Bio

Academic Appointments


Honors & Awards


  • R21-Assay Development for High Throughput Screening Grant, NIH/NCI (2010-2012)
  • Travel Fellowship, Anna Henzl Gabor Young Women in Science Fund (2010)
  • Travel Fellowship, Anna Henzl Gabor Young Women in Science Fund (2009)
  • Postdoctoral Fellowship, Susan G. Komen for the Cure (2008-2011)
  • Scholar-in-Training Award, AACR-Bristol-Myers Squibb Oncology (2008)
  • Research Grant, Mary Kay Ash Charitable Foundation (2007-2009)
  • Travel Fellowship, Anna Henzl Gabor Young Women in Science Fund (2007)
  • Deans Postdoctoral Fellowship, Stanford University-School of Medicine (2007)
  • Scholar-in-Training Award, AACR-Merck (2005)
  • New Jersey Cancer Research Award for Scientific Excellence, NJCRR-Eli Lilly (2002)
  • Gallo Award for Outstanding Cancer Research, The Cancer Institute of New Jersey (2001)
  • Young Investigator’s Award, UMDNJ-Department of Pharmacology (2000)

Professional Education


  • Postdoctoral Fellowship, Stanford University School of Medicine, Medicine-Oncology (2011)
  • PhD, Rutgers University/UMDNJ, Molecular and Cellular Pharmacology (2006)
  • MS, Rutgers University/UMDNJ, Molecular and Cellular Pharmacology (2002)
  • BS, University of Southern California, Exercise Science (1995)

Community and International Work


  • Editor

    Topic

    Oncology

    Partnering Organization(s)

    BioMed Research International

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    No

  • Review Editor

    Topic

    Frontiers in Women?s Cancer

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    No

  • Instructor

    Topic

    Biology of Human Cancer

    Partnering Organization(s)

    UC-Berkeley Extension

    Location

    Bay Area

    Ongoing Project

    No

    Opportunities for Student Involvement

    No

  • Discussion Leader

    Topic

    Oxidative Stress & Disease, Session Topic: Protein and Organelle Dysfunction, and Disease

    Partnering Organization(s)

    Gordon-Kenan Research Seminar

    Ongoing Project

    No

    Opportunities for Student Involvement

    No

Research & Scholarship

Current Research and Scholarly Interests


My research focuses on manipulating oxidative DNA damage and repair mechanisms involved in tumorigenesis to develop novel strategies for the treatment and prevention of triple-negative breast cancers, including hereditary breast cancers due to germline mutations in BRCA1. I discovered that these cancers are defective in their ability to undergo repair of oxidative DNA damage by the DNA base-excision repair pathway. I recognized the potential utility of this defect as a functional target for anti-cancer drugs and then identified small-molecules that alter oxidative damage and response pathways in triple-negative/BRCA1-mutant breast cancer cells. I have subjected these molecules to the initial phases of the drug discovery process and am exploring them for therapeutic and/or chemoprevention purposes.

Publications

Journal Articles


  • A clinical trial of lovastatin for modification of biomarkers associated with breast cancer risk. Breast cancer research and treatment Vinayak, S., Schwartz, E. J., Jensen, K., Lipson, J., Alli, E., McPherson, L., Fernandez, A. M., Sharma, V. B., Staton, A., Mills, M. A., Schackmann, E. A., Telli, M. L., Kardashian, A., Ford, J. M., Kurian, A. W. 2013; 142 (2): 389-398

    Abstract

    Pre-clinical and epidemiologic studies provide rationale for evaluating lipophilic statins for breast cancer prevention. We conducted a single-arm, biomarker modulation trial of lovastatin among women with increased risk of breast cancer. Eligibility criteria included a deleterious germline mutation in BRCA1, BRCA2, CDH1, or TP53; lifetime breast cancer risk of ?20 % as estimated by the Claus model; or personal history of estrogen receptor and progesterone receptor-negative breast cancer. Participants received 40 mg of lovastatin orally twice daily for 6 months. We evaluated the following biomarkers before and after lovastatin use: breast duct cytology (primary endpoint), serum lipids, C-reactive protein, insulin-like growth factor-1, IGF binding protein-3, lipid peroxidation, oxidative DNA damage, 3-hydroxy-3-methylglutaryl CoA reductase genotype, and mammographic density. Thirty women were enrolled, and 26 (86.7 %) completed the study. For the primary endpoint of changes in breast duct cytology sampled by random periareolar fine needle aspiration, most participants [57.7 %, 95 % confidence interval (CI) 38.9-74.5 %] showed no change after lovastatin; 19.2 % (CI 8.1-38.3 %) had a favorable change in cytology, 7.7 % (95 % CI 1.0-25.3 %) had an unfavorable change, and 15.4 % (95 % CI 5.5-34.2 %) had equivocal results due to acellular specimens, usually after lovastatin. No significant changes were observed in secondary biomarker endpoints. The study was generally well-tolerated: 4 (13.3 %) participants did not complete the study, and one (3.8 %) required a dose reduction. This trial was technically feasible, but demonstrated no significant biomarker modulation; contributing factors may include insufficient sample size, drug dose and/or duration. The results are inconclusive and do not exclude a favorable effect on breast cancer risk.

    View details for DOI 10.1007/s10549-013-2739-z

    View details for PubMedID 24166281

  • Breast cancers with compromised DNA repair exhibit selective sensitivity to elesclomol DNA REPAIR Alli, E., Ford, J. M. 2012; 11 (5): 522-524

    Abstract

    The basal-like subtype of breast cancers, including those that contain germline mutations in BRCA1, tend to be triple-negative (i.e. lack expression of estrogen and progesterone receptors and lack overexpression/amplification of the HER2/neu oncogene), which renders them relatively insensitive to existing "targeted" therapy. BRCA1-mutated and basal-like breast cancers harbor compromised ability for repairing oxidative DNA damage by the DNA base-excision repair pathway. We found that this defective repair mechanism predicts sensitivity to elesclomol, an experimental therapeutic that produces elevated levels of oxidative DNA damage. In conclusion, BRCA1-mutated and/or basal-like breast cancers may benefit from treatment regimens that include elesclomol.

    View details for DOI 10.1016/j.dnarep.2012.02.003

    View details for Web of Science ID 000304494500008

    View details for PubMedID 22425348

  • Enhanced sensitivity to cisplatin and gemcitabine in Brca1-deficient murine mammary epithelial cells. BMC pharmacology Alli, E., Sharma, V. B., Hartman, A., Lin, P. S., McPherson, L., Ford, J. M. 2011; 11: 7-?

    Abstract

    Breast cancers due to germline mutations or altered expression of the BRCA1 gene associate with an aggressive clinical course and frequently exhibit a "triple-negative" phenotype, i.e. lack of expression of the estrogen and progesterone hormone receptors and lack of overexpression of the HER2/NEU oncogene, thereby rendering them relatively insensitive to hormonal manipulation and targeted HER2 therapy, respectively. BRCA1 plays a role in multiple DNA repair pathways, and thus, when mutated, results in sensitivity to certain DNA damaging drugs.Here, we used a Brca1 murine mammary epithelial cell (MMEC) model to examine the effect of loss of Brca1 on cellular sensitivity to various chemotherapy drugs. To explore novel therapeutic strategies, we included DNA damaging and non-DNA damaging drugs whose mechanisms are dependent and independent of DNA repair, respectively, and drugs that are used in standard and non-standard lines of therapy for breast cancer. To understand the cellular mechanism, we also determined the role that DNA repair plays in sensitivity to these drugs. We found that cisplatin and gemcitabine had the greatest specific therapeutic benefit to Brca1-deficient MMECs, and that when used in combination produced a synergistic effect. This sensitivity may be attributed in part to defective NER, which is one of the DNA repair pathways normally responsible for repairing DNA adducts produced by cisplatin and is shown in this study to be defective in Brca1-deficient MMECs. Brca1-deficient MMECs were not differentially sensitive to the standard breast cancer chemotherapy drugs doxorubicin, docetaxel or 5-FU.Both cisplatin and gemcitabine should be explored in clinical trials for first line regimens for BRCA1-associated and triple-negative breast cancer.

    View details for DOI 10.1186/1471-2210-11-7

    View details for PubMedID 21771338

  • Synergistic Chemosensitivity of Triple-Negative Breast Cancer Cell Lines to Poly(ADP-Ribose) Polymerase Inhibition, Gemcitabine, and Cisplatin CANCER RESEARCH Hastak, K., Alli, E., Ford, J. M. 2010; 70 (20): 7970-7980

    Abstract

    The basal-like subtype of breast cancer is characterized by a triple-negative (TN) phenotype (estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2/neu negative). TN breast cancers share similar gene expression profiles and DNA repair deficiencies with BRCA1-associated breast cancers. BRCA1-mutant cells exhibit sensitivity to gemcitabine, cisplatin, and poly(ADP-ribose) polymerase (PARP) inhibition; therefore, we hypothesized that TN cancer cells may also exhibit sensitivity to these drugs. In this study, we report that TN breast cancer cells are more sensitive to these drugs compared with non-TN breast cancer cells. Moreover, combination treatments indicated that PARP inhibition by the small-molecule inhibitor PJ34 or siRNA knockdown synergized with gemcitabine and cisplatin in TN cells but not in luminal cancer cells. TN cells exhibited reduced repair of UV-induced cyclobutane pyrimidine dimers after PARP inhibition, suggesting that the synergistic effect of PJ34 and gemcitabine or cisplatin reflected inefficient nucleotide excision repair. Mechanistic investigations revealed that in TN cells, PJ34 reduced the levels of ?Np63? with a concurrent increase in p73 and its downstream target p21. Thus, the sensitivity to combination treatment seemed to be mediated by sustained DNA damage and inefficient DNA repair triggering p63/p73-mediated apoptosis. Our results suggest a novel therapeutic strategy to treat women with TN breast cancer, an aggressive disease that presently lacks effective treatment options.

    View details for DOI 10.1158/0008-5472.CAN-09-4521

    View details for Web of Science ID 000282879900024

    View details for PubMedID 20798217

  • Defective Repair of Oxidative DNA Damage in Triple-Negative Breast Cancer Confers Sensitivity to Inhibition of Poly(ADP-Ribose) Polymerase CANCER RESEARCH Alli, E., Sharma, V. B., Sunderesakumar, P., Ford, J. M. 2009; 69 (8): 3589-3596

    Abstract

    Subtypes of breast cancer that represent the two major types of epithelial cells in the breast (luminal and basal) carry distinct histopathologic profiles. Breast cancers of the basal-like subtype, which include the majority of hereditary breast cancers due to mutations in the breast cancer susceptibility gene 1 (BRCA1), frequently assume triple-negative status, i.e., they lack expression of estrogen receptor-alpha and progesterone receptor, and lack overexpression or amplification of the HER2/NEU oncogene. Defects in DNA damage response pathways result in genome instability and lead to carcinogenesis, but may also be exploited for therapeutic purposes. We analyzed repair of oxidative DNA damage by the base-excision repair (BER) pathway, which when aberrant leads to genomic instability and breast carcinogenesis, in cell lines that represent the different subtypes of breast cancer and in the presence of BRCA1 deficiency. We found that basal-like and BRCA1-mutated breast cancer cells were defective in BER of oxidative DNA damage, and that this defect conferred sensitivity to inhibition of poly(ADP-ribose) polymerase, a DNA repair enzyme. The defect may be attributed, at least in part, to a novel role for BRCA1 in the BER pathway. Overall, these data offer preventive, prognostic, and therapeutic usefulness.

    View details for DOI 10.1158/0008-5472.CAN-08-4016

    View details for Web of Science ID 000265314900045

    View details for PubMedID 19351835

  • Reversal of stathmin-mediated resistance to paclitaxel and vinblastine in human breast carcinoma cells MOLECULAR PHARMACOLOGY Alli, E., Yang, J., Ford, J. M., Hait, W. N. 2007; 71 (5): 1233-1240

    Abstract

    Antimicrotubule agents are commonly used chemotherapy drugs for the treatment of breast and other cancers. However, these agents have variable activity partly because of microtubule regulatory proteins. Stathmin, an 18-kDa phosphoprotein that promotes microtubule depolymerization, was found to be frequently overexpressed in breast cancer. We previously identified stathmin-mediated mechanisms of resistance to antimicrotubule agents, including altered drug binding and delayed transit from G(2) into M phase, where these agents are effective in disrupting microtubule dynamics. We hypothesized that by reversing stathmin-mediated depolymerization of microtubules or by promoting entry into mitosis, this could increase sensitivity to antimicrotubule agents in human breast cancer cells overexpressing stathmin. We found that targeting stathmin or wee-1 expression with RNA interference can induce microtubule polymerization and promote G(2)/M progression, respectively, and sensitize stathmin-overexpressing breast cancer cells to paclitaxel and vinblastine. Furthermore, targeting wee-1 led to the phosphorylation of stathmin, which is known to attenuate its activity. Therefore, these data suggest a novel approach to improving the efficacy of certain antimicrotubule agents against breast cancer by regulating the function of stathmin.

    View details for DOI 10.1124/mol.106.029702

    View details for Web of Science ID 000245974900008

    View details for PubMedID 17272681

  • Silencing of stathmin induces tumor-suppressor function in breast cancer cell lines harboring mutant p53 ONCOGENE Alli, E., Yang, J., Hait, W. N. 2007; 26 (7): 1003-1012

    Abstract

    Cancers harboring dominant-negative p53 mutations are often aggressive and difficult to treat. Direct attempts to restore wild-type p53 function have produced little clinical benefit. We investigated whether targeting a p53-target gene could induce certain tumor-suppressor characteristics. We found that inhibition of stathmin, a microtubule regulator that can be transcriptionally repressed by wild-type p53, restored certain wild-type functions to cancer cells with mutant p53. Silencing of stathmin by small interfering RNA (siRNA) in mutant p53 cell lines lowered expression to that observed following activation of wild-type p53 by DNA damage in wild-type p53 cell lines. siRNA-induced repression of stathmin decreased cell proliferation, viability and clonogenicity in mutant p53 cell lines. Furthermore, knockdown of stathmin partially restored cell-cycle regulation and activation of apoptosis. Therefore, targeting stathmin, a gene product that is overexpressed in the presence of mutant p53, may represent a novel approach to treating cancers with aberrant p53 function.

    View details for DOI 10.1038/sj.onc.1209864

    View details for Web of Science ID 000244245400006

    View details for PubMedID 16909102

  • Tubulin Targeting Agents Update on Cancer Therapeutics Hait WN, Rubin E, Alli E, Goodin S 2006; 2 (1): 1-18
  • Effect of stathmin on the sensitivity to antimicrotubule drugs in human breast cancer CANCER RESEARCH Alli, E., Bash-Babula, J., Yang, J. M., Hait, W. N. 2002; 62 (23): 6864-6869

    Abstract

    Stathmin is a p53-regulated protein known to influence microtubule dynamics. Because several chemotherapeutic agents used to treat breast cancer alter the dynamic equilibrium of tubulin polymerization, stathmin may play an important role in determining the sensitivity to these drugs. Therefore, we evaluated the effect of stathmin expression on the action of taxanes and Vinca alkaloids using a panel of human breast cancer cell lines. Cell lines harboring mutant p53 expressed high levels of stathmin. Two cell lines with different levels of endogenous stathmin expression and isogenic-paired cell lines transfected to overexpress stathmin were used to determine whether or not stathmin modulated the sensitivity to drugs. Overexpression of stathmin decreased polymerization of microtubules, markedly decreased binding of paclitaxel, and increased binding of vinblastine. Stathmin overexpression decreased sensitivity to paclitaxel and, to a lesser extent, to vinblastine. In contrast, stathmin content had no significant effect on the sensitivity to chemotherapeutic drugs that do not target microtubules. Cell lines overexpressing stathmin were more likely to enter G(2) but less likely to enter mitosis as determined by fluorescence-activated cell sorting and mitotic index. This effect was magnified when stathmin-overexpressing cells were treated with vinblastine as measured by the detection of proteins phosphorylated in early mitosis. These data suggest that the action of antimicrotubule drugs can be affected by stathmin in at least two ways: (a) altered drug binding; and (b) growth arrest at the G(2) to M boundary. Mutant p53 breast cancers exhibiting high levels of stathmin may be resistant to antimicrotubule agents.

    View details for Web of Science ID 000179641000015

    View details for PubMedID 12460900

  • A phase I/pilot study of sequential doxorubicin/vinorelbine: Effects on p53 and microtubule-associated protein 4 CLINICAL CANCER RESEARCH Bash-Babula, J., Toppmeyer, D., Labassi, M., Reidy, J., Orlick, M., Senzon, R., Alli, E., Kearney, T., August, D., Shih, W. C., Yang, J. M., Hait, W. N. 2002; 8 (5): 1057-1064

    Abstract

    Few molecular determinants of sensitivity to cancer chemotherapy exist. In experimental systems, p53 regulates the sensitivity to antimicrotubule drugs through its effect on microtubule-associated protein 4 (MAP4). MAP4 is the major microtubule-associated protein in nonneuronal tissues and promotes microtubule polymerization. We reported that wild-type p53 induction by doxorubicin in C127 breast cancer cells repressed MAP4, decreased microtubule polymerization, and increased Vinca alkaloid sensitivity. The goals of this Phase I/pilot clinical trial were to determine: (a) the safety of delivering a DNA-damaging agent (doxorubicin) followed in sequence by treatment with an antimicrotubule drug (vinorelbine); and (b) the feasibility of detecting activation of p53 and repression of MAP4 in patients' tissues.Peripheral blood mononuclear cells (PBMNCs) and tumor were obtained from 16 women with locally advanced (stage IIIb) or metastatic (stage IV) breast cancer before doxorubicin treatment and immediately before treatment with vinorelbine 24 or 48 h later.After doxorubicin treatment, p53 increased in 12 of 14 PBMNC and 4 of 10 tumor samples. Changes in MAP4 were variable; however, in samples in which p53 was induced, MAP4 decreased in 7 of 12 PBMNC and 3 of 4 breast cancer specimens. Immunohistochemistry confirmed lower MAP4 expression in tumor cells after doxorubicin treatment. Seven of 16 patients had a partial response, and treatment was well tolerated.These data demonstrate the ability to detect the activation of p53 and the repression of MAP4 in normal and malignant tissues in patients treated with a DNA-damaging agent, and that an antimicrotubule drug can be administered safely at a time when cells may be more sensitive to treatment.

    View details for Web of Science ID 000175547700016

    View details for PubMedID 12006519

Footer Links:

Stanford Medicine Resources: