A tumor specific antibody to aid breast cancer screening in women with dense breast tissue

Roy, Lopamudra Das; Dillon, Lloye M.; Zhou, Ru; Moore, Laura J.; Livasy, Chad; El-Khoury, Joe M.; Puri, Rahul; Mukherjee, Pinku

doi:10.18632/genesandcancer.134

Cited by 27 publications

(28 citation statements)

References 40 publications

(43 reference statements)

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“…To enhance tumor-specific targeting, in this study, we aimed to investigate PEG-functionalized PLGA NPs conjugated to monoclonal antibody TAB004. TAB004 specifically recognizes the hypoglycosylated tumor form of MUC1 [ 32 , 46 , 47 ] while sparing recognition of MUC1 on normal epithelial cells. Over 80% of PDA expresses this tumor form of MUC1 and is an established target for immunotherapy [ 48 , 49 ].…”

Section: Discussionmentioning

confidence: 99%

Treatment of pancreatic ductal adenocarcinoma with tumor antigen specific-targeted delivery of paclitaxel loaded PLGA nanoparticles

Fowler

Garmon

et al. 2018

BMC Cancer

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BackgroundPancreatic ductal adenocarcinoma (PDA) remains the most aggressive cancers with a 5-year survival below 10%. Systemic delivery of chemotherapy drugs has severe side effects in patients with PDA and does not significantly improve overall survival rate. It is highly desirable to advance the therapeutic efficacy of chemotherapeutic drugs by targeting their delivery and increasing accumulation at the tumor site. MUC1 is a membrane-tethered glycoprotein that is aberrantly overexpressed in > 80% of PDA thus making it an attractive antigenic target.MethodsPoly lactic-co-glycolic acid nanoparticles (PLGA NPs) conjugated to a tumor specific MUC1 antibody, TAB004, was used as a nanocarrier for targeted delivery into human PDA cell lines in vitro and in PDA tumors in vivo. The PLGA NPs were loaded with fluorescent imaging agents, fluorescein diacetate (FDA) and Nile Red (NR) or isocyanine green (ICG) for in vitro and in vivo imaging respectively or with a chemotherapeutic drug, paclitaxel (PTX) for in vitro cytotoxicity assays. Confocal microscopy was used to visualize internalization of the nanocarrier in vitro in PDA cells with high and low MUC1 expression. The in vivo imaging system (IVIS) was used to visualize in vivo tumor targeting of the nanocarrier. MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay was used to determine in vitro cell survival of cells treated with PTX-loaded nanocarrier. One-sided t-test comparing treatment groups at each concentration and two-way ANOVAs comparing internalization of antibody and PLGA nanoparticles.ResultsIn vitro, TAB004-conjugated ICG-nanocarriers were significantly better at internalizing in PDA cells than its non-conjugated counterpart. Similarly, TAB004-conjugated PTX-nanocarriers were significantly more cytotoxic in vitro against PDA cells than its non-conjugated counterpart. In vivo, TAB004-conjugated ICG-nanocarriers showed increased accumulation in the PDA tumor compared to the non-conjugated nanocarrier while sparing normal organs.ConclusionsThe study provides promising data for future development of a novel MUC1-targeted nanocarrier for direct delivery of imaging agents or drugs into the tumor microenvironment.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4393-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Treatment of pancreatic ductal adenocarcinoma with tumor antigen specific-targeted delivery of paclitaxel loaded PLGA nanoparticles

Fowler

Garmon

et al. 2018

BMC Cancer

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“…A second generation anti-tMUC1 CAR harboring TAB004 Ab scFv was synthesized by subcloning the scFv from TAB004 [21] into the SFG-based retroviral backbone plasmid encoding the transmembrane and intracellular domains of CD28 and CD3ζ (synthesized by Dr. John Maher’s group [30]). This CAR contains a myc tag for detection.…”

Section: Methodsmentioning

confidence: 99%

“…In this study, we introduce a novel anti-tMUC1-CAR T cell using scFv derived from a highly specific anti-tMUC1 monoclonal Ab, TAB004, that does not recognize the normal form of MUC1 [21,22]. TAB004 detects tMUC1 on tissues of PDA and breast cancer patients, on PDA cells, and PDA stem cells, but spares recognition of normal epithelial cells [23,24,25].…”

Section: Introductionmentioning

confidence: 99%

Overcoming Immunological Resistance Enhances the Efficacy of a Novel Anti-tMUC1-CAR T Cell Treatment against Pancreatic Ductal Adenocarcinoma

Yazdanifar

Zhou

Grover

et al. 2019

Cells

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Chimeric antigen receptor (CAR) T cells have shown remarkable success in treating hematologic cancers. However, this efficacy has yet to translate to treatment in solid tumors. Pancreatic ductal adenocarcinoma (PDA) is a fatal malignancy with poor prognosis and limited treatment options. We have developed a second generation CAR T cell using the variable fragments of a novel monoclonal antibody, TAB004, which specifically binds the tumor-associated-MUC1 (tMUC1). tMUC1 is overexpressed on ~85% of all human PDA. We present data showing that TAB004-derived CAR T cells specifically bind to tMUC1 on PDA cells and show robust killing activity; however, they do not bind or kill normal epithelial cells. We further demonstrated that the tMUC1-CAR T cells control the growth of orthotopic pancreatic tumors in vivo. We witnessed that some PDA cells (HPAFII and CFPAC) were refractory to CAR T cell treatment. qPCR analysis of several genes revealed overexpression of indoleamine 2, 3-dioxygenases-1 (IDO1), cyclooxygenase 1 and 2 (COX1/2), and galectin-9 (Gal-9) in resistant PDA cells. We showed that combination of CAR T cells and biological inhibitors of IDO1, COX1/2, and Gal-9 resulted in significant enhancement of CAR T cell cytotoxicity against PDA cells. Overcoming PDA resistance is a significant advancement in the field.

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“…TAB 004 is an antibody developed to target tumor-associated MUC1 (tMUC1), an antigen that is present at high levels in the serum of cancer patients, including pancreatic and breast cancer [ 70 ]. MUC1 is present on the surface of normal cells, and contains extensive O -glycan branching on its N-terminus domain.…”

Section: New Emerging Biomarker For Early Detection Of Breast Cancermentioning

confidence: 99%

An overview of mammographic density and its association with breast cancer

2018

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In 2017, breast cancer became the most commonly diagnosed cancer among women in the US. After lung cancer, breast cancer is the leading cause of cancer-related mortality in women. The breast consists of several components, including milk storage glands, milk ducts made of epithelial cells, adipose tissue, and stromal tissue. Mammographic density (MD) is based on the proportion of stromal, epithelial, and adipose tissue. Women with high MD have more stromal and epithelial cells and less fatty adipose tissue, and are more likely to develop breast cancer in their lifetime compared to women with low MD. Because of this correlation, high MD is an independent risk factor for breast cancer. Further, mammographic screening is less effective in detecting suspicious lesions in dense breast tissue, which can lead to late-stage diagnosis. Molecular differences between dense and non-dense breast tissues explain the underlying biological reasons for why women with dense breasts are at a higher risk for developing breast cancer. The goal of this review is to highlight the current molecular understanding of MD, its association with breast cancer risk, the demographics pertaining to MD, and the environmental factors that modulate MD. Finally, we will review the current legislation regarding the disclosure of MD on a traditional screening mammogram and the supplemental screening options available to women with dense breast tissue.

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A tumor specific antibody to aid breast cancer screening in women with dense breast tissue

Cited by 27 publications

References 40 publications

Treatment of pancreatic ductal adenocarcinoma with tumor antigen specific-targeted delivery of paclitaxel loaded PLGA nanoparticles

Treatment of pancreatic ductal adenocarcinoma with tumor antigen specific-targeted delivery of paclitaxel loaded PLGA nanoparticles

Overcoming Immunological Resistance Enhances the Efficacy of a Novel Anti-tMUC1-CAR T Cell Treatment against Pancreatic Ductal Adenocarcinoma

An overview of mammographic density and its association with breast cancer

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