About
230
Publications
14,491
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
6,494
Citations
Introduction
Skills and Expertise
Publications
Publications (230)
Background: We showed recently that immunizing breast cancer patients with the P10s-PADRE vaccine in combination with chemotherapy activates both humoral and cellular immune responses. Induction of specific antibody response was easily determined by measuring anti-P10s antibodies, however, we observed increase in serum interferon-gamma (IFNg) and t...
Introduction: We demonstrated that vaccination of HR+/HER2− breast cancer subjects with P10s-PADRE cancer vaccine in combination with standard-of-care chemotherapy led to generation of antibodies (Ab), activation of Natural Killer (NK) and T cells, increases in IFNγ and TNFα, and increases in TILs and stromal CD3+ T cells. The current study was con...
Introduction: HR+/HER2− breast cancer is the most common form of breast cancer in the United States. HR+/HER2− tumors are known for a low number of tumor-infiltrating lymphocytes (TILs) and considered less immunogenic than other breast cancer subtypes. We have demonstrated that vaccination with P10s-PADRE, a carbohydrate-mimetic-based peptide, canc...
The anti-CSPG4 monoclonal antibodies (mAbs) have shown anti-tumor activity and therapeutic potential for treating breast cancer. In addition, CSPG4 is a dominant tumor-associated antigen that is also involved in normal-tissue development in humans. Therefore, the potential for off-tumor activity remains a serious concern when targeting CSPG4 therap...
Targeting the diverse glycan repertoire expressed on tumor cells is considered a viable therapeutic strategy to deal with tumor cell heterogeneity. Inherently polyspecific, natural, glycan-reactive antibodies are purported to be protective in thwarting infections and in cancer immunotherapy. Tumor-associated carbohydrate antigens (TACAs) are relate...
Background: We have developed P10s-PADRE, a carbohydrate-mimetic-based peptide, cancer vaccine and demonstrated its safety and immunogenicity in a Phase I clinical trial performed in stage IV breast cancer patients. HR+/HER2- breast cancer is the most common form of breast cancer diagnosed in the United States. These patients face a persistent risk...
Breast cancer patients diagnosed with HR+/HER2- tumors face a persistent risk of distant recurrence long after completion of their treatment. Strategies to induce anti-tumor immune responses could complement standard-of-care therapies for these patients. The current study was performed to examine the feasibility, safety and immunogenicity of adding...
Immune response to a given antigen, particularly in cancer patients, is complex and is controlled by various genetic and environmental factors. Identifying biomarkers that can predict robust response to immunization is an urgent need in clinical cancer vaccine development. Given the involvement of DNA methylation in the development of lymphocytes,...
Introduction:
We have previously shown that the expression of carbohydrate (chondroitin 4) sulfotransferase-11 (CHST11) is elevated in human breast cancer tissues, and that its expression in human breast cancer cell lines is associated with aggressive behavior of cells. The clinical significance of CHST11 expression is unknown, and its function in...
Glycosylation is critical for a wide range of biological processes across both normal and disease states. Carbohydrate antigens, for example, are polymeric chains of diverse monomeric sugar molecules that play a fundamental role in the pathogenicity and virulence of many organisms. Moreover, these pathogen‐associated glycan structures can also be f...
We have developed a peptide mimotope-based cancer vaccine, 10s-ADRE, targeting tumor associated carbohydrate antigens (TACAs). We have previously shown safety, feasibility and induction of immune response in a phase I clinical trial in stage IV breast cancer patients. In the current clinical trial, immunization with 10s-ADRE vaccine is combined wit...
Specific antibody reactivities are routinely used as biomarkers, but the antibody repertoire reactivity (igome) profiles are still neglected. Here, we propose rationally designed peptide arrays as efficient probes for these system level biomarkers. Most IgM antibodies are characterized by few somatic mutations, polyspecificity, and physiological au...
Phyllodes tumors of the breast (PTB) are uncommon stromal-epithelial neoplasms, with the main recommended treatment being surgical removal. However, even with adequate resection, the risk of recurrence in the malignant form remains as high as 40%, and there is no recognized consensus on the most effective drugs for PTB. In the present study, an ex...
The promise of idiotype-based therapeutics has been disappointing forcing a new look at the concept and its potential to generate an effective approach for immunotherapy. Here, the idiotype network theory is revisited with regard to the development of efficacious anti-idiotype vaccines. The experience of polyclonal anti-Idiotype reagents in animal...
Colchicine ( COL ) is the major alkaloid isolated from the plant Colchicum autumnale . It shows strong therapeutic effects towards various types of cancer. Its biological activity is related to its ability to bind to tubulin causing microtubule depolymerization, mitotic arrest, and cell death. The colchicine binding site is an attractive target for...
Specific antibody reactivities are routinely used as biomarkers but the use of antibody repertoire profiles is still awaiting recognition. Here we suggest to expedite the adoption of this class of system level biomarkers by rationally designing a peptide array as an efficient probe for an appropriately chosen repertoire compartment. Most IgM antibo...
Evolutionary theories are necessarily invoked for understanding cancer development at the level of species, at the level of cells and tissues, and for developing effective therapies. It is crucial to view cancer in a Darwinian light, where the differential survival of individual cells is based on heritable variations. In the process of this somatic...
The immune system plays a major role in cancer surveillance. Harnessing its power to treat many cancers is now a reality that has led to cures in hopeless situations where no other solutions were available from traditional anticancer drugs. These spectacular achievements rekindled the oncology community’s interest in extending the benefits to all c...
Specific antibody reactivities are routinely used as biomarkers but the use of antibody repertoire profiles is still awaiting recognition. Here we suggest to expedite the adoption of this class of system level biomarkers by rationally designing a peptide array as an efficient probe for an appropriately chosen repertoire compartment. Most IgM antibo...
16
Background: Immunotherapies that activate Natural Killer (NK) cells can lend to their tumor infiltration or help shape the adaptive response toward a T helper type 1 (Th1) profile thought to favor anti-tumor responses. Methods: We have analyzed the functional NK response to immunization with a carbohydrate mimetic peptide (CMP) vaccine in precli...
Background:
As we are moving away from the traditional chemotherapy era to targeted therapy, the validity of old assessment paradigms associated with therapeutics are being raised in the context of immunotherapy. The old paradigm required elaborate assessment of toxicity with no expectation of efficacy in early phase trials. Safety data from Phase...
Active immunization of cancer patients to induce de novo functional anti-tumor immune responses is an alternative/complementary approach to chemotherapy. Tumor vaccines hold the potential to deliver durable, specific and systemic anti-tumor responses in patients. We have been developing active vaccination strategies targeting tumor associated carbo...
Integrating additive or synergistic antitumor effects that focus on distinct elements of tumor biology are the most rational strategies for cancer treatment. Treatments for breast cancer have increased overall survival, but remain limited by lack of efficacy in a subset of breast cancer patients. The real challenge is to define what elements of tum...
Development of cancer vaccines targeting tumor-associated antigens (TAAs) is an alternative approach to chemotherapy with sustained anti-tumor effects. The success of active immunotherapy has been hampered by tumor-induced immune suppressors. Regulatory T cells (Tregs) are a population of immune suppressors with a proven role in regulating anti-tum...
Breast cancer is a heterogeneous disease, and the different biological subtypes have different prognostic impacts. Neoadjuvant trials have recently become popular as they offer several advantages compared to traditional adjuvant trials. Studies have shown that patients who achieve pathological complete response (pCR) after neoadjuvant treatment hav...
Introduction. Tumor initiation and growth are associated with modifications to the glycan structure of glycoproteins, glycolipids and proteoglycans present on the cell surface. Suppression of the anti-tumor immune response is a putative mechanism linking tumor-associated-glycans to tumor progression. Within a tumor microenvironment, the conversion...
Despite progress in breast cancer treatment, disparity persists in survival time between African American (AA) and Caucasian women in the US. Tumor stage and tumor grade are the major prognostic factors that define tumor aggressiveness and contribute to racial disparity between AA and Caucasian women. Studying the interaction of race with tumor gra...
Background
The effect of moderately elevated blood glucose levels among non-diabetic subjects on cancer prognosis is not well described. The goal of this study was to examine the association of elevated random blood glucose (RBG) levels in non-diabetic breast cancer patients with overall survival (OS) and time to tumor recurrence (TTR).
Results
Fo...
Solvents play an important role in protein folding, protein-protein associations, stability, and specificity of recognition as in the case of antibody-antigen interactions through hydrogen bonds. One of the underappreciated features of protein-associated waters is that it weakens inter-and intra-molecular interactions by modulating electrostatic in...
Tumor-associated carbohydrate antigens (TACAs) support cell survival that could be interrupted by anti-TACA antibodies. Among TACAs that mediate cell survival signals are the neolactoseries antigen Lewis Y (LeY) and the ganglioside GD2. To induce sustained immunity against both LeY and GD2, we developed a carbohydrate mimicking peptide (CMP) as a s...
This review describes the development of monoclonal antibodies and the inception of their use in cancer therapy, their impact on defining cancer biomarkers, and their structural utility in new cancer vaccine development.
© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reser...
The co-evolution of the potential N-glycosylation sites of HIV Clade B gp120 was mapped onto the coevolution network of the protein structure using mean field direct coupling analysis (mfDCA). This was possible for 327 positions with suitable entropy and gap content. Indications of pressure to preserve the evolving glycan shield are seen as well as...
Background: Multiple studies indicate that type II diabetes is associated with an increased mortality in breast cancer. However, in these studies the class of anti-diabetic therapy, remains an obvious confounding factor. Higher mortality has been reported in breast cancer patients treated with insulin than with metformin. Choosing a population of b...
Vol 33, No 15_suppl (May 20 Supplement), 2015: e12502
Background: Multiple studies indicate that type II diabetes is associated with an increased mortality in breast cancer. However, in these studies the class of anti-diabetic therapy, remains an obvious confounding factor. Higher mortality has been reported in breast cancer patients treated with i...
The development of breast cancer is linked to the loss of estrogen receptor (ER) during the course of tumor progression, resulting in loss of responsiveness to hormonal treatment. The mechanisms underlying dynamic ERα gene expression change in breast cancer remain unclear. A range of physiological and biological changes, including increased adipose...
This review discusses the concept of expectations in assessing direct benefit to participants in phase I immunotherapy studies. With the push toward a faster assessment of clinical benefit or efficacy, limiting phase I studies to safety determination only is now viewed as obsolete and has been replaced by designs that draw attention to therapeutic...
Abstract. Our previously published data link P-selectin reactive chondroitin sulfate structures on the surface of breast cancer cells to metastatic behavior of cells. We have shown that a particular sulfation pattern mediated by the expression of carbohydrate (chondroitin 4) sulfotransferase-11 (CHST11) correlates with P-selectin binding and aggres...
We know that certain components including demographics, cultural background, lifestyle choices and lack of access to health care contribute strongly to health disparities in rural regions of the United States. This paper explores perceptions of health, the environment, and the relationships between them that impact breast cancer mortality in the Ar...
Purpose: High levels of Tumor Associated Carbohydrate Antigens (TACAs) correlate with metastasis and worse prognosis. In this dose-escalation Phase I clinical trial, we analyzed the safety and immune response to a reverse-engineered Carbohydrate Mimetic Peptide (CMP), named P10s, in 6 subjects with advanced breast cancer.
Experimental Design: A Pha...
Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA
Introduction: Lung cancer is the most common cancer worldwide, and the leading cancer killer in both men and women in the United States. The 5-year survival rate for lung cancer ranges from <2% to about 70% depending on stage. Current treatment options including surgery, chemoth...
![Figure 2. LIGPLOT [59] of LeY recognition by the germline model...](profile/Anastas-Pashov/publication/264745358/figure/fig6/AS:669707862540305@1536682205819/LIGPLOT-59-of-LeY-recognition-by-the-germline-model-structure-where-Fuc-represents_Q320.jpg)
Antibody response to carbohydrate antigens is often independent of T cells and the process of affinity/specificity improvement is considered strictly dependent on the germinal centers. Antibodies induced during a T cell-independent type 2 (TI-2) response are less variable and less functionally versatile than those induced with T cell help. The anti...
Tumor-Associated Carbohydrate Antigens (TACAs) are broad-spectrum targets for immunotherapy. Immunization with Carbohydrate Mimetic Peptides (CMPs) is a strategy to induce broad-spectrum TACA-reactive antibodies hypothesized to interfere with cellular pathways involved in tumor cell survival. A Phase I study was conducted with a first-in-man CMP re...
Molecular mimicry is fundamental to biology and transcends to many disciplines ranging from immune pathology to drug design. Structural characterization of molecular partners has provided insight into the origins and relative importance of complementarity in mimicry. Chemical complementarity is easy to understand; amino acid sequence similarity bet...
The Wistar Institute under Hilary Koprowski's direction played a preeminent role in bringing the fruits of basic science to clinic through biotechnology and life science enterprises. Koprowski's early view on the utility of monoclonal antibodies has been validated to some extent, because monoclonal therapeutics form one of the fastest growing and m...
Clinical research data generated by a federation of collection mechanisms and systems often produces highly dissimilar data with varying quality. Poor data quality can result in the inefficient use of research data or can even require the repetition of the performed studies, a costly process. This work presents two tools for improving data quality...
Introduction. We have previously demonstrated that the expression levels of carbohydrate (chondroitin 4) sulfotransferase-11 (CHST11) correlates with P-selectin binding and aggressiveness (basal-like, triple-negative and mesenchymal phenotype) of human breast cancer. The present study was performed to establish stably transfected cell lines and stu...
Changes in cell surface glycosylation are a hallmark of the transition from normal to inflamed and neoplastic tissue. Tumor-associated carbohydrate antigens (TACAs) challenge our understanding of immune tolerance, while functioning as immune targets that bridge innate immune surveillance and adaptive antitumor immunity in clinical applications. T-c...
Two major obstacles in developing cancer vaccines are identifying unique tumor-associated antigens (TAA) and overcoming the lack of structural information about TAAs. Unlike progress with T cell-based vaccines, B cell vaccines are less well developed due to discontinuous or spatially disposed B cell epitopes. Synthetic peptides that emulate B cell...
A basic tenet of antibody-based immunity is their specificity to antigenic determinates from foreign pathogen products to abnormal cellular components such as in cancer. However, an antibody has the potential to bind to more than one determinate, be it an antigen or another antibody. These observations led to the idiotype network theory (INT) to ex...
Post-translational modifications of lipids and proteins are important determinants in defining function in both normal- and disease-state biology (Apweiler et al. 1999; Bertozzi and Kiessling 2001; Shental-Bechor and Levy 2009; Varki 1993). In particular, the addition of glycan residues synthesized by the repertoire of glycosyltransferases and glyc...
Introduction: We have previously demonstrated that chondroitin sulfates (CS) play a crucial role in metastatic potential of breast cancer cells. We have shown that the expression level of carbohydrate (chondroitin 4) sulfotransferase-11 (CHST11) correlates with CS-A expression and aggressiveness of human breast cancer cells. The current study was m...
Epidemiological studies have linked obesity with basal-like breast cancer risk in both premenopausal and postmenopausal women, suggesting that obesity may affect tumor phenotype by skewing the microenvironment toward support of more aggressive tumor cell phenotypes (typically ER/PR⁻, HER-2⁻). In order to study the interactions between adipocytes an...
Among the most challenging of clinical targets for cancer immunotherapy are Tumor Associated Carbohydrate Antigens (TACAs). To augment immune responses to TACA we are developing carbohydrate mimetic peptides (CMPs) that are sufficiently potent to activate broad-spectrum anti-tumor reactivity. However, the activation of immune responses against term...
Supplemental Figure S1. Transient transfection of MDA-MB-231 cells with CHST11 siRNA inhibits CHST11 expression (A), anti-CS-A (C) and P-selectin (D) binding with no effect on CSPG4 mRNA (B) or the surface expression of the PG (E).
Supplemental Figure S2. Fold change in the expression of CHST11 and CSPG4 mRNA after transient transfection with CSPG4 siRNA. The expression of genes was measured 48 hours post transfection by qRT-PCR. Fold change is calculated based on the expression of genes in vehicle-treated cells. GAPDH message was used to normalize the data. Transfection with...
We have previously demonstrated that chondroitin sulfate glycosaminoglycans (CS-GAGs) on breast cancer cells function as P-selectin ligands. This study was performed to identify the carrier proteoglycan (PG) and the sulfotransferase gene involved in synthesis of the surface P-selectin-reactive CS-GAGs in human breast cancer cells with high metastat...
Disparities in breast cancer survival rates suggest that biological processes contribute. Translational research addressing health disparities would benefit from using a community-based participatory approach (CBPR) to examine biological processes commonly seen as the proximal causes of illness as well as behavioral and social-ecological "causes of...
Preclinical animal studies convincingly demonstrate that tumor immunity to self-antigens can be actively induced and can translate into effective anti-tumor responses. Among the most challenging of clinical targets for cancer immunotherapy is Tumor Associated Carbohydrate Antigens (TACA). The molecular characterization of TACA suggest that these gl...
Aberrant glycosylation is a universal feature of cancer cells, and certain glycan structures are well-known markers for tumor progression. Availability and composition of sugars in the microenvironment may affect cell glycosylation. Recent studies of human breast tumor cell lines indicate their ability to take up and utilize fructose. Here we teste...
Radiofrequency ablation (RFA), a minimally invasive surgical procedure has an increasing application in the surgical treatment of tumors. Data indicate that RFA might stimulate anti-cancer immunity possibly through the induction of necrosis and heat shock proteins (HSP) expression. This study tests a hypothesis that RFA leads to bidirectional immun...
Effective immunotherapy for cancer depends on cellular responses to tumor antigens. The role of major histocompatibility complex (MHC) in T-cell recognition and T-cell receptor repertoire selection has become a central tenet in immunology. Structurally, this does not contradict earlier findings that T-cells can differentiate between small hapten st...
Learning from the successes of other vaccines that enhance natural and existing protective responses to pathogens, the current effort in HIV vaccine research is directed toward inducing cytotoxic responses. Nevertheless, antibodies are fundamental players in vaccine development and are still considered in the context of passive specific immunothera...
The expression of the Tumor Associated Carbohydrate Antigens such as the neolactoseries antigen Lewis Y (LeY) and gangliosides such as GM2 and GD2/GD3 are amplified on breast cancer cells and is linked to poor prognosis and high risk of disease relapse. Immunotherapy to direct responses to TACA is, therefore, perceived to be of clinical benefit. To...
A macromolecular association scheme is presented whereby a unification of macromolecular interaction and polyelectrolyte theories is developed facilitating an understanding of ion effects on polyelectrolyte transitions. The theory follows the Debye-Hückel-Manning treatment for calculating the difference in net fractional charge associated with a po...
The immune system plays an intricate role in tumorigenesis, therefore cancer immunotherapy borrows concepts both from autoimmunity and vaccinology. Due to tumor-induced immune suppression, the adjuvant setting seems most suitable for immunotherapy, which optimally targets multiple tumor associated antigens after removal of the bulk of the tumor. Th...
Because of its restricted distribution in normal tissues and its high expression on tumors of neuroectodermal origin, GD2 ganglioside is an excellent target for active specific immunotherapy. However, GD2 usually elicits low-titered IgM and no IgG or cellular immune responses, limiting its usefulness as a vaccine for cancer patients. We have previo...
The number of breast cancer patients diagnosed with ductal carcinoma in situ (DCIS) continues to grow. Laboratory and clinical data indicate that DCIS can progress to invasive disease. Carbohydrate-mediated cell-cell adhesion and tumor-stroma interaction play crucial roles in tumorigenesis and tumor aggressive behavior. Breast carcinogenesis may re...
Obesity increases mammary tumor development in Zucker rats following a single administration of the procarcinogen 7,12-dimenthylbenz(a)anthracene (DMBA). Fifty-day-old obese and lean female Zucker rats were orally gavaged with 65 mg/kg DMBA and sacrificed 139 days post DMBA treatment. At the end of the experiment, mammary tumors were detected in 68...
The majority of pathogen vaccines are used within the prophylactic setting as opposed to the therapeutic setting proposed for cancer vaccines. Due to the intricate role of the immune system in tumorigenesis, tumor immunotherapy may have to borrow approaches from autoimmunity. The size of the malignant population that has to be eliminated, the assoc...
Limited immune responses to tumor-associated carbohydrate antigens (TACA) are due in part to their being self-antigens. Immunization with xenoantigens of TACA provides an approach to break tolerance and augment responses to TACA. Carbohydrate mimetic peptides (CMPs) as xenoantigens can induce serum antibodies that target shared carbohydrate residue...
The metastatic breast cancer cell line, 4T1, abundantly expresses the oligosaccharide sialylated Lewis x (sLe(x)). SLe(x) oligosaccharide on tumor cells can be recognized by E- and P-selectin, contributing to tumor metastatic process. We observed that both selectins reacted with this cell line. However, contrary to the E-selectin reactivity, which...
Obesity is associated with increased risk for postmenopausal, but not premenopausal breast cancer. Recently, we reported that intact obese Zucker rats had increased susceptibility to DMBA-induced mammary tumors compared to lean Zucker rats. In the present study, we investigated whether excessive adipose tissue would promote mammary tumor induction...
Mechanisms of broad cross-protection, as seen in viral infection and also applied to vaccines, emphasize preexisting antibodies, CD8+ memory T cells, and accelerated B-cell responses reactive with conserved regions in antigens. Another practical application to induce broad-spectrum responses is making use of multispecific antigen recognition by ant...
The induction of high affinity antibodies capable of broad neutralization and protection against infection and/or disease is a major goal in the development of a vaccine for human immunodeficiency virus (HIV). Insights into the structure and function of the envelope (Env) protein of HIV-1 suggest that the virus is under strong selection pressure by...
Carbohydrate mimetic peptides are designable, and they can carry T-cell epitopes and circumvent tolerance. A mimic-based human immunodeficiency virus (HIV) vaccine can be a viable alternative to carbohydrate-based antigens if the diversity of epitopes found on gp120 can be recapitulated. To improve existing mimics, an attempt was made to study the...
Carbohydrate mimetic peptides of tumor associated carbohydrate antigens (TACA) are T-cell-dependent antigens and, therefore, immunization with these surrogates is predicted to overcome the low immunogenicity of carbohydrate antigens. Consistent with this hypothesis, we show that among the potential immune cells involved, peptide immunization led to...
The mechanisms that guide organ-specific metastases are not fully established. The aberrant expression of carbohydrates may play a fundamental role in defining the molecular mechanisms for metastases to distant organs and facilitate positive interactions within the target organ. The purpose of the present study was to determine the glycomic profile...
Cell surface carbohydrate structures are an important class of tumor antigens. SALe a and its structural isomer SA-LeX have been identified as carbohydrate determinants expressed on many carcinomas, 1 and both have been shown to represent functional ligands of selectins. The crucial role of selectin-dependent neutrophil adhesion in their recruitmen...
The application of in vitro NMR spectroscopy and HNMR metabonomics to breast cancer characterization and detection is discussed. It is a powerful tool for analyzing both aqueous and lipophilic extracts from breast cancer tissue, allowing for the detection and identification of several metabolites that serve as biomarkers for various stages of disea...
Expression of sialyl Lewis(x) (sLe(x)) and sLe(a) on tumor cells is thought to facilitate metastasis by promoting cell adhesion to selectins on vascular endothelial cells. Experiments supporting this concept usually bypass the early steps of the metastatic process by employing tumor cells that are injected directly into the blood. We investigated t...
