Theresa A. Proia

AstraZeneca (United States)

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Matthew Griffin

Cardiff University

Ronald Herbst

AstraZeneca (United States)

Nabendu Pore

AstraZeneca (United States)

Melanie M. Frigault

AstraZeneca (United States)

Ina Bisha

AstraZeneca (Germany)

Nathan Standifer

Tempest Technologies (United States)

John Meekin

AstraZeneca (United States)

Philip Martin

University of California Division of Agriculture and Natural Resources

Maria Libera Ascierto

AstraZeneca (United States)

Maria Jure‐Kunkel

Genmab (United States)

Cooperative Institutions

AstraZeneca (United States)

190

AstraZeneca (United Kingdom)

131

AstraZeneca (Brazil)

The University of Texas MD Anderson Cancer Center

Harvard University

Kala Pharmaceuticals (United States)

Massachusetts Institute of Technology

University of Cambridge

Dana-Farber Cancer Institute

University of Colorado Denver

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Supplementary Tables S5-S7 from AZD4573 Is a Highly Selective CDK9 Inhibitor That Suppresses MCL-1 and Induces Apoptosis in Hematologic Cancer Cells

Justin Cidado Scott Boiko Theresa A. Proia Douglas Ferguson Steven W. Criscione

List of proteins modulated by AZD4573 (S5), genes rapidly modulated by AZD4573 (S6), and AZD4573 cancer cell line pharmacology (S7).

10.1158/1078-0432.22473186.v1

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Supplementary Materials and Methods and Supplementary Tables 1-2 from Macrophage Activation Status Rather than Repolarization Is Associated with Enhanced Checkpoint Activity in Combination with PI3Kγ Inhibition

Larissa S. Carnevalli Molly A. Taylor Matthew King Anna Coenen-Stass Adina Hughes

Supplementary Materials and Methods. Suplementary Table 1. Tumor Immuno-phenotyping. Suplementary Table 2. Flow cytometry panels.

Table (database)

10.1158/1535-7163.22522330.v1

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Supplementary Figure S5 from Resistance to Durvalumab and Durvalumab plus Tremelimumab Is Associated with Functional STK11 Mutations in Patients with Non–Small Cell Lung Cancer and Is Reversed by STAT3 Knockdown

Nabendu Pore Song Wu Nathan Standifer Maria Jure‐Kunkel Melissa de los Reyes

Characterization of innate and adaptive immune cell recruitment to CT26 STK11 KO tumors compared to CT26 WT. (A) Work flow for single cell RNA (scRNA) analysis of CD45+ cells isolated from CT26 WT and STK11 KO clones. Data analysis including cell quality control and filtering steps used to subset the raw scRNA-seq data into CD45+ cells and the two main immune cell populations subsequently analyzed as described in the Supplementary Appendix. (B) Number of CD45+ immune cells per sample used for downstream analysis. (C) Uniform Manifold Approximation and Projection (UMAP) of CD45+ immune cells colored by major cell populations as determined by Louvain clustering: B cell, monocyte/macrophage/DC (Mono.Macro.DC), neutrophil, T cell/NK cell (T.NK), basophil, and pDC clusters are represented as indicated. (D) UMAP plots showing the expression of key genes used in the identification of immune cell clusters. Ptprc = CD45, immune cell marker; Cd3e = epsilon subunit of CD3 complex, T cell marker; Ncr1 = NKp46, NK cell marker; Csf1r = CSF1 receptor, monocyte/macrophage marker; Csf3r = CSF3 (G-CSF) receptor, neutrophil/gMDSC marker; Siglech, Siglec H, plasmacytoid DC marker; CD19, B cell marker; Mcpt8 = mast cell protease 8, basophil/mast cell marker. (E) Percentage of each cell cluster among CD45+ immune population per sample. (F) Comparison between median percentage of immune cell clusters for CT26 WT and STK11 KO clones as indicated. *p < 0.05, one-way ANOVA. (G) Levels of intratumoral granulocytic (Ly6G+) cells as a fraction of CD45+ immune cells in WT and STK11 KO CT26 tumors as determined by flow cytometry. (H) UMAP representation showing single-cell RNA subclustering of the monocyte/macrophage/DC sub-populations as determined by Louvain clustering. (I) Top highly expressed genes between monocyte/macrophage/DC sub-clusters used for annotation as labeled in K and L. (J) Percentage of monocyte/macrophage/DC sub-populations per sample. (K) Comparison between median percentage of cells that are present in each monocyte/macrophage/DC cluster among CT26 WT and STK11 KO clones. *p < 0.05, one-way ANOVA comparing CT26 STK11 KO clones to CT26 WT. (L) Hierarchical clustering of monocyte/macrophage subpopulations (Mono.Macro) based on M1 and M2 gene signatures, as defined by Orecchioni M, et al (5). Genes were also subjected to hierarchical clustering. (M) Levels of intra-tumoral CD163+ tumor-associated macrophages determined by IHC. (N) CD45neg tumor and non-immune stromal cell RNA levels of chemokines and chemokines associated with recruitment and suppressive function of MDSCs and TAMs and of TMEM173/STING.

10.1158/2159-8290.22540421

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Supplementary Figure S8 from Resistance to Durvalumab and Durvalumab plus Tremelimumab Is Associated with Functional STK11 Mutations in Patients with Non–Small Cell Lung Cancer and Is Reversed by STAT3 Knockdown

Nabendu Pore Song Wu Nathan Standifer Maria Jure‐Kunkel Melissa de los Reyes

Antitumor efficacy of TNFRSF agonist immunotherapies in CT26 STK11wt or KO mice. Survival of mice engrafted with (A) CT26 WT or (B) CT26 STK11 KO clone 26C16 treated with isotype control antibodies, anti-PD-L1 plus anti-CTLA-4 mAbs or immune agonist Abs anti-OX40, anti-ICOS, or anti-CD137, as indicated.

Durvalumab

Tremelimumab

CD137

clone (Java method)

10.1158/2159-8290.22540412.v1

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Abstract 1141: Pharmacokinetic and pharmacodynamic evaluation of human tumor xenograft models treated upon administration of trastuzumab deruxtecan

Cancer Research (2022)

Theresa A. Proia Jelena Urosevic Christina Vasalou Rebecca Sargeant Matthew Griffin

Abstract Introduction: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate comprised of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor approved for the treatment of HER2 positive metastatic breast and gastric cancer. T-DXd has demonstrated antitumor activity in both HER2+ and HER2-low patient populations. Methods: To establish exposure profiles of T-DXd and link with tumor biomarker changes, we administered a single IV dose of T-DXd at 10 mg/kg in human tumor xenograft models representing HER2-positive (NCI-N87; nude) and Her2-low (Capan-1; NOD-SCID) and collected tumor and plasma from 6 h to 336 h post dose. We measured tumor volume in addition to total ADC, total antibody, and free payload in the plasma and assessed biomarkers related to DNA damage in the tumor by western blot (WB) and immunohistochemistry (IHC). Results: In HER2+ NCI-N87 tumor-bearing mice, T-DXd plasma AUC was 342.6ug/ml*day and T1/2 was 3.5 days, while in the HER2-low Capan-1 tumor-bearing mice, T-DXd plasma AUC was 297.2ug/ml*day and T1/2 was 1.4 days. Plasma exposures of free payload (DXd) were less than 1 ng/mL. Both models responded to T-DXd, demonstrating regression over the 14 day study (T/C =-6.08%, NCI-N87 and -96.1%, Capan-1). In NCI-N87, we observed rapid and sustained increases in gamma H2AX (gH2AX), with a 3.5-fold increase in % positive staining by IHC (H-score p<0.001) with gH2AX foci as early as 24h post treatment, and sustained out to 96h. Western blot analysis and quantification of gH2AX revealed a 4.3-fold increase at 48h (p<0.0001), which was sustained out to 96h. Further, we observed significant increases in pRAD50 at 24h (3.6-fold increase by IHC, H-score p<0.001) which was sustained out to 96h. In Capan-1, we observed more diffuse staining of gH2AX and non-significant 1.4-fold increase in gH2AX at 24h. pRAD50 increases were delayed in the Capan-1 model with a 2.8-fold increase observed at 48h and sustained out to 168h post treatment. Conclusions: Plasma exposure of T-DXd in NCI-N87 tumor bearing mice was prolonged compared to Capan-1, possibly due to mouse strain differences. The increased systemic exposure resulted in more rapid and sustained DNA damage as measured by gH2AX and pRAD50 in the NCI-N87 tumor compared to Capan-1. This profile suggests exploration of combinations with DNA damage response inhibitors to inform design of dose and schedule of combination therapy may be warranted. Citation Format: Theresa Proia, Jelena Urosevic, Christina Vasalou, Rebecca Sargeant, Matthew Griffin, Jiaqi Yuan, Anton I. Rosenbaum, Jerome Mettetal. Pharmacokinetic and pharmacodynamic evaluation of human tumor xenograft models treated upon administration of trastuzumab deruxtecan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1141.

Pharmacodynamics

10.1158/1538-7445.am2022-1141

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Abstract 1813: The genetic makeup of patient-derived xenografts shapes the immune landscape of humanized mice tumors

Cancer Research (2021)

Maneesh Singh Laura Bradshaw Laura B. Prickett Griffin Matthew Maryann San Martin

Abstract The complex interplay between the immune system and cancer cells is challenging to model in preclinical species. Many commonly mutated genes that influence tumorigenesis actively participate in the activation, recruitment or suppression of the immune system. A growing body of clinical findings indicates that defined oncogenic driver mutations correlate with immune contexture and associated immunotherapy responses. The goal of this study was to generate a hematopoietic stem cells (HSCs) transplanted humanized mice model using patient-derived xenografts with defined mutations to understand whether genetic alterations in the cancer cells can influence the tumor's immune landscape. Loss of function in the tumor suppressor gene STK11/LKB1 are observed in 5-30% of NSCLC. Patients with STK11 mutations do not typically respond to immune checkpoint blockade, and analysis of patient tumor biopsies indicates that these tumors are poorly infiltrated by immune cells such as T cells and dendritic cells, but with higher density of suppressive myeloid cells and associated cytokines. Therefore, there is an interest to understand ways to improve IO responses in these patients. To determine whether we could recapitulate this biology in a preclinical model, we implanted three STK11mut and one wild type PDX on humanized mice generated from six cord blood donors, and compared the immune infiltration in these tumors. Our results demonstrate efficient engraftment of human immune cells in the peripheral blood (53.1%), spleen (64.2%), and bone marrow (59.3%) of humanized mice (n=29, animals). Along with T and B cells, myeloid immune populations such as monocytes, macrophages and dendritic cells, which are absent in the previous generation of humanized mice, were present in the peripheral blood (monocytes 4.7%, dendritic cells 7.2% ) and bone marrow (macrophage 27.8%, neutrophils 21.6% and 10.2% dendritic cells ) of humanized mice. Tumor human immune subpopulation cells were significantly different (One-way Anova analysis) between the STK11mut (n=3) vs. wild type (n=1) humanized PDXs models (n=7 animals/PDX model). Three STK11mut tumors had low percentage of human CD45+ leukocytes infiltration (STK11mut; 0.9, 1.1 and 2.3% vs. wt; 6.6%) We also found a significantly reduced percentage of CD8+ cytotoxic T cells (STK11mut; 5.6, 3.2, 3.1% vs. wt; 9.6%) and dendritic cells subsets (STK11mut; 3.6, 2.2, 3.1% vs. wt; 5.6%) in the STK11mut PDXs implanted on humanized mice. We have shown efficient engraftment of a multilineage human immune system in immunodeficient mice and a selective infiltration of human immune cells subsets in PDXs representing a key genetic segment of NSCLC. Our novel humanized PDX model can recapitulate human tumor immune reconstitution, providing a valuable opportunity to evaluate the benefit of immunomodulatory therapies and personalize immune intervention strategies. Citation Format: Maneesh Singh, Laura Bradshaw, Laura B. Prickett, Griffin Matthew, Maryann San Martin, Noel Monks, Lisa Drew, Simon T. Barry, Corinne Reimer, Theresa Proia. The genetic makeup of patient-derived xenografts shapes the immune landscape of humanized mice tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1813.

Humanized mouse

Cancer Immunotherapy

Immune checkpoint

10.1158/1538-7445.am2021-1813

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23814, an Inhibitory Antibody of Ligand-Mediated Notch1 Activation, Modulates Angiogenesis and Inhibits Tumor Growth without Gastrointestinal Toxicity

Molecular Cancer Therapeutics (2015)

Theresa A. Proia Feng Jiang Alisa Bell Richard Nicoletti Lingxin Kong

Dysregulation of Notch signaling has been implicated in the development of many different types of cancer. Notch inhibitors are being tested in the clinic, but in most cases gastrointestinal and other toxicities have limited the dosage and, therefore, the effectiveness of these therapies. Herein, we describe the generation of a monoclonal antibody against the ligand-binding domain of the Notch1 receptor that specifically blocks ligand-induced activation. This antibody, 23814, recognizes both human and murine Notch1 with similar affinity, enabling examination of the effects on both tumor and host tissue in preclinical models. 23814 blocked Notch1 function in vivo, inhibited functional angiogenesis, and inhibited tumor growth without causing gastrointestinal toxicity. The lack of toxicity allowed for combination of 23814 and the VEGFR inhibitor tivozanib, resulting in significant growth inhibition of several VEGFR inhibitor-resistant tumor models. Analysis of the gene expression profiles of an extensive collection of murine breast tumors enabled the successful prediction of which tumors were most likely to respond to the combination of 23814 and tivozanib. Therefore, the use of a specific Notch1 antibody that does not induce significant toxicity may allow combination treatment with angiogenesis inhibitors or other targeted agents to achieve enhanced therapeutic benefit.

10.1158/1535-7163.mct-14-1104

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STAT3Antisense Oligonucleotide Remodels the Suppressive Tumor Microenvironment to Enhance Immune Activation in Combination with Anti–PD-L1

Clinical Cancer Research (2020)

Theresa A. Proia Maneesh Singh Richard Woessner Larissa S. Carnevalli Gayathri Bommakanti

Danvatirsen is a therapeutic antisense oligonucleotide (ASO) that selectively targets STAT3 and has shown clinical activity in two phase I clinical studies. We interrogated the clinical mechanism of action using danvatirsen-treated patient samples and conducted back-translational studies to further elucidate its immunomodulatory mechanism of action.Paired biopsies and blood samples from danvatirsen-treated patients were evaluated using immunohistochemistry and gene-expression analysis. To gain mechanistic insight, we used mass cytometry, flow cytometry, and immunofluorescence analysis of CT26 tumors treated with a mouse surrogate STAT3 ASO, and human immune cells were treated in vitro with danvatirsen.Within the tumors of treated patients, danvatirsen uptake was observed mainly in cells of the tumor microenvironment (TME). Gene expression analysis comparing baseline and on-treatment tumor samples showed increased expression of proinflammatory genes. In mouse models, STAT3 ASO demonstrated partial tumor growth inhibition and enhanced the antitumor activity when combined with anti-PD-L1. Immune profiling revealed reduced STAT3 protein in immune and stromal cells, and decreased suppressive cytokines correlating with increased proinflammatory macrophages and cytokine production. These changes led to enhanced T-cell abundance and function in combination with anti-PD-L1.STAT3 ASO treatment reverses a suppressive TME and promotes proinflammatory gene expression changes in patients' tumors and mouse models. Preclinical data provide evidence that ASO-mediated inhibition of STAT3 in the immune compartment is sufficient to remodel the TME and enhance the activity of checkpoint blockade without direct STAT3 inhibition in tumor cells. Collectively, these data provide a rationale for testing this combination in the clinic.

Proinflammatory cytokine

10.1158/1078-0432.ccr-20-1066

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Supplementary Figures 1 and 2 from STAT3 Antisense Oligonucleotide Remodels the Suppressive Tumor Microenvironment to Enhance Immune Activation in Combination with Anti–PD-L1

Theresa A. Proia Maneesh Kumar Singh Richard Woessner Larissa S. Carnevalli Gayathri Bommakanti

Patient STAT reductions and reproducibility of replicates

10.1158/1078-0432.22477028

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Abstract 1650: Discovery of AZD4573, a potent and selective inhibitor of CDK9 that enables transient target engagement for the treatment of hematologic malignancies

Cancer Research (2018)

Bernard Barlaam Chris De Savi Lisa Drew Andrew D. Ferguson Douglas Ferguson

Abstract Cyclin-dependent kinase 9 (CDK9) is a serine/threonine kinase that regulates elongation of transcription through phosphorylation of RNA polymerase II at serine 2 (p-Ser2-RNAPII). Transient inhibition of CDK9 results in reduced protein levels for genes that have short half-lives of transcripts and proteins, thus presenting a potential therapeutic opportunity in tumors dependent upon oncogenes fitting such criteria. One example is Mcl-1, an anti-apoptotic protein that plays a key role in cancer cell survival. A potent and selective CDK9 inhibitor having appropriate physical properties and pharmacokinetics (intravenous administration and short t1/2) would enable short yet tuneable target engagement, allowing high flexibility in order to optimize the efficacy / tolerability balance in the clinic. We previously reported the identification of AZ5576 from an amidopyridine series, as a potent, highly selective and orally bioavailable preclinical inhibitor of CDK9. Here we report further optimization of this series with a focus on pharmacokinetic and physicochemical properties suitable for an intravenous agent with short target engagement. We discuss the Structure Activity Relationships (SAR) and Structure Property Relationships (SPR) in this series, specifically increasing human metabolic clearance (in order to achieve short half-life) and solubility whilst improving potency. This work led to the identification of AZD4573, a potent inhibitor of CDK9 (IC50 of <0.004 μM) with fast-off binding kinetics (t1/2 16 min) and high selectivity versus other kinases, including other CDK family kinases. AZD4573 exhibits a short half-life in multiple preclinical species (less than one hour in rat, dog and monkey) and good solubility for intravenous administration. Short-term treatment with AZD4573 led to a rapid dose- and time-dependent decrease in cellular pSer2-RNAPII, resulting in activation of caspase 3 and cell apoptosis in a broad range of haematological cancer cell lines (e.g. caspase activation EC50 0.0137 μM in an acute myeloid leukemia model MV4-11). Correspondingly, in vivo efficacy was demonstrated in xenograft models derived from multiple haematological tumours (e.g. regression at 15 mg/kg twice weekly in MV4-11 xenografts). These results support AZD4573 as a clinical candidate for the treatment of haematological malignancies (first disclosure of the structure at this meeting). 1 Cidado J et al, AZ5576, a novel, potent and selective CDK9 inhibitor, induces rapid cell death and achieves efficacy in multiple preclinical hematological models, AACR poster presentation, 3572 (2016) Citation Format: Bernard Barlaam, Chris De Savi, Lisa Drew, Andrew D. Ferguson, Douglas Ferguson, Chungang Gu, Janet Hawkins, Alexander W. Hird, Michelle L. Lamb, Nichole O'Connell, Kurt Pike, Theresa Proia, Maryann San Martin, Melissa M. Vasbinder, Jeff Varnes, Jianyan Wang, Wenlin Shao. Discovery of AZD4573, a potent and selective inhibitor of CDK9 that enables transient target engagement for the treatment of hematologic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1650.

Tolerability

CDK inhibitor

Cyclin-dependent kinase 9

10.1158/1538-7445.am2018-1650

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