Sarah Bacus

United Diagnostics, Garden City Park, New York, United States

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Publications (117)

  • Christopher A Hamm · Diarmuid Moran · Kakuturu Rao · [...] · Sarah Bacus
    [Show abstract] [Hide abstract] ABSTRACT: Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer that remains poorly understood at the molecular level. Comprehensive tumor profiling was performed to understand clinically actionable alterations in IBC. Targeted-next-generation sequencing and IHC were performed to identify activated pathways in IBC tumor tissues. siRNA studies examined the impact of IBC genomic variants in cellular models. IBC tumor tissues were further characterized for immune infiltration and immune checkpoint expression by IHC. Genomic analysis identified recurrent alterations in core biological pathways including activating and targetable variants in HER/PI3K/mTOR signaling. High rates of activating HER3 point mutations were discovered in IBC tumors. Cell line studies confirmed a role for mutant HER3 in IBC cell proliferation. Immunological analysis revealed a subset of IBC tumors associated with high CD8+/PD-L1+ lymphocyte infiltration. Immune infiltration positively correlated with an NGS-based estimate of neo-antigen exposure derived from the somatic mutation rate and mutant allele frequency, iScore. Additionally, DNA mismatch repair alterations, which may contribute to higher iScores, occurred at greater frequency in tumors with higher immune infiltration. Our study identifies genomic alterations that mechanistically contribute to oncogenic signaling in IBC and provides a genetic basis for the selection of clinically relevant targeted and combination therapeutic strategies. Furthermore, an NGS-based estimate of neo-antigen exposure developed in this study (iScore) may be a useful biomarker to predict immune infiltration in IBC and other cancers. The iScore may be associated with greater levels of response to immunotherapies such as PD-L1/PD-1 targeted therapies.
    Article · Apr 2016 · Molecular Cancer Therapeutics
  • Source
    Neil L Spector · Faith C Robertson · Sarah Bacus · [...] · Kevin M Koch
    [Show abstract] [Hide abstract] ABSTRACT: The paradigm shift in cancer treatment from cytotoxic drugs to tumor targeted therapies poses new challenges, including optimization of dose and schedule based on a biologically effective dose, rather than the historical maximum tolerated dose. Optimal dosing is currently determined using concentrations of tyrosine kinase inhibitors in plasma as a surrogate for tumor concentrations. To examine this plasma-tumor relationship, we explored the association between lapatinib levels in tumor and plasma in mice and humans, and those effects on phosphorylation of human epidermal growth factor receptors (HER) in human tumors.
    Full-text Article · Nov 2015 · PLoS ONE
  • Kimberly Doherty · Dominique Talbert · Patricia Trusk · [...] · Sarah Bacus
    Article · Sep 2015
  • Dominique R. Talbert · Kimberly Doherty · Patricia Trusk · [...] · Sarah Bacus
    Article · Aug 2015 · Cancer Research
  • Diarmuid Moran · Christopher A. Hamm · Kakuturu Rao · [...] · Sarah S. Bacus
    [Show abstract] [Hide abstract] ABSTRACT: Inflammatory breast Cancer (IBC) is a rare aggressive breast cancer in which cancer cells block the lymph vessels in the skin of the breast. IBC tumors have a high rate of ERBB2 positivity and response to ERBB2 targeted therapies. Due to the rarity of this cancer, the molecular etiology of this disease is poorly understood. Materials & Methods A 208 gene next-generation sequencing (NGS) panel was used to analyze 20 IBC patient tumor and matched normal samples. Tissues were stained for cell signaling proteins and immune-markers. Cell line studies were performed to understand the impact of genomic variants on therapeutic selection. Results Common pathway alterations reoccur among IBC samples that influence genome stability, PI3K signaling, and ERBB signaling. NGS revealed alterations in both the ERBB/PI3K pathways, including: ERBB2 amplification, ERBB3 mutations, and activating PI3K mutations. Immunohistochemistry (IHC) staining for pS6 and pERBB3 identified ERBB/PI3K pathway activity in IBC samples. Cell line studies using siRNA and neutralizing antibodies demonstrate that mutant ERBB3 signaling contributes to IBC proliferation. IBC tumors with high levels of CD8+ immune infiltrate have a significantly higher somatic mutation rate than other IBC tumors. A proposed score (iScore) based on the somatic mutation rate and the average mutant allele frequency, showed greater correlation with the level of CD8+ immune infiltration. Furthermore, tumors with high CD8+ infiltrating lymphocytes were associated with a higher frequency of alterations in DNA mismatch repair (MMR) genes. IHC revealed high levels of the immune checkpoint signaling molecule PD-L1 in the inflammatory infiltrate of IBC tumors. Conclusions This study identifies a higher level of ERBB3 mutations than reported in other cancers and an important role for ERBB3 mutation in IBC. ERBB3 targeted therapies in combination with ERBB/PI3K drugs may be important for IBC treatment. Furthermore, high somatic mutations rates in a subset of IBC tumors harboring MMR mutations lead to greater levels of PD-L1+ immune infiltrates, which suggests a possible benefit from immunotherapies such as anti-PD-L1 antibodies. iScore, a more predictive value of immune infiltration in tumors, may be indicative of the level of neoantigen exposure to the immune system. The utility of the newly proposed iScore is currently being investigated as a method to predict immune cell infiltrates and immunotherapy response in other tumor types.
    Conference Paper · Apr 2015
  • [Show abstract] [Hide abstract] ABSTRACT: Safety pharmacology studies that evaluate new drug entities for potential cardiac liability remain a critical component of drug development. Current studies have shown that in vitro tests utilizing human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CM) may be beneficial for preclinical risk evaluation. We recently demonstrated that an in vitro multi-parameter test panel assessing overall cardiac health and function could accurately reflect the associated clinical cardiotoxicity of 4 FDA-approved targeted oncology agents using hiPS-CM. The present studies expand upon this initial observation to assess whether this in vitro screen could detect cardiotoxicity across multiple drug classes with known clinical cardiac risks. Thus, 24 drugs were examined for their effect on both structural (viability, reactive oxygen species generation, lipid formation, troponin secretion) and functional (beating activity) endpoints in hiPS-CM. Using this screen, the cardiac-safe drugs showed no effects on any of the tests in our panel. However, 16 of 18 compounds with known clinical cardiac risk showed drug-induced changes in hiPS-CM by at least one method. Moreover, when taking into account the Cmax values, these 16 compounds could be further classified depending on whether the effects were structural, functional, or both. Overall, the most sensitive test assessed cardiac beating using the xCELLigence platform (88.9%) while the structural endpoints provided additional insight into the mechanism of cardiotoxicity for several drugs. These studies show that a multi-parameter approach examining both cardiac cell health and function in hiPS-CM provides a comprehensive and robust assessment that can aid in the determination of potential cardiac liability. Copyright © 2015 Elsevier Inc. All rights reserved.
    Article · Apr 2015 · Toxicology and Applied Pharmacology
  • Diarmuid M. Moran · Patricia B. Trusk · Karen Pry · [...] · Sarah S. Bacus
    Article · Dec 2014 · Molecular Cancer Research
  • D. M. Moran · K. Rao · P. Bacon-Trusk · [...] · s.bacus
    [Show abstract] [Hide abstract] ABSTRACT: Background: Inflammatory breast cancer (IBC) is a rare aggressive breast cancer in which cancer cells block the lymph vessels in the skin of the breast. IBC tumors are typically hormone receptor negative but have shown a high rate of HER2 (human epidermal growth factor receptor 2) positivity and response to HER2 targeted therapies such as lapatinib. Genomic drivers associated with progression and drug response of IBC are not well established. This study interrogates the mutational background of IBC to understand drug responses in breast cancer. Materials and Methods: A targeted NGS panel that covers whole coding regions of 208 of the most common cancer related genes (copy numbers and somatic mutations) and rearrangements in 17 well characterized cancer genes was used to analyze 20 IBC patient tumor and matched normal samples. Pathway analysis was performed on genomic variants identified. Cell line studies were performed to understand the impact of genomic variants on drug treatment. Results: Intra- and inter-tumor heterogeneity was observed across the IBC samples studied, however, common pathway motifs were also identified among cases. Multiple variants in the HER signaling pathway were observed including HER2 amplification (54% of samples) and a high rate of ERBB3 mutations (26% of samples). ERBB3 point mutations were discovered in hotspot regions in both the extracellular and kinase domains and occurred at higher rates than previously observed in other cancers. Genomic alterations were also identified among many genes of the PI3K-mTOR pathway in the majority of IBC cases. Activity of the PI3K-mTOR pathway was further confirmed by immunohistochemistry for phosphorylated S6, a target of mTOR kinase activity. Cell studies demonstrated potent effects of lapatinib on proliferation of IBC cells harboring ERBB3 mutations in conjunction with HER2 amplification. Breast cancer cells harboring PI3K mutations and HER2 amplification were less sensitive to lapatinib but were synergistically responsive to a combination of PI3KCA inhibitors and lapatinib. Other frequent genomic alterations were also detected in pathways related to chromatin modification, DNA repair, APC, JAK-STAT, KIT and Notch signaling which may also be novel drug targets in IBC. Notably, hotspot and/or kinase domain mutations were discovered in JAK (1 & 2) and KIT genes in multiple IBC samples. Conclusions: Genomic and protein analysis of IBC identified multiple pathways that may be targetable using single and/or combination targeted therapies in all cases studied. This study also highlighted that drugs such as PI3K/mTOR and novel ERBB3 targeted therapies, used alone or in combination with HER2 inhibitors, may be important in the treatment of IBC. Co-occurrence of ERBB3 mutations and HER2 amplification/overexpression likely sensitize cancer cells to HER2 targeted therapies and should be further explored in other HER2 positive cancers.
    Conference Paper · Nov 2014
  • C. M. Martersteck · S. A. Shell · K. J. Pry · S. S. Bacus
    Conference Paper · Nov 2014
  • [Show abstract] [Hide abstract] ABSTRACT: Ponatinib, a multi-targeted TKI and potent pan-ABL inhibitor, approved for the treatment of Ph+ALL and CML, was temporarily withdrawn from the US market due to severe vascular adverse events. Cardiac-specific toxicities including myocardial infarction, severe congestive heart failure, and cardiac arrhythmias have also been shown with ponatinib. Targeted oncology agents such as ponatinib have transformed cancer treatment but often induce toxicity due to inhibition of survival pathways shared by both cancer and cardiac cells. These toxicities are often missed by the standard preclinical toxicity assessment methods, which include human Ether-à-go-go-Related Gene (hERG) and animal toxicity testing. In this study, we show that a multi-parameter in vitro toxicity screening approach using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM)accurately predicted the cardiac toxicity potential of ponatinib. This in vitro model evaluated ponatinib's effect on the overall cell health, mitochondrial stress, and function of hiPSC-CM and also provided mechanistic insight into the signaling pathways and cellular structures altered with treatment. We show here that ponatinib rapidly inhibits pro-survival signaling pathways, induces structural cardiac toxicity (as shown by actin cytoskeleton damage, mitochondrial stress, cell death, and troponin secretion), and disrupts cardiac cell beating. Most of these effects occurred at doses between 10 - 50X ponatinib's Cmax, a dose range shown to be relevant for accurate prediction of in vivo toxicity. Together these studies show that a comprehensive in vitro screening tool in a more relevant human cardiac cell model can improve the detection of cardiac toxicity with targeted oncology agents such as ponatinib.
    Article · Oct 2014 · Toxicological Sciences
  • Dominique Talbert · Kimberly Doherty · Patricia Trusk · [...] · Sarah Bacus
    Article · Oct 2014 · Cancer Research
  • Diarmuid M. Moran · Patricia B. Trusk · Karen Pry · [...] · Sarah S. Bacus
    Article · Oct 2014 · Cancer Research
  • Source
    Full-text Conference Paper · Jul 2014
  • Diarmuid M Moran · Patricia B Trusk · Karen J Pry · [...] · Sarah S Bacus
    [Show abstract] [Hide abstract] ABSTRACT: KRAS gene mutation is linked to poor prognosis and resistance to therapeutics in Non Small Cell Lung Cancer (NSCLC). In this study, we have explored the possibility of exploiting inherent differences in KRAS mutant cell metabolism for treatment. This study identified a greater dependency on folate metabolism pathways in KRAS mutant compared to KRAS wild type NSCLC cell lines. Microarray gene expression and biological pathway analysis identified higher expression of folate metabolism and purine synthesis related pathways in KRAS mutant NSCLC cells compared to wildtype counterparts. Moreover, pathway analysis and knockdown studies suggest a role for MYC transcriptional activity in the expression of these pathways in KRAS mutant NSCLC cells. Furthermore, KRAS knockdown and overexpression studies demonstrated the ability of KRAS to regulate expression of genes that comprise folate metabolism pathways. Proliferation studies demonstrated higher responsiveness to methotrexate, pemetrexed and other antifolates in KRAS mutant NSCLC cells. Surprisingly, KRAS gene expression is downregulated in KRAS wildtype and KRAS mutant cells by antifolates which may also contribute to higher efficacy of antifolates in KRAS mutant NSCLC cells. In vivo analysis of multiple tumorgraft models in nude mice identified a KRAS mutant tumor among the pemetrexed responsive tumors and also demonstrated an association between expression of folate pathway gene, Methylenetetrahydrofolate Dehydrogenase 2 (MTHFD2), and antifolate activity. Collectively, we identify altered regulation of folate metabolism in KRAS mutant NSCLC cells that may account for higher antifolate activity in this subtype of NSCLC.
    Article · Mar 2014 · Molecular Cancer Therapeutics
  • D. Talbert · K. Doherty · D. Moran · [...] · S. Bacus
    Article · Jan 2014 · Molecular Cancer Therapeutics
  • Source
    [Show abstract] [Hide abstract] ABSTRACT: The human epidermal growth factor receptor 2 (HER2) receptor tyrosine kinase (RTK) oncogene is an attractive therapeutic target for the treatment of HER2 addicted tumors. While lapatinib, an FDA-approved small molecule HER2 and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), represents a significant therapeutic advancement in the treatment of HER2+ breast cancers, responses to lapatinib have not been durable. Consequently, elucidation of mechanisms of acquired therapeutic resistance to HER-directed therapies is of critical importance. Using a functional protein pathway activation mapping strategy, along with targeted genomic knockdowns applied to a series of isogenic-matched pairs of lapatinib sensitive and resistant cell lines, we now report an unexpected mechanism of acquired resistance to lapatinib and other TKIs in class. The signaling analysis revealed that while HER2 was appropriately inhibited in lapatinib resistant cells, EGFR tyrosine phosphorylation was incompletely inhibited. Using a targeted molecular knockdown approach to interrogate the causal molecular underpinnings of EGFR persistent activation, we found that lapatinib resistant cells were no longer oncogene addicted to HER2-HER3-PI3K signaling as seen in the parental lapatinib sensitive cell lines, but instead were dependent upon an heregulin (HRG)-driven HER3-EGFR-PI3K-PDK1 signaling axis. Two FDA-approved EGFR TKIs could not overcome HRG-HER3 mediated activation of EGFR, or reverse lapatinib resistance. The ability to overcome EGFR-mediated acquired therapeutic resistance to lapatinib was demonstrated through molecular knockdown of EGFR and treatment with the irreversible pan-HER TKI neratinib, which blocked HRG-dependent phosphorylation of HER3 and EGFR, resulting in apoptosis of resistant cells. In addition, whereas HRG reversed lapatinib-mediated antitumor effects in parental HER2+ breast cancer cells, neratinib was comparatively resistant to the effects of HRG in parental cells. Finally, we showed that HRG expression is an independent negative predictor of clinical outcome in HER2+ breast cancers, providing potential clinical relevance to our findings. Molecular analysis of acquired therapeutic resistance to lapatinib identified a new resistance mechanism based on incomplete and "leaky" inhibition of EGFR by lapatinib. The selective pressure applied by incomplete inhibition of the EGFR drug target resulted in selection of ligand-driven feedback that sustained EGFR activation in the face of constant exposure to the drug. Inadequate target inhibition driven by a ligand-mediated autocrine feedback loop may represent a broader mechanism of therapeutic resistance to HER TKIs and suggests adopting a different strategy for selecting more effective TKIs to advance into the clinic.
    Full-text Article · Sep 2013 · Breast cancer research: BCR
  • Dominique R. Talbert · Robert L. Wappel · Diarmuid M. Moran · [...] · Sarah S. Bacus
    Article · Aug 2013 · Cancer Research
  • Article · Aug 2013 · Cancer Research
  • [Show abstract] [Hide abstract] ABSTRACT: Tyrosine kinase inhibitors (TKi) have greatly improved the treatment and prognosis of multiple cancer types. However, unexpected cardiotoxicity has arisen in a subset of patients treated with these agents that was not wholly predicted by pre-clinical testing, which centers around animal toxicity studies and inhibition of the human Ether-à-go-go-Related Gene (hERG) channel. Therefore, we sought to determine whether a multi-parameter test panel assessing the effect of drug treatment on cellular, molecular, and electrophysiological endpoints could accurately predict cardiotoxicity. We examined how 4 FDA-approved TKi agents impacted cell viability, apoptosis, reactive oxygen species (ROS) generation, metabolic status, impedance, and ion channel function in human cardiomyocytes. The 3 drugs clinically associated with severe cardiac adverse events (crizotinib, sunitinib, nilotinib) all proved to be cardiotoxic in our in vitro tests while the relatively cardiac-safe drug erlotinib showed only minor changes in cardiac cell health. Crizotinib, an ALK/ MET inhibitor, led to increased ROS production, caspase activation, cholesterol accumulation, disruption in cardiac cell beat rate, and blockage of ion channels. The multi-targeted TKi sunitinib showed decreased cardiomyocyte viability, AMPK inhibition, increased lipid accumulation, disrupted beat pattern, and hERG block. Nilotinib, a second generation Bcr-Abl inhibitor, led to increased ROS generation, caspase activation, hERG block, and an arrhythmic beat pattern. Thus, each drug showed a unique toxicity profile that may reflect the multiple mechanisms leading to cardiotoxicity. This study demonstrates that a multi-parameter approach can provide a robust characterization of drug-induced cardiomyocyte damage that can be leveraged to improve drug safety during early phase development.
    Article · May 2013 · Toxicology and Applied Pharmacology
  • Dominique R. Talbert · Robert L. Wappel · Diarmuid M. Moran · [...] · Sarah S. Bacus
    Article · Jan 2013 · Journal of Cancer Therapy

Publication Stats

6k Citations


  • 2005-2006
    • United Diagnostics
      Garden City Park, New York, United States
    • Duke University
      Durham, North Carolina, United States
  • 2004-2005
    • University of Texas MD Anderson Cancer Center
      Houston, Texas, United States
  • 2002-2005
    • University of Houston
      Houston, Texas, United States
  • 1996-2004
    • Weizmann Institute of Science
  • 2001
    • University of Illinois at Chicago
      Chicago, Illinois, United States