Rachel Abbotts, MD/PhD

Research Assistant Professor

Organization:

West Virginia University WVU Cancer Institute

Department:

Department of Medical Oncology

Classification:

Faculty

• BS, University of Leeds, 2004
• MBChB, University of Leeds, 2006
• MRCP, Royal College of Physicians London, 2008
• PhD, Molecular Oncology, University of Nottingham, 2014

Contributions to Science

1. Understanding the role of mutant p53 in the viral mimicry response to epigenetic therapy: Endogenous retroviruses (ERV) are ancient viral genomes that became integrated into mammalian DNA during evolution. Low doses of epigenetic therapy such as DNA methyltransferase inhibitors (DNMTis) stimulate ERV re-expression, producing cytosolic RNA accumulation that is recognized by the cell as a foreign virus – a process known as viral mimicry. Recognition of ERV nucleic acid species utilizes the stimulator of interferon signaling (STING) pathway, which is commonly suppressed in non-small cell lung cancer, and is correlated to immune checkpoint therapy resistance. DNMTi therapy can thus activate STING-mediated immune responses that prime tumors for immune checkpoint therapy response. Response to DNMTi may be dependent on mutation status of the tumor suppressor TP53, which modulates many pathways integrated into the cellular antiviral response, including inflammatory and immune signaling, mitochondrial function, and DNA damage and apoptotic responses. My work utilizes cellular, organoid, and murine models to evaluate mechanisms governing differential responses in TP53-wildtype and -mutant settings. As TP53-mutant status is correlated with low basal STING and poor response to standard therapy, this work has important future implications for treatment strategy in the ~50% of NSCLC harboring TP53 missense mutations. This work was previously supported by a Career Enhancement Program grant from the NIH Epigenetics SPORE.

1. Abbotts R*, Stojanovic L*, Tripathi, K, Coon CM, Marker R, Guarnieri J, Wallace D, Liu S, Wan J, Topper MJ, Nephew KP, Baylin SB, Rassool FV. ZNFX1 is a master regulator for epigenetic reprogramming of mitochondrial inflammasome signaling and pathogen mimicry in cancer cells. *co-first authors. Resubmitted to Cancer Res following revisions in response to reviewer comments.

2. Therapeutic induction of DNA repair defects in NSCLC using epigenetic agents: During my postdoctoral and early faculty career in the Rassool lab at the University of Maryland Baltimore, I utilized inhibitors of DNA methyltransferase (DNMTi) in non-small cell lung cancer (NSCLC) models to induce defects in DNA repair, mediated by reduced expression of key double strand break repair genes. These include factors involved in homologous recombination repair, leading to sensitization to PARP inhibitors, and in non-homologous end joining, producing radiosensitization. This work was supported by an American Cancer Society Institutional Research Grant.

1. Abbotts R*, Dellomo AJ, Rassool FV. Pharmacologic Induction of BRCAness in BRCA-Proficient Cancers: Expanding PARP Inhibitor Use. Cancers 2022; 14(11): 2640 (*corresponding author).
2. Abbotts R, Topper M, Biondi C, Fontaine D, Goswami R, Stojanovic L, Choi EY, McLaughlin L, Xia L, Mahmood J, Lapidus RG, Baylin SB, Rassool FV. DNA methyltransferase inhibitors induce a BRCAness phenotype that sensitizes NSCLC to PARP inhibitor and ionizing radiation. Proc Natl Acad Sci U S A 2019; 116 (45): 22609-22618.
3. Dellomo AJ, Abbotts R, Eberly CL, Karbowski M, Baer MR, Kingsbury TJ, Rassool FV. PARP1 PARYlates and stabilizes STAT5 in FLT3-ITD acute myeloid leukemia and other STAT5-activated cancers. Transl Oncol 2022; 15(1): 101283.
4. Puts G, Jarrett S, Leonard M, Matsangos N, Snyder D, Wang Y, Vincent R, Portney B, Abbotts R, McLaughlin L, Zalzman M, Rassool F, Kaetzel D. Metastasis Suppressor NME1 Modulates Choice of Double-Strand Break Repair Pathways in Melanoma Cells by Enhancing Alternative NHEJ while Inhibiting NHEJ and HR. Int J Mol Sci 2020;21(16): 5896.
5. Abbotts R, Golato T, Wilson DM 3rd. Role of DNA repair in carcinogenesis and cancer therapeutics. Invited review Encyclopedia of Cancer, Third Edition 2019. Amsterdam, The Netherlands: Elsevier.

3. Synthetic lethal targeting of a homologous recombination defect in PTEN-deficient melanoma using inhibitors of human apurinic/apyrimidinic endonuclease 1: My graduate research at the University of Nottingham focused upon modulation of the base excision DNA repair protein APE1 as a therapeutic target in melanoma. I expanded upon the drug development program in place in the laboratory of Dr. Srinivasan Madhusudan to screen potential small molecule inhibitors of APE1 endonuclease activity using a radionuclide incision assay. I assessed the most promising inhibitory compounds for synthetic lethality in PTEN-deficient cells, which had recently emerged as potential marker for a double strand break repair defect. This work was supported by a successful application to a nationally competitive Medical Research Council Clinical Research Training Fellowship, and was awarded a student prize at the National Cancer Research Institute (NCRI) Annual Conference in 2012.

1. Abbotts R and Wilson DM 3rd. Coordination of DNA Single Strand Break Repair. Free Radic Biol Med 2017: 107:228-244.
2. Abbotts R, Jewell R, Nsengimana J, Maloney DJ, Simeonov A et al. Targeting human apurinic/apyrimidinic endonuclease 1 (APE1) in phosphatase and tensin homolog (PTEN) deficient melanoma cells for personalized therapy. Oncotarget 2014; 5(10): 3273-86.
3. Sultana R, Abdel-Fatah T, Abbotts R, Hawkes C, Albarakati N, Seedhouse CH, Ball G, Chan S, Rakha EA, Ellis IO, Madhusudan S. Targeting XRCC1 deficiency in breast cancer for personalized therapy. Cancer Res 2013; 75(5): 1621-34
4. Abdel-Fatah T, Sultana R, Abbotts R, Hawkes C, Seedhouse C, Chan S, Madhusudan S. Clinicopathological and functional significance of XRCC1 expression in ovarian cancer. Int J Cancer 2013; 132(12): 2778-86
5. Sultana R, McNeill DR, Abbotts R, Mohammed MZ, Zdziencka MZ, Qutob H, Seedhouse C, Laughton CA, Fischer PM, Patel PM, Wilson DM 3^rd, Madhusudan S. Synthetic lethal targeting of DNA double-strand break repair deficient cells by human apurinic/apyrimidinic endonuclease inhibitors. Int J Cancer 2012; 131(10):2433-44

Complete List of Published Work
https://www.ncbi.nlm.nih.gov/myncbi/rachel.abbotts.2/bibliography/public/

Dr. Rachel Abbotts, MBChB PhD, joined the WVU Cancer Institute in 2024 as a Research Assistant Professor in the Department of Medical Oncology. Dr. Abbotts is an accomplished basic science researcher whose background also encompasses translational and clinical research and practice in cancer therapy. After completing clinical-academic training in adult internal medicine and medical oncology at the Universities of Manchester and Nottingham (UK), Dr. Abbotts was awarded a three-year Clinical Research Training Fellowship by the Medical Research Council. She joined the laboratory of Professor Srinivasan Madhusudan at the University of Nottingham, where she conducted research on development of DNA repair inhibitors targeting the key base excision repair protein APE1, and applied these to PTEN-deficient melanomas in a synthetic lethality approach, leading to the award of her PhD in 2014. Subsequently, she joined the laboratory of Dr. David Wilson III at the National Institute on Aging, where she focused on the role of base excision DNA repair in the maintenance of mitochondrial health in skeletal muscle. This work, supported by competitive NIH intramural funding, received the NIH Fellows Award for Research Excellence.  

A subsequent faculty appointment in the lab of Dr. Feyruz Rassool at the University of Maryland Baltimore focused on the mechanisms underpinning the therapeutic efficacy of a novel treatment combination regimen in non-small cell lung and other cancers. Her work, published in PNAS, demonstrated that epigenetic modulation by DNMT inhibitors (DNMTi) induces a defect in double strand break repair that sensitizes cancer cells to PARP inhibitors and radiation therapy. In December 2019, Dr. Abbotts was awarded an UMB Institutional Research Grant, funded by the American Cancer Society, to support studies linking this DNMTi-induced repair defect to induction of an interferon-stimulated immune response that modulate response to immune checkpoint therapy. This work built upon our existing understanding of DNMTi-induced ‘viral mimicry’, wherein drug-induced demethylation of endogenous retroviral elements in the human genome leads to cytosolic accumulation of RNA species that are recognized by cellular antiviral mechanisms as foreign nucleic acids, thus triggering immune signaling. This work contributed to the Rassool lab identifying the little-studied RNA binding protein ZNFX1 as a key cytosolic sensor of ERV RNA, linking this protein to a key role in activating a mitochondrial signaling response to virus or viral mimics.

Dr. Abbotts’ pathway to research independence has focused on the role of TP53 in directing the viral mimicry response. The TP53 tumor suppressor is the most commonly altered gene in cancer, with mutational hotspots in the DNA binding domain producing protein with defective folding (structural mutants) or DNA interface (DNA binding mutants). Notably, mutational category can impact functional response to virus or viral mimics, by basally modulating critical elements of the mitochondrial-mediated antiviral response, including bioenergetics, mitochondrial DNA repair, and inflammatory signaling. Dr. Abbotts is employing a range of techniques to interrogate these responses, including next-gen sequencing, state-of-the-art biochemical, molecular, and functional studies, and novel clinically relevant models of lung cancer. As TP53-mutant status is correlated with poor response to standard therapy, this work has important future implications for treatment strategy in the ~50% of lung cancers harboring TP53 missense mutations. The therapeutic potential of Dr. Abbotts’ work was recognized in 2022 by the NIH Epigenetics SPORE with the award of a Career Enhancement Program grant.

Dr. Abbotts has over 14 years’ experience in molecular biology research, developing expertise in widely varied experimental techniques, and remains an enthusiastic and productive bench scientist. She is an experienced project mentor of students from high school through to graduate level, and aims to maximize technical and knowledge expertise through intramural and external collaborations.

Research interests

I study the role of cancer-associated TP53 mutation at the intersection of mitochondrial bioenergetics, mtDNA repair, and cellular antiviral signaling. Studies encompass the spectrum of preclinical research:

1. Interrogation of in-house and publicly available bioinformatic datasets to identify candidate genes, molecular pathways, and functional outcomes impacted by DNMTi treatment, with candidate implementation into future biomarker strategy using in vivo models, primary tumor sample cultures, and clinical trial correlative analyses.
2. Functional characterization of therapeutic sequelae in vitro via wide-ranging molecular & cell-based assays, with a focus on differential therapy responses observed in NSCLC TP53 oncogenic variants.
3. The evaluation of DNMTi treatment in clinically relevant models includes patient-derived organoid/CAF co-cultures and immunocompetent murine models.