S S Bacus

University of Illinois at Chicago, Chicago, Illinois, United States

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Publications (87)607.1 Total impact

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    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.
    American Association for Cancer Research Annual Meeting, Philadelphia, PA; 04/2015
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    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.
    Toxicology and Applied Pharmacology 04/2015; 285(1). DOI:10.1016/j.taap.2015.03.008 · 3.63 Impact Factor
  • Molecular Cancer Research 12/2014; 12(12 Supplement):B25-B25. DOI:10.1158/1557-3125.RASONC14-B25 · 4.50 Impact Factor
  • C. M. Martersteck · S. A. Shell · K. J. Pry · S. S. Bacus
    Annual Meeting of the Association-for-Molecular-Pathology (AMP); 11/2014
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    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.
    Toxicological Sciences 10/2014; 143(1). DOI:10.1093/toxsci/kfu215 · 4.48 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):3674-3674. DOI:10.1158/1538-7445.AM2014-3674 · 9.28 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):4410-4410. DOI:10.1158/1538-7445.AM2014-4410 · 9.28 Impact Factor
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    Intelligent Systems for Molecular Biology, Boston, MA; 07/2014
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    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.
    Molecular Cancer Therapeutics 03/2014; 13(6). DOI:10.1158/1535-7163.MCT-13-0649 · 6.11 Impact Factor
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    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.
    Breast cancer research: BCR 09/2013; 15(5):R85. DOI:10.1186/bcr3480 · 5.88 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):3101-3101. DOI:10.1158/1538-7445.AM2013-3101 · 9.28 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):4423-4423. DOI:10.1158/1538-7445.AM2013-4423 · 9.28 Impact Factor
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    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.
    Toxicology and Applied Pharmacology 05/2013; 272(1). DOI:10.1016/j.taap.2013.04.027 · 3.63 Impact Factor
  • Journal of Cancer Therapy 01/2013; 04(04):907-918. DOI:10.4236/jct.2013.44102
  • Cancer Research 06/2012; 72(8 Supplement):5252-5252. DOI:10.1158/1538-7445.AM2012-5252 · 9.28 Impact Factor
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    ABSTRACT: Epidermal growth factor (EGF)-like growth factors control tumor progression as well as evasion from the toxic effects of chemotherapy. Accordingly, antibodies targeting the cognate receptors, such as EGFR/ErbB-1 and the co-receptor HER2/ErbB-2, are widely used to treat cancer patients, but agents that target the EGF-like growth factors are not available. To circumvent the existence of 11 distinct ErbB ligands, we constructed a soluble fusion protein (hereinafter: TRAP-Fc) comprising truncated extracellular domains of EGFR/ErbB-1 and ErbB-4. The recombinant TRAP-Fc retained high-affinity ligand binding to EGF-like growth factors and partially inhibited growth of a variety of cultured tumor cells. Consistently, TRAP-Fc displayed an inhibitory effect in xenograft models of human cancer, as well as synergy with chemotherapy. Additionally, TRAP-Fc inhibited invasive growth of mammary tumor cells and reduced their metastatic seeding in the lungs of animals. Taken together, the activities displayed by TRAP-Fc reinforce critical roles of EGF-like growth factors in tumor progression, and they warrant further tests of TRAP-Fc in preclinical models.
    Oncogene 11/2011; 31(30):3505-15. DOI:10.1038/onc.2011.518 · 8.56 Impact Factor
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    ABSTRACT: A phase II study of dasatinib, an inhibitor of multiple oncogenic tyrosine kinases including Src, was conducted to evaluate 16-week progression-free rate and tolerability in patients with previously treated metastatic breast cancer (MBC). Real-time assessment of potential tissue biomarkers of Src inhibition was used to optimize dosing. Eligibility criteria required that patients have measurable MBC, biopsiable tumor, and unlimited prior therapies. For the analysis of change in protein biomarkers of Src inhibition, focal adhesion kinase, paxillin, and p-Src, patients underwent metastatic biopsies at baseline and 4 weeks. Patients who tolerated the starting dose of dasatinib (50 or 70 mg orally twice daily) for the first 28-day cycle, and displayed suboptimal Src inhibition, were escalated to a higher dose (70 or 100 mg). The trial was closed early with 31 patients because of a statistical boundary that required at least 4 (13%) patients without disease progression to continue accrual. These 31 patients had a median of 2 prior lines of chemotherapy for MBC. The most notable toxicity was pleural effusions in 16 patients (52%). Twenty patients had evaluable metastatic biopsies. None of the tumors showed the predefined optimal level of Src inhibition at week 4. Single-agent dasatinib did not exhibit significant antitumor activity in patients with heavily pretreated MBC. There were no clinically meaningful decreases before and after dasatinib exposure between exploratory tissue biomarkers of Src inhibition which may be attributable to challenges in defining biomarker endpoints for multitargeted tyrosine kinase inhibitors.
    Clinical Cancer Research 08/2011; 17(18):6061-70. DOI:10.1158/1078-0432.CCR-11-1071 · 8.19 Impact Factor
  • Cancer Research 07/2011; 71(8 Supplement):1146-1146. DOI:10.1158/1538-7445.AM2011-1146 · 9.28 Impact Factor
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    ABSTRACT: ErbB2 tyrosine kinase inhibitors (TKI) block tyrosine autophosphorylation and activation of the full-length transmembrane ErbB2 receptor (p185(ErbB2)). In addition to p185(ErbB2), truncated forms of ErbB2 exist in breast cancer cell lines and clinical tumors. The contribution of these truncated forms, specifically those expressed in tumor cell nuclei, to the development of therapeutic resistance to ErbB2 TKIs has not been previously shown. Here, we show that expression of a 95-kDa tyrosine phosphorylated form of ErbB2, herein referred to as p95L (lapatinib-induced p95) was increased in ErbB2(+) breast cancer cells treated with potent ErbB2 TKIs (lapatinib, GW2974). Expressed in tumor cell nuclei, tyrosine phosphorylation of p95L was resistant to inhibition by ErbB2 TKIs. Furthermore, the expression of p95L was increased in ErbB2(+) breast cancer models of acquired therapeutic resistance to lapatinib that mimic the clinical setting. Pretreatment with proteasome inhibitors blocked p95L induction in response to ErbB2 TKIs, implicating the role of the proteasome in the regulation of p95L expression. In addition, tyrosine phosphorylated C-terminal fragments of ErbB2, generated by alternate initiation of translation and similar in molecular weight to p95L, were expressed in tumor cell nuclei, where they too were resistant to inhibition by ErbB2 TKIs. When expressed in the nuclei of lapatinib-sensitive ErbB2(+) breast cancer cells, truncated ErbB2 rendered cells resistant to lapatinib-induced apoptosis. Elucidating the function of nuclear, truncated forms of ErbB2, and developing therapeutic strategies to block their expression and/or activation may enhance the clinical efficacy of ErbB2 TKIs.
    Molecular Cancer Therapeutics 06/2011; 10(8):1367-74. DOI:10.1158/1535-7163.MCT-10-0991 · 6.11 Impact Factor
  • Cancer Research 04/2011; 71(8 Supplement):4529-4529. DOI:10.1158/1538-7445.AM2011-4529 · 9.28 Impact Factor

Publication Stats

5k Citations
607.10 Total Impact Points

Institutions

  • 2014
    • University of Illinois at Chicago
      Chicago, Illinois, United States
  • 2011
    • Quintiles
      Reading, England, United States
  • 2008
    • Johns Hopkins Medicine
      Baltimore, Maryland, United States
  • 1996–2006
    • United Diagnostics
      Garden City Park, New York, United States
  • 2005
    • Duke University
      Durham, North Carolina, United States
  • 2004
    • University of Texas MD Anderson Cancer Center
      Houston, Texas, United States
  • 1992–2004
    • Weizmann Institute of Science
      Israel
    • Elmhurst College
      Elmhurst, Illinois, United States
  • 2002
    • Ventana Systems, Inc.
      Harvard, Massachusetts, United States
  • 1994
    • Northwestern University
      • Department of Pathology
      Evanston, Illinois, United States
  • 1988
    • Duke University Medical Center
      Durham, North Carolina, United States