Thomas McFall, PhD
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.
Systems Pharmacology for synthetic lethal targets.
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). 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. Moreover, my experience at Ideaya has provided ample training in large -scale project management skills for developing pharmacological agents in multi-disciplinary teams. My role as Senior Scientist include project management, experimental design, liaison for academic collaborations (Broad Institute, Sanger Institute and University of California San Diego), and liaison for GlaxoSmithKline collaboration.
Systems Pharmacology to determine MAPK Dependencies
As a professional collaborator, I maintain a close relationship with my former post-doc mentor Ed Stites. Together, we have embarked to elucidate the role of biophysical parameters of RAS and MAPK-related proteins to refine the definition and characterization of molecular biomarkers. We have recently reported (Science Sig.) that a key parameter in determining if a RAS mutant renders cells insensitive to EGFR inhibition, is its ability to bind to the tumor suppressor NF1. Moreover, there are roughly Twenty Ras mutations that account for 95% of mutations within the human population. We have sought to characterize each of these mutations and determine sensitivity to widely available drugs, such as the anti-EGFR antibody cetuximab. This work has yielded a manuscript accepted and in-press at Cell Reports.
Systems pharmacology approach to treating cancer.
RAS signaling. As a trainee in the Stites lab 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 and Molecular & Cellular Oncology. Moreover, these findings have led to interest in the initiation of a pilot clinical trial study at the Moore’s Cancer Center. This work has been expanded to investigating all the other RAS mutants that occur as outlined in the research plan.
MAPK signaling cross talk with apo-estrogen receptor
In collaboration with Shumei Kato, MD and Razelle Kurzrock, MD (Moore’s Cancer Center), we 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 and continues to respond to this day. 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.
Analysis of the role of nuclear receptors in the progression of cancer.
Progesterone receptor biology. As a graduate student I studied the role of the progesterone receptors (PR) and their role in mediating breast cancer invasiveness. These studies lead to the identification of the short isoform (PR-A) mediating invasiveness by suppressing the repressive effects of the estrogen receptor alpha. Before these studies, it was thought that the long isoform (PR-B) was mediating this effect, independent of estrogen action. These studies clarified the role of low hormone levels on breast cancer invasiveness, and event that is observed in women post-menopause. Furthermore, we have been able to show the role of non-coding microRNAs being regulated by hormone receptors and their role in regulating invasive pathways both in vitro and in vivo. We have published two articles in JBC and Oncotarget on this subject matter.
Targeting ELK1/AR tethering to inhibit prostate cancer cell growth. As a graduate student I supported my colleague Dr. Rosati in the investigation of ELK1 tethering to the androgen receptor. We found that AR drives proliferative genes by tethering to ELK1 on the chromatin. We further examined and mapped exactly where AR tethers to ELK1, and developed a drug screen to identify a small molecule that could block this interaction. We were able to design several small molecules, which has led to a phase 1 clinical trial. This work had led to three publications and a clinical trial.
The role of glucocorticoid receptor alpha in lung cancer treatment strategies. As a student I acted as a co-leader in building a hypothesis driven project elucidating a mechanism of resistance in non-small cell lung cancers to Pemetrexed. We identified that NSCLC’s overexpressing glucocorticoid receptor (GR-Alpha) and were treated with dexamethasone were more resistant to Pemetrexed. Dexamethasone is given one day before Pemetrexed treatment due to skin rash. We showed that GR-alpha high tumors are arrested in G1-phase (transiently) resulting in decreased efficacy of pemetrexed. This study has been verified by a clinical trial and is expected to change the current treatment schedule. Furthermore, we have been able to show long term Dexamethasone treatment as a possible palliative care can cause decreased tumor burden, and increase cellular senescence in GR-alpha high tumors. This work has led to two publications (Scientific Reports and Journal of Thoracic Oncology) and has also led to the initiation of a clinical trial.
(Kato S, McFall T, Takahashi K, Bamel K, Ikeda S, Eskander RN, Plaxe S, Parker B, Stites E, Kurzrock R.) Oncologist. 2021 04;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 11 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 09 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 12 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 10 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 01 26;293(4):1163-1177 PMID: 29162724 PMCID: PMC5787796 SCOPUS ID: 2-s2.0-85041241242 11/23/2017
The Amino-terminal Domain of the Androgen Receptor Co-opts Extracellular Signal-regulated Kinase (ERK) Docking Sites in ELK1 Protein to Induce Sustained Gene Activation That Supports Prostate Cancer Cell Growth.
(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
Hybrid Enzalutamide Derivatives with Histone Deacetylase Inhibitor Activity Decrease Heat Shock Protein 90 and Androgen Receptor Levels and Inhibit Viability in Enzalutamide-Resistant C4-2 Prostate Cancer Cells.
(Rosati R, Chen B, Patki M, McFall T, Ou S, Heath E, Ratnam M, Qin Z.) Mol Pharmacol. 2016 09;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