Patricia McCoon

The JAK2 Inhibitor AZD1480 Potently Blocks Stat3 Signaling and Oncogenesis in Solid Tumors

Persistent activation of Stat3 is oncogenic and is prevalent in a wide variety of human cancers. Chronic cytokine stimulation is associated with Stat3 activation in some tumors, implicating cytokine receptor-associated Jak family kinases. Using Jak2 inhibitors, we demonstrate a central role of Jaks in modulating basal and cytokine-induced Stat3 activation in human solid tumor cell lines. Inhibition of Jak2 activity is associated with abrogation of Stat3 nuclear translocation and tumorigenesis. The Jak2 inhibitor AZD1480 suppresses the growth of human solid tumor xenografts harboring persistent Stat3 activity. We demonstrate the essential role of Stat3 downstream of Jaks by inhibition of tumor growth using short hairpin RNA targeting Stat3. Our data support a key role of Jak kinase activity in Stat3-dependent tumorigenesis.

Antibody-mediated blockade of integrin ?v?6 inhibits tumor progression in vivo by a transforming growth factor-?–regulated mechanism

The alpha(v)beta(6) integrin is up-regulated on epithelial malignancies and has been implicated in various aspects of cancer progression. Immunohistochemical analysis of alpha(v)beta(6) expression in 10 human tumor types showed increased expression relative to normal tissues. Squamous carcinomas of the cervix, skin, esophagus, and head and neck exhibited the highest frequency of expression, with positive immunostaining in 92% (n = 46), 84% (n = 49), 68% (n = 56), and 64% (n = 100) of cases, respectively. We studied the role of alpha(v)beta(6) in Detroit 562 human pharyngeal carcinoma cells in vitro and in vivo. Prominent alpha(v)beta(6) expression was detected on tumor xenografts at the tumor-stroma interface resembling the expression on human head and neck carcinomas. Nonetheless, coculturing cells in vitro with matrix proteins did not up-regulate alpha(v)beta(6) expression. Detroit 562 cells showed alpha(v)beta(6)-dependent adhesion and activation of transforming growth factor-beta (TGF-beta) that was inhibited >90% with an alpha(v)beta(6) blocking antibody, 6.3G9. Although both recombinant soluble TGF-beta receptor type-II (rsTGF-beta RII-Fc) and 6.3G9 inhibited TGF-beta-mediated Smad2/3 phosphorylation in vitro, there was no effect on proliferation. Conversely, in vivo, 6.3G9 and rsTGF-beta RII-Fc inhibited xenograft tumor growth by 50% (n = 10, P < 0.05) and >90% (n = 10, P < 0.001), respectively, suggesting a role for the microenvironment in this response. However, stromal collagen and smooth muscle actin content in xenograft sections were unchanged with treatments. Although further studies are required to consolidate in vitro and in vivo results and define the mechanisms of tumor inhibition by alpha(v)beta(6) antibodies, our findings support a role for alpha(v)beta(6) in human cancer and underscore the therapeutic potential of function blocking alpha(v)beta(6) antibodies.

A phase I, open-label, multi-center study of the JAK2 inhibitor AZD1480 in patients with myelofibrosis

The anti-tumor activity of AZD1480, a potent, selective inhibitor of Janus-associated kinases 1 and 2, was demonstrated in preclinical models of myeloproliferative neoplasms. In a phase I clinical study, 35 patients with myelofibrosis received 2.5-70mg AZD1480 orally once daily (QD) or 10 or 15mg twice daily (BID) continuously during repeated 28-day cycles. Two patients experienced dose-limiting toxicities: one patient in the 2.5mg QD cohort had a grade 3 lung infiltration/acute pneumonia, and one patient receiving 50mg QD had grade 3 presyncope. Dosing was stopped at 70mg QD after the first patient experienced an adverse neurological event (AE) and evidence of low-grade neurological toxicity in patients on lower doses after the initial month of therapy became apparent. The most common AZD1480-related AEs were dizziness and anemia. AZD1480 was absorbed quickly and eliminated from the plasma rapidly, with a mean terminal half-life of 2.45-8.06h; accumulation was not observed after repeated daily dosing for 28 days. Four patients showed evidence of clinical improvement based on IWG-MRT 2006 criteria. AZD1480 was relatively well tolerated, however, low-grade, reversible neurological toxicity was therapy limiting and led to study termination.

Antisense STAT3 inhibitor decreases viability of myelodysplastic and leukemic stem cells

Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are associated with disease-initiating stem cells that are not eliminated by conventional therapies. Transcriptomic analysis of stem and progenitor populations in MDS and AML demonstrated overexpression of STAT3 that was validated in an independent cohort. STAT3 overexpression was predictive of a shorter survival and worse clinical features in a large MDS cohort. High STAT3 expression signature in MDS CD34+ cells was similar to known preleukemic gene signatures. Functionally, STAT3 inhibition by a clinical, antisense oligonucleotide, AZD9150, led to reduced viability and increased apoptosis in leukemic cell lines. AZD9150 was rapidly incorporated by primary MDS/AML stem and progenitor cells and led to increased hematopoietic differentiation. STAT3 knockdown also impaired leukemic growth in vivo and led to decreased expression of MCL1 and other oncogenic genes in malignant cells. These studies demonstrate that STAT3 is an adverse prognostic factor in MDS/AML and provide a preclinical rationale for studies using AZD9150 in these diseases.

Abstract 2641: AZD4635 A2A receptor occupancy in cynomolgus monkey using PET and its application to an oncology clinical development program

Introduction AZD4635 is an A2A receptor antagonist currently being tested as monotherapy and in combination with durvalumab in patients with advanced solid cancers. High adenosine levels found in tumors are immune suppressive and therefore AZD4635 could potentiate immune checkpoint inhibitors such as durvalumab (anti-PDL1). Predictions of A2A receptor engagement in patients at different doses and at different time points may enable better interpretation of clinical biomarker data measuring effects on immune modulation. A quantitative assessment of the receptor occupancy in the brain of non-human primates was conducted for AZD4635 with PET imaging and the resulting PK/PD model was applied to predict occupancy in humans in tumors. Methods PET measurements of A2AR occupancy in brain was performed using the radioligand [18F]MNI-444 in three anesthetized cynomologus monkeys. PET data acquisition was performed for 120 min following IV-administration of [18F]MNI-444 at baseline and following pretreatment of AZD4635. Sampling for AZD4635 plasma exposure determination was performed. As part of PK/PD analysis of the occupancy data, a novel modification of the non Invasive-LOGAN data analysis of the PET data was performed to obtain a time course of occupancy for each dose. A bio-phase PK/PD mathematical model was then used to describe the relationship of occupancy with circulating concentrations of AZD4635. In parallel, a PK model for AZD4635 in humans was developed using data from cohort 1 (Clinical trial NCT02740985) after 125 mg and used for PK predictions for alternative doses of AZD4635 in the clinic. Results A clear Exposure-Effect relationship was observed for AZD4635-driven A2AR occupancy in cyno brain when dosed 30 min prior to PET measurement. The PK/PD analysis of cyno PET-determined receptor occupancy provided an Occ50 that is in line with the in vitro potency for the compound under physiological concentrations of adenosine in the brain. The resulting PK/PD model has then been applied to predict the level of occupancy in human tumours at other clinically relevant doses. Different simulations were done varying the amount of endogenous adenosine levels. Conclusions AZD4635 was shown to occupy A2AR in cyno brain in an exposure dependent manner. The resulting PK/PD model built using this dataset was used to run simulations of expected tumor receptor occupancy in man and aid clinical dose selection for AZD4635. Sensitivity analysis has shown that prediction of human occupancy in the tumour is highly dependent on adenosine concentrations in the tumour. Simulations with tumor adenosine concentrations of 1 μM indicate that AZD4635 is predicted to provide ~90% receptor occupancy over the whole dosing interval at a clinically relevant dose. Citation Format: Peter Johnstrom, Pablo Morentin Gutierrez, Katarina Varnas, Magnus Schou, Akihiro Takano, Lorraine Jones, Ganesh Mugundu, Patricia McCoon, Paul Lyne, Jeffrey Infante, Gerald Falchook, Manish Patel, Janet Karlix, Melinda Merchant, James Clarke, Alan Cross, Nicholas Seneca, Lars Farde, Miles Congreve, Jon S. Mason, Fiona H. Marshall. AZD4635 A2A receptor occupancy in cynomolgus monkey using PET and its application to an oncology clinical development program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2641. doi:10.1158/1538-7445.AM2017-2641

Abstract 3684: Inhibition of STAT3 by antisense oligonucleotide treatment decreases the immune suppressive tumor microenvironment in syngeneic and GEM tumor models

AZD9150, a gen2.5 antisense oligonucleotide (ASO) targeting human STAT3, has improved drug-like properties compared to previous generation ASO therapeutics, including increased stability and resistance to nucleases, reduced proinflammatory effects, and enhanced potency. We have previously reported that in tumors, STAT3 ASOs are taken up preferentially in stromal and immune cells of the tumor microenvironment (TME). Since AZD9150 is selective for human STAT3, we used a surrogate ASO (muSTAT3 ASO) to explore the pharmacodynamics of ASO-mediated STAT3 inhibition in syngeneic and genetically engineered mouse (GEM) tumor models, focusing on effects in the TME. In mice bearing subcutaneous CT-26 tumors, treatment with muSTAT3 ASO at 50 mg/kg, s.c., on a qdx5/wk schedule decreased STAT3 levels in immune cell subsets in the tumor and in circulating leukocytes by 40 - 60%, similar to the decrease in STAT3 achievable in circulating leukocytes in human patients after AZD9150 treatment. In a Nanostring analysis (nCounter mouse immunology panel) of CT-26 tumors from muSTAT3 ASO treated mice, CD163 (M2 immune suppressive macrophage marker) was the gene most consistently and significantly downregulated, by an average of 84% in three independent experiments, and was confirmed by immunohistochemistry (IHC). Flow cytometry analysis of myeloid subpopulations - tumor associated macrophages (F4/80+ TAMs), monocytic myeloid derived suppressor cells, and granulocytic cells - showed a decrease in TAMs averaging 69% across three independent experiments. The analysis was extended to include IHC for arginase (Arg, a marker of functional immune suppression activity). Subpopulations of cells identified included Arg+, CD163+, and Arg+CD163+. Treatment with muSTAT3 ASO decreased these populations by 79%, 88% and 97% respectively, compared to control treatment. These populations were also analyzed in two GEM tumor models - the KPC pancreatic cancer model, and a PTEN -/- prostate cancer model - which have a TME more representative of that found in tumors in the clinic. While the specific changes varied across the models, likely reflecting differences in TME makeup, a reduction in immune suppressive cell populations was present in both GEM models, including a decrease in CD163+ cells of 79% (along with modest antitumor activity) in the PTEN -/- prostate model after muSTAT3 ASO treatment. These results indicate that selective STAT3 inhibition can reduce immune suppressive cell populations in the TME, and suggest that STAT3 inhibition has the potential to enhance the antitumor activity of T-cell targeted therapies, such as those targeting the PD1-PDL1 axis. In support of this hypothesis, we observed that addition of muSTAT3 ASO to anti-PD-L1 Ab treatment significantly enhanced the antitumor activity of PD-L1 Ab treatment in two subcutaneous syngeneic tumor models, CT-26 and A20. Citation Format: Rich Woessner, Vasu Sah, Patricia McCoon, Shaun Grosskurth, Nanhua Deng, Rachel DuPont, Deborah Lawson, Lourdes Pablo, Corinne Reimer, Marco A. De Velasco, Hirotsugu Uemura, Juliana Candido, Paul Lyne. Inhibition of STAT3 by antisense oligonucleotide treatment decreases the immune suppressive tumor microenvironment in syngeneic and GEM tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3684. doi:10.1158/1538-7445.AM2017-3684

Abstract A94: STAT3 antisense treatment decreases M2 macrophage infiltration and enhances the activity of checkpoint inhibitors in preclinical tumor models

AZD9150 is a gen2.5 antisense oligonucleotide (ASO) targeting STAT3. Gen2.5 ASOs exhibit enhanced drug-like properties compared to previous generations of antisense therapeutics, including increased stability and resistance to nucleases, a marked decrease in proinflammatory effects, and enhanced potency. The immune suppressive effects of STAT3 signaling are well established (Kortylewski et al.; Nat. Med. 2005 and Curr. Opin. Immunol. 2008). Preclinical experiments were carried out to determine the potential for combination of a STAT3 ASO with checkpoint inhibitor therapy, and to explore the mechanism of the antitumor activity of STAT3 ASOs observed in mouse models. The antitumor activity of STAT3 ASO treatment, as a single agent and in combination with checkpoint inhibitors, was evaluated in syngeneic mouse models, including CT-26. ASO uptake and STAT3 knockdown were evaluated by immunohistochemistry (IHC), and the pharmacodynamic effects of STAT3 ASO treatment in mice were evaluated by IHC, flow cytometry and immune gene expression profiling. In contrast to many tumor cell lines, CT26 cells take up ASOs poorly, including gen2.5 ASOs, thus as expected the tumor-associated activity of STAT3 ASOs in CT26 tumors in vivo was primarily in stromal and immune compartments (including circulating PBMCs), rather than directly in tumor cells. This was observed in several murine tumor models, as well as in clinical samples. Expression analysis of CT-26 tumor lysates taken from STAT3 ASO-treated (50 mg/kg QDx5/wk) mice using the Nanostring mouse immunology panel (561 immune related genes) identified CD163 as the gene most consistently modulated after STAT3 ASO treatment, with an average knockdown of 85% relative to control treated tumors, across 3 independent experiments. This result was confirmed by immunohistochemistry, which showed a marked reduction in the number of tumor infiltrating CD163+ cells after STAT3 ASO treatment. CD163 is a marker of M2 macrophages, and the presence of M2 macrophages in a tumor can create an immune suppressive environment which has the potential to reduce the effectiveness of checkpoint inhibitor therapy. Consistent with this hypothesis, the addition of STAT3 ASO treatment enhanced the response to a checkpoint inhibitor antibody targeting PD-L1 (clone 10F.9G2). When treatment began 2 days after tumor implant, single agent STAT3 ASO and PD-L1 antibody treatments resulted in response rates (regression or no tumor growth during the course of the experiment) of 0% and 14% respectively, while the rate was 50% with the combination. The combination remained active when treatments were delayed until established tumors were present (140 mm3 average tumor volume), with single agent and combination regression rates of 0%, and 20% respectively. These results suggest the addition of AZD9150 treatment as a promising approach to enhance the response to checkpoint inhibitor therapy Citation Format: Richard D. Woessner, Patricia McCoon, Shaun Grosskurth, Paul Lyne, Kirsten Bell, Mike Collins, Nanhua Deng, Rachel DuPont, Michele Johnstone, Youngsoo Kim, Deborah Lawson, Robert MacLeod, Lourdes Pablo, Corinne Reimer, Vasu Sah, Margaret Veldman-Jones. STAT3 antisense treatment decreases M2 macrophage infiltration and enhances the activity of checkpoint inhibitors in preclinical tumor models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A94.

Abstract A93: STAT3 inhibition enhances the activity of immune checkpoint inhibitors in murine syngeneic tumor models by creating a more immunogenic tumor microenvironment

The multifaceted role of STAT3 in enhancing tumor growth by tumor cell intrinsic as well as extrinsic (stromal and immune modulatory) mechanisms is well documented. Elevated STAT3 in tumor cells can lead to increased expression of cytokines, such as IL-6, which can create an immune suppressive environment in the tumor stroma. In addition, STAT3 signaling in cells of the immune system has the potential to contribute to an immune suppressive environment by several mechanisms, including suppression of dendritic cell (DC) maturation and function, enhanced myeloid derived suppressor cell (MDSC) activity, and suppression of T-cell mediated antitumor activity. An immune suppressive environment can reduce the antitumor activity of checkpoint inhibitors such as anti-PD-L1 antibodies by suppressing the ability of T-cell mediated immunity to respond to checkpoint reversal. Therefore, we hypothesized that inhibition of STAT3 has the potential to increase the anti-tumor effects of immune checkpoint inhibitors. To investigate this hypothesis, we explored the ability of a mouse STAT3 targeted antisense oligonucleotide (ASO) to enhance the antitumor activity of an anti-PD-L1 mAb in a syngeneic murine tumor model. In mice bearing subcutaneous CT-26 tumors, the combination of the STAT3 ASO plus an anti-PD-L1 mAb provided greater antitumor activity than either agent alone. Increased activity was observed when treatment was initiated soon (2 days) after tumor implantation, as well as when treatment was initiated after tumors were established (~150 mm3). When treatment was initiated soon after tumor implantation, single agents as well as the combination were initially effective, but the combination led to long term suppression of tumor growth in a greater percentage of mice (80% for the combination, vs. 20% for single agents). When treatment was initiated after tumors were established, STAT3 ASO or anti-PD-L1 antibody as single agents had significant initial antitumor activity (55% after 14 days of treatment). However, the single agent activity was transient, with the tumor growth rate returning to that of vehicle control (5 day doubling time) after two weeks of treatment. In contrast, the combination treatment led to a sustained reduction in mean tumor growth rate (15 days doubling time), and regression in 20 - 30% of tumors after four weeks of treatment. Treatment with the STAT3 ASO was associated with tumor infiltrating leukocyte changes consistent with enhanced antitumor immunity, including an increase in CD8+ effector T-cells. Combination benefit for STAT3 ASO plus anti-PD-L1 antibody was also observed in other immunocompetent murine tumor models. The data indicate that, in these models, inhibition of STAT3 has immunomodulatory activity, and can enhance the activity of immune checkpoint inhibitors, such as those targeting PD-L1. Citation Format: Rich Woessner, Patricia McCoon, Kirsten Bell, Rachel DuPont, Mike Collins, Deborah Lawson, Prasad Nadella, Lourdes Pablo, Corinne Reimer, Vasu Sah, Paul Lyne. STAT3 inhibition enhances the activity of immune checkpoint inhibitors in murine syngeneic tumor models by creating a more immunogenic tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A93.

Abstract CT239: Clinical and preclinical evidence of an immune modulating role for the STAT3-targeting ASO AZD9150 and potential to enhance clinical responses to anti-PDL1 therapy

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA AZD9150 is a therapeutic Generation 2.5 antisense oligonucleotide (ASO) targeting STAT3 that has completed two phase I clinical studies, in patients with HCC and DLBCL, with durable clinical responses seen in both trials. Biomarker studies using patient samples and related preclinical experiments were performed to investigate the mechanism of action of AZD9150. Patients were treated with three loading doses of AZD9150 in the first week followed by weekly dosing, at doses ranging from 1.0 to 3.0 mg/kg. In the DLBCL study, paired tumor biopsies were collected pre-treatment and on-treatment to evaluate drug uptake and target knockdown by immunohistochemistry (IHC). In the HCC study, blood samples were collected at baseline and at multiple time points on-treatment to evaluate target knockdown and gene expression changes. IHC staining of DLBCL patients’ tumor biopsies (at 2 & 3 mg/kg) demonstrated that the drug distributes to the tumor, with strongest uptake in stromal cells, including endothelium, fibroblasts, and immune cells. Pronounced decreases (absence of staining on-treatment) in STAT3 were observed in the endothelium of several samples. More limited STAT3 modulation was observed in tumor cells. Flow cytometry analysis of HCC patients’ blood samples revealed an average decrease in STAT3 protein staining of 49% across all peripheral leukocyte populations in the 1 mg/kg cohort. Clinical pharmacodynamics and mechanism of action were explored further by conducting a gene expression study with the Nanostring nCounter Human Immunology Panel v2 to evaluate STAT3 RNA knockdown and 593 additional immune genes in peripheral leukocytes collected from HCC patients. Statistically significant decreases of >30% in STAT3 expression were observed in 14/32 patients by the fourth week of treatment. These STAT3 changes are accompanied by +/- 40% changes in expression by additional genes associated with decreased myeloid trafficking and function, increased antigen presentation, and increased CD8 effector cell function. These data provide evidence that AZD9150 treatment may remove or reprogram immunosuppressive elements employed by tumors, leading to therapeutic benefit. Preclinical studies were carried out to investigate immune cell changes within tumors and the benefit of combining STAT3 ASO with PDL1 blockade. Monotherapy STAT3 ASO treatment resulted in CT26 tumor growth inhibition (80%) when tested in immune competent Balb/c but not immune-deficient NSG mice, and was associated with two-fold increases in CD45+ and CD8+ cell infiltrate into tumors. Mice treated with STAT3 ASO and anti-PD-L1 blocking antibody resulted in a 50% response rate for the combination treatment, vs. only 14% with anti-PD-L1 Ab alone. These data suggest that the effects of STAT3 ASO are mechanistically complementary to immune checkpoint inhibitors and that the combination with AZD9150 could broaden clinical responses to these important therapies. This hypothesis will be tested in upcoming clinical trials with AZD9150 and MEDI4736. Citation Format: Patricia E. Mccoon, Rich Woessner, Shaun Grosskurth, Chris Womack, Mason Yamashita, Gene Hung, Robert MacLeod, Kirsten Bell, Mike Collins, Rachel DuPont, Vivian Jacobs, Michele Johnstone, Margaret Veldman-Jones, Paul Lyne. Clinical and preclinical evidence of an immune modulating role for the STAT3-targeting ASO AZD9150 and potential to enhance clinical responses to anti-PDL1 therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT239. doi:10.1158/1538-7445.AM2015-CT239

Abstract A200: Toward quantitative PI3K pathway PD analysis in clinical samples using an automated capillary electrophoresis-immunoassay platform.

Here we report results of an independent evaluation of an automated capillary electrophoresis-immunoassay system for its utility in generating quantitative and reproducible pharmacodynamic (PD) biomarker data for the PI3K pathway using clinical specimens. Quantitative measurement of PD biomarkers associated with drug -target engagement in tumor tissue is an increasingly important part of evaluating new cancer therapies in early clinical trials. PD data are currently being used along with safety, pharmacokinetics, and efficacy data to make more informed clinical decisions regarding likelihood of success and progression of drugs into Phase II testing. Despite this increased focus, there are still very few assay platforms that support automated, reproducible and quantitative methods amenable to the small tumor biopsies available for these analyses. The Peggy™ (ProteinSimple) platform provides automated separation of proteins by size or charge and quantitation of analytes over a broad dynamic range from tissue samples using as little as 40 ng protein. Accompanied by the ability to process 96-samples in a single run, this platform is amenable to both pre-clinical and clinical PD determination. Our initial studies focused on evaluating the feasibility of developing a set of robust, quantitative PD biomarker assays that could be used systematically across our oncology portfolio to monitor the PI3K pathway. Here we present results for a panel of biomarkers associated with the PI3K pathway using cell lines and tumor xenografts in which we measured responses to drug treatments using AKT and mTOR inhibitors. Further, in a set of prospectively collected breast cancer core needle biopsies, we were able to detect baseline levels of these biomarkers. Taken together, these data suggest that this platform will be useful in quantitatively measuring changes in multiple PD biomarkers in a single tumor biopsy. Going forward, we propose to utilize this approach alone or in tandem with other immunoassay formats, such as immunohistochemistry, to provide greater insight into tumor biology and the effects of drug treatment following PI3K -AKT inhibition in the clinic to help inform important clinical decisions. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A200. Citation Format: Patricia E. Mccoon, Lourdes Pablo, Kristen McEachern, Emily Foster, Chris Womack, Lillian Castriotta, Jeff Brown, Carl Barrett. Toward quantitative PI3K pathway PD analysis in clinical samples using an automated capillary electrophoresis-immunoassay platform. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A200.