6 results on '"Proia, Theresa A."'
Search Results
2. Quantitative evaluation of trastuzumab deruxtecan pharmacokinetics and pharmacodynamics in mouse models of varying degrees of HER2 expression.
- Author
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Vasalou, Christina, Proia, Theresa A., Kazlauskas, Laura, Przybyla, Anna, Sung, Matthew, Mamidi, Srinivas, Maratea, Kim, Griffin, Matthew, Sargeant, Rebecca, Urosevic, Jelena, Rosenbaum, Anton I., Yuan, Jiaqi, Aluri, Krishna C., Ramsden, Diane, Hariparsad, Niresh, Jones, Rhys D.O., and Mettetal, Jerome T.
- Subjects
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LABORATORY mice , *PHARMACOKINETICS , *PHARMACODYNAMICS , *TRASTUZUMAB , *HUMAN growth , *ANTINEOPLASTIC agents - Abstract
Trastuzumab deruxtecan (T‐DXd; DS‐8201; ENHERTU®) is a human epithelial growth factor receptor 2 (HER2)‐directed antibody drug conjugate (ADC) with demonstrated antitumor activity against a range of tumor types. Aiming to understand the relationship between antigen expression and downstream efficacy outcomes, T‐DXd was administered in tumor‐bearing mice carrying NCI‐N87, Capan‐1, JIMT‐1, and MDA‐MB‐468 xenografts, characterized by varying HER2 levels. Plasma pharmacokinetics (PK) of total antibody, T‐DXd, and released DXd and tumor concentrations of released DXd were evaluated, in addition to monitoring γΗ2AX and pRAD50 pharmacodynamic (PD) response. A positive relationship was observed between released DXd concentrations in tumor and HER2 expression, with NCI‐N87 xenografts characterized by the highest exposures compared to the remaining cell lines. γΗ2AX and pRAD50 demonstrated a sustained increase over several days occurring with a time delay relative to tumoral‐released DXd concentrations. In vitro investigations of cell‐based DXd disposition facilitated the characterization of DXd kinetics across tumor cells. These outputs were incorporated into a mechanistic mathematical model, utilized to describe PK/PD trends. The model captured plasma PK across dosing arms as well as tumor PK in NCI‐N87, Capan‐1, and MDA‐MB‐468 models; tumor concentrations in JIMT‐1 xenografts required additional parameter adjustments reflective of complex receptor dynamics. γΗ2AX longitudinal trends were well characterized via a unified PD model implemented across xenografts demonstrating the robustness of measured PD trends. This work supports the application of a mechanistic model as a quantitative tool, reliably projecting tumor payload concentrations upon T‐DXd administration, as the first step towards preclinical‐to‐clinical translation. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
3. Targeting melanoma’s MCL1 bias unleashes the apoptotic potential of BRAF and ERK1/2 pathway inhibitors
- Author
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Sale, Matthew J., Minihane, Emma, Monks, Noel R., Gilley, Rebecca, Richards, Frances M., Schifferli, Kevin P., Andersen, Courtney L., Davies, Emma J., Vicente, Mario Aladren, Ozono, Eiko, Markovets, Aleksandra, Dry, Jonathan R., Drew, Lisa, Flemington, Vikki, Proia, Theresa, Jodrell, Duncan I., Smith, Paul D., and Cook, Simon J.
- Published
- 2019
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4. PARP inhibition is a modulator of anti-tumor immune response in BRCA-deficient tumors.
- Author
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Staniszewska, Anna D., Armenia, Joshua, King, Matthew, Michaloglou, Chrysiis, Reddy, Avinash, Singh, Maneesh, San Martin, Maryann, Prickett, Laura, Wilson, Zena, Proia, Theresa, Russell, Deanna, Thomas, Morgan, Delpuech, Oona, O'Connor, Mark J., Leo, Elisabetta, Angell, Helen, and Valge-Archer, Viia
- Subjects
IMMUNOMODULATORS ,POLY(ADP-ribose) polymerase ,KILLER cells ,IMMUNE checkpoint proteins ,LETHAL mutations - Abstract
PARP inhibitors are synthetically lethal with BRCA1/2 mutations, and in this setting, accumulation of DNA damage leads to cell death. Because increased DNA damage and subsequent immune activation can prime an anti-tumor immune response, we studied the impact of olaparib ± immune checkpoint blockade (ICB) on anti-tumor activity and the immune microenvironment. Concurrent combination of olaparib, at clinically relevant exposures, with ICB gave durable and deeper anti-tumor activity in the Brca1m BR5 model vs. monotherapies. Olaparib and combination treatment modulated the immune microenvironment, including increases in CD8+ T cells and NK cells, and upregulation of immune pathways, including type I IFN and STING signaling. Olaparib also induced a dose-dependent upregulation of immune pathways, including JAK/STAT, STING and type I IFN, in the tumor cell compartment of a BRCA1m (HBCx-10) but not a BRCA WT (HBCx-9) breast PDX model. In vitro, olaparib induced BRCAm tumor cell-specific dendritic cell transactivation. Relevance to human disease was assessed using patient samples from the MEDIOLA (NCT02734004) trial, which showed increased type I IFN, STING, and JAK/STAT pathway expression following olaparib treatment, in line with preclinical findings. These data together provide evidence for a mechanism and schedule underpinning potential benefit of ICB combination with olaparib. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
5. Frontiers in cancer immunotherapy—a symposium report.
- Author
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Cable, Jennifer, Greenbaum, Benjamin, Pe'er, Dana, Bollard, Catherine M., Bruni, Sofia, Griffin, Matthew E., Allison, James P., Wu, Catherine J., Subudhi, Sumit K., Mardis, Elaine R., Brentjens, Renier, Sosman, Jeffry A., Cemerski, Saso, Zavitsanou, Anastasia‐Maria, Proia, Theresa, Egeblad, Mikala, Nolan, Garry, Goswami, Sangeeta, Spranger, Stefani, and Mackall, Crystal L.
- Subjects
CHIMERIC antigen receptors ,IMMUNOTHERAPY ,CYTOTOXIC T cells ,CD19 antigen - Abstract
Cancer immunotherapy has dramatically changed the approach to cancer treatment. The aim of targeting the immune system to recognize and destroy cancer cells has afforded many patients the prospect of achieving deep, long‐term remission and potential cures. However, many challenges remain for achieving the goal of effective immunotherapy for all cancer patients. Checkpoint inhibitors have been able to achieve long‐term responses in a minority of patients, yet improving response rates with combination therapies increases the possibility of toxicity. Chimeric antigen receptor T cells have demonstrated high response rates in hematological cancers, although most patients experience relapse. In addition, some cancers are notoriously immunologically "cold" and typically are not effective targets for immunotherapy. Overcoming these obstacles will require new strategies to improve upon the efficacy of current agents, identify biomarkers to select appropriate therapies, and discover new modalities to expand the accessibility of immunotherapy to additional tumor types and patient populations. [ABSTRACT FROM AUTHOR]
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- 2021
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6. Genetic Predisposition Directs Breast Cancer Phenotype by Dictating Progenitor Cell Fate.
- Author
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Proia, Theresa A., Keller, Patricia J., Gupta, Piyush B., Klebba, Ina, Jones, Ainsley D., Sedic, Maja, Gilmore, Hannah, Tung, Nadine, Naber, Stephen P., Schnitt, Stuart, Lander, Eric S., and Kuperwasser, Charlotte
- Subjects
GENETICS of breast cancer ,CANCER cells ,CANCER in women ,CANCER patients ,BRCA genes ,TUMOR suppressor genes ,GENETICS - Abstract
Women with inherited mutations in the BRCA1 gene have increased risk of developing breast cancer but also exhibit a predisposition for the development of aggressive basal-like breast tumors. We report here that breast epithelial cells derived from patients harboring deleterious mutations in BRCA1 (BRCA1
mut/+ ) give rise to tumors with increased basal differentiation relative to cells from BRCA1+/+ patients. Molecular analysis of disease-free breast tissues from BRCA1+/+ patients revealed defects in progenitor cell lineage commitment even before cancer incidence. Moreover, we discovered that the transcriptional repressor Slug is an important functional suppressor of human breast progenitor cell lineage commitment and differentiation and that it is aberrantly expressed in BRCA1mut/+ tissues. Slug expression is necessary for increased basal-like phenotypes prior to and after neoplastic transformation. These findings demonstrate that the genetic background of patient populations, in addition to affecting incidence rates, significantly impacts progenitor cell fate commitment and, therefore, tumor phenotype. [ABSTRACT FROM AUTHOR]- Published
- 2011
- Full Text
- View/download PDF
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