018

  • (Patki M, McFall T, Rosati R, Huang Y, Malysa A, Polin L, Fielder A, Wilson MR, Lonardo F, Back J, Li J, Matherly LH, Bepler G, Ratnam M.) Sci Rep. 2018 Oct 30;8(1):16006 PMID: 30375484 PMCID: PMC6207728 SCOPUS ID: 2-s2.0-85055615805 10/31/2018

  • (McFall T, McKnight B, Rosati R, Kim S, Huang Y, Viola-Villegas N, Ratnam M.) J Biol Chem. 2018 Jan 26;293(4):1163-1177 PMID: 29162724 PMCID: PMC5787796 SCOPUS ID: 2-s2.0-85041241242 11/23/2017

  • (Rosati R, Patki M, Chari V, Dakshnamurthy S, McFall T, Saxton J, Kidder BL, Shaw PE, Ratnam M.) J Biol Chem. 2016 Dec 09;291(50):25983-25998 PMID: 27793987 PMCID: PMC5207070 SCOPUS ID: 2-s2.0-85002706288 10/30/2016

  • (Rosati R, Chen B, Patki M, McFall T, Ou S, Heath E, Ratnam M, Qin Z.) Mol Pharmacol. 2016 Sep;90(3):225-37 PMID: 27382012 PMCID: PMC4998664 SCOPUS ID: 2-s2.0-84984848137 07/07/2016

  • (McFall T, Patki M, Rosati R, Ratnam M.) Oncotarget. 2015 Oct 20;6(32):33146-64 PMID: 26356672 PMCID: PMC4741755 SCOPUS ID: 2-s2.0-84946031365 09/12/2015

  • (Patki M, Gadgeel S, Huang Y, McFall T, Shields AF, Matherly LH, Bepler G, Ratnam M.) J Thorac Oncol. 2014 Apr;9(4):519-26 PMID: 24736075 PMCID: PMC4075060 SCOPUS ID: 2-s2.0-84922479677 04/17/2014