Publications by authors named "Alan Huang"

59 Publications

Significance of CD8 T cell infiltration-related biomarkers and the corresponding prediction model for the prognosis of kidney renal clear cell carcinoma.

Aging (Albany NY) 2021 10 4;13(19):22912-22933. Epub 2021 Oct 4.

Phase I Clinical Trial Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250012, Shandong, P.R. China.

Cytotoxic T cells expressing cell surface CD8 played a key role in anti-cancer immunotherapy, including kidney renal clear cell carcinoma (KIRC). Here we set out to comprehensively analyze and evaluate the significance of CD8 T cell-related markers for patients with KIRC. We checked immune cell response in KIRC and identified cell type-specific markers and related pathways in the tumor-infiltrating CD8 T (TIL-CD8T) cells. We used these markers to explore their prognostic signatures in TIL-CD8 T by evaluating their prognostic efficacy and group differences at various levels. Through pan-cancer analysis, 12 of 63 up-regulated and 162 of 396 down-regulated genes in CD8+ T cells were found to be significantly correlated with the survival prognosis. Based on our highly integrated multi-platform analyses across multiple datasets, we constructed a 6-gene risk scoring model specific to TIL-CD8T. In this model, high TIL-CD8 sig score was corresponding to a higher incidence frequency of copy number variation and drug sensitivity to sorafenib. Moreover, the prognosis of patients with the same or similar immune checkpoint gene levels could be distinguished from each other by TIL-CD8 sig score.
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http://dx.doi.org/10.18632/aging.203584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8544304PMC
October 2021

Dynamic reconfiguration of pro-apoptotic BAK on membranes.

EMBO J 2021 Oct 15;40(20):e107237. Epub 2021 Sep 15.

The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia.

BAK and BAX, the effectors of intrinsic apoptosis, each undergo major reconfiguration to an activated conformer that self-associates to damage mitochondria and cause cell death. However, the dynamic structural mechanisms of this reconfiguration in the presence of a membrane have yet to be fully elucidated. To explore the metamorphosis of membrane-bound BAK, we employed hydrogen-deuterium exchange mass spectrometry (HDX-MS). The HDX-MS profile of BAK on liposomes comprising mitochondrial lipids was consistent with known solution structures of inactive BAK. Following activation, HDX-MS resolved major reconfigurations in BAK. Mutagenesis guided by our HDX-MS profiling revealed that the BCL-2 homology (BH) 4 domain maintains the inactive conformation of BAK, and disrupting this domain is sufficient for constitutive BAK activation. Moreover, the entire N-terminal region preceding the BAK oligomerisation domains became disordered post-activation and remained disordered in the activated oligomer. Removal of the disordered N-terminus did not impair, but rather slightly potentiated, BAK-mediated membrane permeabilisation of liposomes and mitochondria. Together, our HDX-MS analyses reveal new insights into the dynamic nature of BAK activation on a membrane, which may provide new opportunities for therapeutic targeting.
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http://dx.doi.org/10.15252/embj.2020107237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8521275PMC
October 2021

Assessment of the Clinical Trials Safety Profile of PD-1/PD-L1 Inhibitors Among Patients With Cancer: An Updated Systematic Review and Meta-Analysis.

Front Oncol 2021 24;11:662392. Epub 2021 May 24.

Special Needs Department of Proton Therapy Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.

Background: Understanding the safety and adverse event profiles of PD-1/PD-L1 inhibitors is important in guiding cancer immunotherapy. Consequently, we designed this meta-analysis to evaluate the safety of PD-1/PD-L1 inhibitors in clinical trials involving cancer patients.

Methods: Four safety indicators comprising treatment-related adverse events, death, discontinuation of therapy and grades 3-5 adverse events were evaluated using the random effect model. The quality of enrolled trials was assessed using the Newcastle Ottawa Scale (NOS).

Results: Forty-four clinical trials were included in the final meta-analysis. Compared with chemotherapy, the risk of death due to the use of PD-1/PD-L1 inhibitors was much lower than that experienced in the control group (OR = 0.65, 95%CI: [0.47, 0.91], I = 0%, Z = 2.52 (P = 0.01)). Similar observations were apparent regarding the other three indicators of safety and also when the use of PD-1/PD-L1 inhibitors alone is compared with the combined use of PD-1/PD-L1 and CTLA-4. When used together with chemotherapy, PD-1/PD-L1 inhibitors increased the incidence of the adverse events as compared to the use of chemotherapy alone. Increased risks for adverse events were also noticed with the use of PD-1/PD-L1 inhibitors over the use of a placebo.

Conclusion: The use of PD-1/PD-L1 inhibitors alone is associated with a better safety profile compared to either the use of chemotherapy or the use of PD-1/PD-L1 inhibitors with other anticancer regimens.
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http://dx.doi.org/10.3389/fonc.2021.662392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184020PMC
May 2021

Clinical Performance of the Point-of-Care cobas Liat for Detection of SARS-CoV-2 in 20 Minutes: a Multicenter Study.

J Clin Microbiol 2021 01 21;59(2). Epub 2021 Jan 21.

Department of Pathology and Laboratory Medicine, University of California Davis, California, USA

Highly accurate testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the point of care (POC) is an unmet diagnostic need in emergency care and time-sensitive outpatient care settings. Reverse transcription-PCR (RT-PCR) technology is the gold standard for SARS-CoV-2 diagnostics. We performed a multisite U.S. study comparing the clinical performance of the first U.S. Food and Drug Administration (FDA)-authorized POC RT-PCR for detection of SARS-CoV-2 in 20 min, the cobas Liat SARS-CoV-2 and influenza A/B nucleic acid test, to the most widely used RT-PCR laboratory test, the cobas 68/8800 SARS-CoV-2 test. Clinical nasopharyngeal swab specimens from 444 patients with 357 evaluable specimens at five U.S. clinical laboratories were enrolled from 21 September 2020 to 23 October 2020. The overall agreement between the Liat and 68/8800 systems for SARS-CoV-2 diagnostics was 98.6% (352/357). Using Liat, positive percent agreement for SARS-CoV-2 was 100% (162/162) and the negative percent agreement was 97.4% (190/195). The Liat is an RT-PCR POC test that provides highly accurate SARS-CoV-2 results in 20 min with performance equivalent to that of high-throughput laboratory molecular testing. Rapid RT-PCR testing at the POC can enable more timely infection control and individual care decisions for coronavirus disease 2019.
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http://dx.doi.org/10.1128/JCM.02811-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111162PMC
January 2021

FGF401 and vinorelbine synergistically mediate antitumor activity and vascular normalization in FGF19-dependent hepatocellular carcinoma.

Exp Mol Med 2020 11 25;52(11):1857-1868. Epub 2020 Nov 25.

Oncology Translational Research, Novartis Institutes for Biomedical Research at Basel, Basel, Switzerland.

Hepatocellular carcinoma (HCC) is a lethal cancer with limited therapeutic options, and standard therapy with sorafenib provides only modest survival benefits. Fibroblast growth factor 19 (FGF19) has been proposed as a driver oncogene, and targeting its receptor, FGFR-4, may provide a better alternative to standard therapy for patients with FGF19-driven tumors. Sixty-three HCC patient-derived xenograft (PDX) models were screened for FGF19 expression. Mice bearing high and low FGF19-expressing tumors were treated with FGF401 and/or vinorelbine, and the antitumor activity of both agents was assessed individually and in combination. Tumor vasculature and intratumoral hypoxia were also examined. High FGF19 expression was detected in 14.3% (9 of 63) of the HCC models tested and may represent a good target for HCC treatment. FGF401 potently inhibited the growth of high FGF19-expressing HCC models regardless of FGF19 gene amplification. Furthermore, FGF401 inhibited the FGF19/FGFR-4 signaling pathway, cell proliferation, and hypoxia, induced apoptosis and blood vessel normalization and prolonged the overall survival (OS) of mice bearing high FGF19 tumors. FGF401 synergistically acted with the microtubule-depolymerizing drug vinorelbine to further suppress tumor growth, promote apoptosis, and prolong the OS of mice bearing high FGF19 tumors, with no evidence of increased toxicity. Our study suggests that a subset of patients with high FGF19-expressing HCC tumors could benefit from FGF401 or FGF401/vinorelbine treatment. A high level of FGF19 in a tumor may serve as a potential biomarker for patient selection.
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http://dx.doi.org/10.1038/s12276-020-00524-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080677PMC
November 2020

Optimization of AsCas12a for combinatorial genetic screens in human cells.

Nat Biotechnol 2021 01 13;39(1):94-104. Epub 2020 Jul 13.

Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Cas12a RNA-guided endonucleases are promising tools for multiplexed genetic perturbations because they can process multiple guide RNAs expressed as a single transcript, and subsequently cleave target DNA. However, their widespread adoption has lagged behind Cas9-based strategies due to low activity and the lack of a well-validated pooled screening toolkit. In the present study, we describe the optimization of enhanced Cas12a from Acidaminococcus (enAsCas12a) for pooled, combinatorial genetic screens in human cells. By assaying the activity of thousands of guides, we refine on-target design rules and develop a comprehensive set of off-target rules to predict and exclude promiscuous guides. We also identify 38 direct repeat variants that can substitute for the wild-type sequence. We validate our optimized AsCas12a toolkit by screening for synthetic lethalities in OVCAR8 and A375 cancer cells, discovering an interaction between MARCH5 and WSB2. Finally, we show that enAsCas12a delivers similar performance to Cas9 in genome-wide dropout screens but at greatly reduced library size, which will facilitate screens in challenging models.
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http://dx.doi.org/10.1038/s41587-020-0600-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854777PMC
January 2021

Synthetic lethality as an engine for cancer drug target discovery.

Nat Rev Drug Discov 2020 01 11;19(1):23-38. Epub 2019 Nov 11.

Tango Therapeutics, Cambridge, MA, USA.

The first wave of genetically targeted therapies for cancer focused on drugging gene products that are recurrently mutated in specific cancer types. However, mutational analysis of tumours has largely been exhausted as a strategy for the identification of new cancer targets that are druggable with conventional approaches. Furthermore, some known genetic drivers of cancer have not been directly targeted yet owing to their molecular structure (undruggable oncogenes) or because they result in functional loss (tumour suppressor genes). Functional genomic screening based on the genetic concept of synthetic lethality provides an avenue to discover drug targets in all these areas. Although synthetic lethality is not a new idea, recent advances, including CRISPR-based gene editing, have made possible systematic screens for synthetic lethal drug targets in human cancers. Such approaches have broad potential to drive the discovery of the next wave of genetic cancer targets and ultimately the introduction of effective medicines that are still needed for most cancers.
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http://dx.doi.org/10.1038/s41573-019-0046-zDOI Listing
January 2020

CD56 CD16 Natural Killer Cell Profiling in Melanoma Patients Receiving a Cancer Vaccine and Interferon-α.

Front Immunol 2019 29;10:14. Epub 2019 Jan 29.

University of Pittsburgh Hillman Cancer Center, Pittsburgh, PA, United States.

Natural killer (NK) cells are innate cytotoxic and immunoregulatory lymphocytes that have a central role in anti-tumor immunity and play a critical role in mediating cellular immunity in advanced cancer immunotherapies, such as dendritic cell (DC) vaccines. Our group recently tested a novel recombinant adenovirus-transduced autologous DC-based vaccine that simultaneously induces T cell responses against three melanoma-associated antigens for advanced melanoma patients. Here, we examine the impact of this vaccine as well as the subsequent systemic delivery of high-dose interferon-α2b (HDI) on the circulatory NK cell profile in melanoma patients. At baseline, patient NK cells, particularly those isolated from high-risk patients with no measurable disease, showed altered distribution of CD56 CD16 and CD56 CD16 NK cell subsets, as well as elevated serum levels of immune suppressive MICA, TN5E/CD73 and tactile/CD96, and perforin. Surprisingly, patient NK cells displayed a higher level of activation than those from healthy donors as measured by elevated CD69, NKp44 and CCR7 levels, and enhanced K562 killing. Elevated cytolytic ability strongly correlated with increased representation of CD56 CD16 NK cells and amplified CD69 expression on CD56 CD16 NK cells. While intradermal DC immunizations did not significantly impact circulatory NK cell activation and distribution profiles, subsequent HDI injections enhanced CD56 CD16 NK cell numbers when compared to patients that did not receive HDI. Phenotypic analysis of tumor-infiltrating NK cells showed that CD56 CD16 NK cells are the dominant subset in melanoma tumors. NanoString transcriptomic analysis of melanomas resected at baseline indicated that there was a trend of increased CD56 NK cell gene signature expression in patients with better clinical response. These data indicate that melanoma patient blood NK cells display elevated activation levels, that intra-dermal DC immunizations did not effectively promote systemic NK cell responses, that systemic HDI administration can modulate NK cell subset distributions and suggest that CD56 CD16 NK cells are a unique non-cytolytic subset in melanoma patients that may associate with better patient outcome.
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http://dx.doi.org/10.3389/fimmu.2019.00014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361792PMC
December 2019

Capmatinib (INC280) Is Active Against Models of Non-Small Cell Lung Cancer and Other Cancer Types with Defined Mechanisms of MET Activation.

Clin Cancer Res 2019 05 23;25(10):3164-3175. Epub 2019 Jan 23.

Novartis Institutes for BioMedical Research, Oncology Disease Area, Basel, Switzerland.

Purpose: The selective MET inhibitor capmatinib is being investigated in multiple clinical trials, both as a single agent and in combination. Here, we describe the preclinical data of capmatinib, which supported the clinical biomarker strategy for rational patient selection.

Experimental Design: The selectivity and cellular activity of capmatinib were assessed in large cellular screening panels. Antitumor efficacy was quantified in a large set of cell line- or patient-derived xenograft models, testing single-agent or combination treatment depending on the genomic profile of the respective models.

Results: Capmatinib was found to be highly selective for MET over other kinases. It was active against cancer models that are characterized by amplification, marked overexpression, exon 14 skipping mutations, or MET activation via expression of the ligand hepatocyte growth factor (HGF). In cancer models where is the dominant oncogenic driver, anticancer activity could be further enhanced by combination treatments, for example, by the addition of apoptosis-inducing BH3 mimetics. The combinations of capmatinib and other kinase inhibitors resulted in enhanced anticancer activity against models where activation co-occurred with other oncogenic drivers, for example activating mutations.

Conclusions: Activity of capmatinib in preclinical models is associated with a small number of plausible genomic features. The low fraction of cancer models that respond to capmatinib as a single agent suggests that the implementation of patient selection strategies based on these biomarkers is critical for clinical development. Capmatinib is also a rational combination partner for other kinase inhibitors to combat MET-driven resistance.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2814DOI Listing
May 2019

Infigratinib Mediates Vascular Normalization, Impairs Metastasis, and Improves Chemotherapy in Hepatocellular Carcinoma.

Hepatology 2019 03;69(3):943-958

Department of General Surgery, Singapore General Hospital, Singapore.

The fibroblast growth factor (FGF) signaling cascade is a key signaling pathway in hepatocarcinogenesis. We report high FGF receptor (FGFR) expression in 17.7% (11 of 62) of hepatocellular carcinoma (HCC) models. Infigratinib, a pan-FGFR inhibitor, potently suppresses the growth of high-FGFR-expressing and sorafenib-resistant HCCs. Infigratinib inhibits FGFR signaling and its downstream targets, cell proliferation, the angiogenic rescue program, hypoxia, invasion, and metastasis. Infigratinib also induces apoptosis and vessel normalization and improves the overall survival of mice bearing FGFR-driven HCCs. Infigratinib acts in synergy with the microtubule-depolymerizing drug vinorelbine to promote apoptosis, suppress tumor growth, and improve the overall survival of mice. Increased expression levels of FGFR-2 and FGFR-3 through gene amplification correlate with treatment response and may serve as potential biomarkers for patient selection. Conclusion: Treatments with Infigratinib alone or in combination with vinorelbine may be effective in a subset of patients with HCC with FGFR-driven tumors.
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http://dx.doi.org/10.1002/hep.30481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635738PMC
March 2019

Alpelisib Plus Fulvestrant in PIK3CA-Altered and PIK3CA-Wild-Type Estrogen Receptor-Positive Advanced Breast Cancer: A Phase 1b Clinical Trial.

JAMA Oncol 2019 02 14;5(2):e184475. Epub 2019 Feb 14.

Department of Medicine, University of California at San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco.

Importance: The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in patients with estrogen receptor-positive (ER+), endocrine therapy-resistant breast cancers.

Objective: To assess the maximum tolerated dose (MTD), safety, and activity of alpelisib, an oral, PI3Kα-specific inhibitor, plus fulvestrant in patients with ER+ advanced breast cancer (ABC).

Design, Setting, And Participants: An open-label, single-arm, phase 1b study of alpelisib plus fulvestrant was conducted at 10 centers in 5 countries. Participants were 87 postmenopausal women with PIK3CA-altered or PIK3CA-wild-type ER+ ABC, whose cancer progressed during or after antiestrogen therapy. The study began enrolling patients October 5, 2010, and the data cutoff was March 22, 2017.

Interventions: Escalating doses of alpelisib were administered once daily, starting at 300 mg, plus fixed-dose fulvestrant, 500 mg, in the dose-escalation phase; alpelisib at the recommended phase 2 dose plus fulvestrant in the dose-expansion phase.

Main Outcomes And Measures: The primary end point was determination of the MTD of once-daily alpelisib plus fulvestrant. Secondary end points included safety and preliminary activity.

Results: From October 5, 2010, to March 22, 2017, 87 women (median age: 58 years [range, 37-79 years]; median of 5 prior lines of antineoplastic therapy) received escalating once-daily doses of alpelisib (300 mg, n = 9; 350 mg, n = 8; 400 mg, n = 70) plus fixed-dose fulvestrant (500 mg). During dose escalation, dose-limiting toxic effects were reported in 1 patient (alpelisib, 400 mg): diarrhea (grade 2), vomiting, fatigue, and decreased appetite (all grade 3). The MTD of alpelisib when combined with fulvestrant was 400 mg once daily, and the recommended phase 2 dose was 300 mg once daily. Overall, the most frequent grade 3/4 adverse events with alpelisib, 400 mg, once daily (≥10% of patients), regardless of causality, were hyperglycemia (19 [22%]) and maculopapular rash (11 [13%]); 9 patients permanently discontinued therapy owing to adverse events. Median progression-free survival at the MTD was 5.4 months (95% CI, 4.6-9.0 months). Median progression-free survival with alpelisib, 300 to 400 mg, once daily plus fulvestrant was longer in patients with PIK3CA-altered tumors (9.1 months; 95% CI, 6.6-14.6 months) vs wild-type tumors (4.7 months; 95% CI, 1.9-5.6 months). Overall response rate in the PIK3CA-altered group was 29% (95% CI, 17%-43%), with no objective tumor responses in the wild-type group.

Conclusions And Relevance: Alpelisib plus fulvestrant has a manageable safety profile in patients with ER+ ABC, and data suggest that this combination may have greater clinical activity in PIK3CA-altered vs wild-type tumors.

Trial Registration: ClinicalTrials.gov identifier: NCT01219699.
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http://dx.doi.org/10.1001/jamaoncol.2018.4475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439561PMC
February 2019

Differential responses of MET activations to MET kinase inhibitor and neutralizing antibody.

J Transl Med 2018 09 12;16(1):253. Epub 2018 Sep 12.

Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA.

Background: Aberrant MET tyrosine kinase signaling is known to cause cancer initiation and progression. While MET inhibitors are in clinical trials against several cancer types, the clinical efficacies are controversial and the molecular mechanisms toward sensitivity remain elusive.

Methods: With the goal to investigate the molecular basis of MET amplification (MET) and hepatocyte growth factor (HGF) autocrine-driven tumors in response to MET tyrosine kinase inhibitors (TKI) and neutralizing antibodies, we compared cancer cells harboring MET (MKN45 and MHCCH97H) or HGF-autocrine (JHH5 and U87) for their sensitivity and downstream biological responses to a MET-TKI (INC280) and an anti-MET monoclonal antibody (MetMab) in vitro, and for tumor inhibition in vivo.

Results: We find that cancer cells driven by MET are more sensitive to INC280 than are those driven by HGF-autocrine activation. In MET cells, INC280 induced a DNA damage response with activation of repair through the p53BP1/ATM signaling pathway. Although MetMab failed to inhibit MET cell proliferation and tumor growth, both INC280 and MetMab reduced HGF-autocrine tumor growth. In addition, we also show that HGF stimulation promoted human HUVEC cell tube formation via the Src pathway, which was inhibited by either INC280 or MetMab. These observations suggest that in HGF-autocrine tumors, the endothelial cells are the secondary targets MET inhibitors.

Conclusions: Our results demonstrate that MET and HGF-autocrine activation favor different molecular mechanisms. While combining MET TKIs and ATM inhibitors may enhance the efficacy for treating tumors harboring MET, a combined inhibition of MET and angiogenesis pathways may improve the therapeutic efficacy against HGF-autocrine tumors.
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http://dx.doi.org/10.1186/s12967-018-1628-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134500PMC
September 2018

Let's Talk About B: Barriers to Hepatitis B Screening and Vaccination Among Asian and South Asian Immigrants in British Columbia.

J Racial Ethn Health Disparities 2018 12 19;5(6):1337-1345. Epub 2018 Mar 19.

Digital Emergency Medicine, Department of Emergency Medicine, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.

Introduction: Chronic hepatitis B (HBV) is prevalent among Asian immigrants in Canada with high morbidity and mortality rates. While some studies have identified barriers to health care and information access, few have studied the impact of culturally relevant information and addressed challenges with recommendations for effective public education and outreach programs.

Methods: Culturally tailored HBV education workshops were delivered over a 12-month period to Chinese, Filipino, Korean and Punjabi immigrants in Lower Mainland, British Columbia (BC). Data from pre- and post-workshop surveys and 2-week and 1-month follow-up interviews were collected and analyzed to evaluate knowledge gaps and challenges around HBV prevention and screening. Barriers, health care service gaps and facilitators identified in the interviews were coded and analyzed.

Results: Data were collected from 827 workshop participants. Our results show that targeted immigrants in Lower Mainland, BC face many barriers to accessing HBV screening and vaccination. Limited knowledge and awareness of HBV vaccination/prevention/treatment, limited English proficiency and eLiteracy skills, system and provider level barriers to accessing HBV care, and immigration related barriers are among the reported challenges. More than half of participants who took part in the HBV education workshops engaged in actions related to HBV prevention or management.

Conclusion: Study findings support the need for culturally tailored HBV public education and outreach programs to further advance HBV immunization and awareness in BC. Addressing barriers and developing targeted programmatic strategies identified in this study will promote more effective HBV education programming and improve uptake of HBV screening and vaccination in BC's immigrant populations.
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http://dx.doi.org/10.1007/s40615-018-0483-0DOI Listing
December 2018

Phosphatidylinositol 3-Kinase α-Selective Inhibition With Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study.

J Clin Oncol 2018 05 5;36(13):1291-1299. Epub 2018 Feb 5.

Dejan Juric, Massachusetts General Hospital Cancer Center, Boston; Alan Huang, Novartis Institutes for BioMedical Research, Cambridge, MA; Jordi Rodon and Josep Tabernero, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona; Marta Gil-Martin, Catalan Institute of Oncology - Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain; Filip Janku, The University of Texas MD Anderson Cancer Center, Houston, TX; Howard A. Burris, Sarah Cannon Research Institute and Tennessee Oncology; Jordan Berlin, Vanderbilt-Ingram Cancer Center, Nashville, TN; Jan H.M. Schellens, Netherlands Cancer Institute, Amsterdam, the Netherlands; Mark R. Middleton, National Institute for Health Research, Oxford Biomedical Research Centre, Churchill Hospital, Oxford, United Kingdom; Martin Schuler, West German Cancer Center, University Duisburg-Essen, and German Cancer Consortium, Partner Site University Hospital Essen, Essen; Ruth Seggewiss-Bernhardt, Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Würzburg, Germany; Hope S. Rugo, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; Douglas Bootle, David Demanse, Lars Blumenstein, and Cornelia Quadt, Novartis Pharma AG, Basel, Switzerland; Christina Coughlin, Novartis Pharmaceuticals Corporation, East Hanover, NJ; and José Baselga, Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose We report the first-in-human phase Ia study to our knowledge ( ClinicalTrials.gov identifier: NCT01219699) identifying the maximum tolerated dose and assessing safety and preliminary efficacy of single-agent alpelisib (BYL719), an oral phosphatidylinositol 3-kinase α (PI3Kα)-selective inhibitor. Patients and Methods In the dose-escalation phase, patients with PIK3CA-altered advanced solid tumors received once-daily or twice-daily oral alpelisib on a continuous schedule. In the dose-expansion phase, patients with PIK3CA-altered solid tumors and PIK3CA-wild-type, estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer received alpelisib 400 mg once daily. Results One hundred thirty-four patients received treatment. Alpelisib maximum tolerated doses were established as 400 mg once daily and 150 mg twice daily. Nine patients (13.2%) in the dose-escalation phase had dose-limiting toxicities of hyperglycemia (n = 6), nausea (n = 2), and both hyperglycemia and hypophosphatemia (n = 1). Frequent all-grade, treatment-related adverse events included hyperglycemia (51.5%), nausea (50.0%), decreased appetite (41.8%), diarrhea (40.3%), and vomiting (31.3%). Alpelisib was rapidly absorbed; half-life was 7.6 hours at 400 mg once daily with minimal accumulation. Objective tumor responses were observed at doses ≥ 270 mg once daily; overall response rate was 6.0% (n = 8; one patient with endometrial cancer had a complete response, and seven patients with cervical, breast, endometrial, colon, and rectal cancers had partial responses). Stable disease was achieved in 70 (52.2%) patients and was maintained > 24 weeks in 13 (9.7%) patients; disease control rate (complete and partial responses and stable disease) was 58.2%. In patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer, median progression-free survival was 5.5 months. Frequently mutated genes (≥ 10% tumors) included TP53 (51.3%), APC (23.7%), KRAS (22.4%), ARID1A (13.2%), and FBXW7 (10.5%). Conclusion Alpelisib demonstrated a tolerable safety profile and encouraging preliminary activity in patients with PIK3CA-altered solid tumors, supporting the rationale for selective PI3Kα inhibition in combination with other agents for the treatment of PIK3CA-mutant tumors.
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http://dx.doi.org/10.1200/JCO.2017.72.7107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5920739PMC
May 2018

Genomic Analysis of Nasopharyngeal Carcinoma Reveals TME-Based Subtypes.

Mol Cancer Res 2017 12 29;15(12):1722-1732. Epub 2017 Aug 29.

Novartis Institute for Biomedical Research, Shanghai, China.

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV) associated cancer characterized by a poor prognosis and a high level of lymphocyte infiltrate. Genetic hallmarks of NPC are not completely known but include deletion of the p16 () locus and mutations in NF-κB pathway components, with a relatively low total mutational load. To better understand the genetic landscape, an integrated genomic analysis was performed using a large clinical cohort of treatment-naïve NPC tumor specimens. This genomic analysis was generally concordant with previous studies; however, three subtypes of NPC were identified by differences in immune cell gene expression, prognosis, tumor cell morphology, and genetic characteristics. A gene expression signature of proliferation was poorly prognostic and associated with either higher mutation load or specific EBV gene expression patterns in a subtype-specific manner. Finally, higher levels of stromal tumor-infiltrating lymphocytes associated with good prognosis and lower expression of a WNT and TGFβ pathway activation signature. This study represents the first integrated analysis of mutation, copy number, and gene expression data in NPC and suggests how tumor genetics and EBV infection influence the tumor microenvironment in this disease. These insights should be considered for guiding immunotherapy treatment strategies in this disease. .
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http://dx.doi.org/10.1158/1541-7786.MCR-17-0134DOI Listing
December 2017

The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation.

Sci Transl Med 2017 05;9(391)

Oncology Translational Medicine, Novartis Institute for Biomedical Research, Cambridge, MA 02139, USA.

Although targeted therapies are often effective systemically, they fail to adequately control brain metastases. In preclinical models of breast cancer that faithfully recapitulate the disparate clinical responses in these microenvironments, we observed that brain metastases evade phosphatidylinositide 3-kinase (PI3K) inhibition despite drug accumulation in the brain lesions. In comparison to extracranial disease, we observed increased HER3 expression and phosphorylation in brain lesions. HER3 blockade overcame the resistance of -amplified and/or -mutant breast cancer brain metastases to PI3K inhibitors, resulting in marked tumor growth delay and improvement in mouse survival. These data provide a mechanistic basis for therapeutic resistance in the brain microenvironment and identify translatable treatment strategies for -amplified and/or -mutant breast cancer brain metastases.
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http://dx.doi.org/10.1126/scitranslmed.aal4682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5917603PMC
May 2017

Orthogonality of the Mean and Error Distribution in Generalized Linear Models.

Commun Stat Theory Methods 2017 17;46(7):3290-3296. Epub 2016 Nov 17.

University of Technology Sydney and University of Wisconsin-Madison.

We show that the mean-model parameter is always orthogonal to the error distribution in generalized linear models. Thus, the maximum likelihood estimator of the mean-model parameter will be asymptotically efficient regardless of whether the error distribution is known completely, known up to a finite vector of parameters, or left completely unspecified, in which case the likelihood is taken to be an appropriate semiparametric likelihood. Moreover, the maximum likelihood estimator of the mean-model parameter will be asymptotically independent of the maximum likelihood estimator of the error distribution. This generalizes some well-known results for the special cases of normal, gamma and multinomial regression models, and, perhaps more interestingly, suggests that asymptotically efficient estimation and inferences can always be obtained if the error distribution is nonparametrically estimated along with the mean. In contrast, estimation and inferences using misspecified error distributions or variance functions are generally not efficient.
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http://dx.doi.org/10.1080/03610926.2013.851241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5396964PMC
November 2016

Combined ALK and MDM2 inhibition increases antitumor activity and overcomes resistance in human mutant neuroblastoma cell lines and xenograft models.

Elife 2017 04 20;6. Epub 2017 Apr 20.

Disease Area Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States.

The efficacy of ALK inhibitors in patients with -mutant neuroblastoma is limited, highlighting the need to improve their effectiveness in these patients. To this end, we sought to develop a combination strategy to enhance the antitumor activity of ALK inhibitor monotherapy in human neuroblastoma cell lines and xenograft models expressing activated ALK. Herein, we report that combined inhibition of ALK and MDM2 induced a complementary set of anti-proliferative and pro-apoptotic proteins. Consequently, this combination treatment synergistically inhibited proliferation of wild-type neuroblastoma cells harboring amplification or mutations in vitro, and resulted in complete and durable responses in neuroblastoma xenografts derived from these cells. We further demonstrate that concurrent inhibition of MDM2 and ALK was able to overcome ceritinib resistance conferred by MYCN upregulation in vitro and in vivo. Together, combined inhibition of ALK and MDM2 may provide an effective treatment for wild-type neuroblastoma with aberrations.
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http://dx.doi.org/10.7554/eLife.17137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435462PMC
April 2017

Transverse water relaxation in whole blood and erythrocytes at 3T, 7T, 9.4T, 11.7T and 16.4T; determination of intracellular hemoglobin and extracellular albumin relaxivities.

Magn Reson Imaging 2017 05 16;38:234-249. Epub 2016 Dec 16.

The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA; F.M. Kirby Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA. Electronic address:

Blood is a physiological substance with multiple water compartments, which contain water-binding proteins such as hemoglobin in erythrocytes and albumin in plasma. Knowing the water transverse (R) relaxation rates from these different blood compartments is a prerequisite for quantifying the blood oxygenation level-dependent (BOLD) effect. Here, we report the Carr-Purcell-Meiboom-Gill (CPMG) based transverse (R) relaxation rates of water in bovine blood samples circulated in a perfusion system at physiological temperature in order to mimic blood perfusion in humans. R values of blood plasma, lysed packed erythrocytes, lysed plasma/erythrocyte mixtures, and whole blood at 3 T, 7 T, 9.4 T, 11.7 T and 16.4 T were measured as a function of hematocrit or hemoglobin concentration, oxygenation, and CPMG inter-echo spacing (τ). R in lysed cells showed a small τ dependence, attributed to the water exchange rate between free and hemoglobin-bound water to be much faster than τ. This was contrary to the tangential dependence in whole blood, where a much slower exchange between cells and blood plasma applies. Whole blood data were fitted as a function of τ using a general tangential correlation time model applicable for exchange as well as diffusion contributions to R, and the intercept R at infinitely short τ was determined. The R values at different hematocrit and the R values of lysed erythrocyte/plasma mixtures at different hemoglobin concentration were used to determine the relaxivity of hemoglobin inside the erythrocyte (r) and albumin (r) in plasma. The r values obtained from lysed erythrocytes and whole blood were comparable at full oxygenation. However, while r determined from lysed cells showed a linear dependence on oxygenation, this dependence became quadratic in whole blood. This possibly suggests an additional relaxation effect inside intact cells, perhaps due to hemoglobin proximity to the erythrocyte membrane. However, we cannot exclude that this is a consequence of the simple tangential model used to remove relaxation contributions from exchange and diffusion. The extensive data set presented should be useful for future theory development for the transverse relaxation of blood.
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http://dx.doi.org/10.1016/j.mri.2016.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437867PMC
May 2017

Prostatic Acid Phosphatase Alters the RANKL/OPG System and Induces Osteoblastic Prostate Cancer Bone Metastases.

Endocrinology 2016 Dec 26;157(12):4526-4533. Epub 2016 Oct 26.

Department of Urology (A.K.); Department of Genetics and Genomic Sciences (S.I.), Graduate School of Biomedical Sciences; and Division of Endocrinology, Diabetes and Bone Disease (S.Yao, K.L.O.-C., A.H., E.M.G., A.C.L.), Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029; and Departments of Basic Science and Craniofacial Biology (S.Yak.), New York University College of Dentistry, New York, New York 10010.

Prostate cancer (PCa) is unique in its tendency to produce osteoblastic (OB) bone metastases. There are no existing therapies that specifically target the OB phase that affects 90% of men with bone metastatic disease. Prostatic acid phosphatase (PAP) is secreted by PCa cells in OB metastases and increases OB growth, differentiation, and bone mineralization. The purpose of this study was to investigate whether PAP effects on OB bone metastases are mediated by autocrine and/or paracrine alterations in the receptor activator of nuclear factor κ-B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system. To investigate whether PAP modulated these factors and altered the bone reaction, we knocked down PAP expression in VCaP cells and stably overexpressed PAP in PC3M cells, both derived from human PCa bone metastases. We show that knockdown of PAP in VCaP cells decreased OPG while increasing RANK/RANKL expression. Forced overexpression of PAP in PC3M cells had the inverse effect, increasing OPG while decreasing RANK/RANKL expression. Coculture of PCa cells with MC3T3 preosteoblasts also revealed a role for secretory PAP in OB-PCa cross talk. Reduced PAP expression in VCaP cells decreased MC3T3 proliferation and differentiation and reduced their OPG expression. PAP overexpression in PC3M cells altered the bone phenotype creating OB rather than osteolytic lesions in vivo using an intratibial model. These findings demonstrate that PAP secreted by PCa cells in OB bone metastases increases OPG and plays a critical role in the vicious cross talk between cancer and bone cells. These data suggest that inhibition of secretory PAP may be an effective strategy for PCa OB bone lesions.
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http://dx.doi.org/10.1210/en.2016-1606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133341PMC
December 2016

Hepatitis B Awareness and Knowledge in Asian Communities in British Columbia.

Can J Gastroenterol Hepatol 2016 29;2016:4278724. Epub 2016 Mar 29.

Division of Gastroenterology, Department of Medicine, University of British Columbia, GLDHCC, 2775 Laurel Street, 5th Floor, Vancouver, BC, Canada V5Z 1M9.

Background. Our study examined hepatitis B virus (HBV) awareness and knowledge in Asian communities in British Columbia (BC). Methods. A statistical random sample representation of Chinese, Korean, Filipino, South Asian, and Southeast Asian populations in Greater Vancouver was surveyed by telephone. Multiple logistic regression analysis was performed to identify predictors of HBV knowledge. Results. General awareness of HBV was reported in 78.8% (798/1013). HBV awareness was the highest in Chinese (89%) and Filipino (88%) populations and the lowest in the South Asian (56%) population. "Reasonable" knowledge of HBV was elicited in 76.8% (778/1013). Higher HBV knowledge was associated with younger age (p = 0.014), higher education (p < 0.0001), Chinese ethnicity (p < 0.0001), and use of media (p = 0.01) and Internet (p = 0.024) for health information. Compared to the Chinese (OR = 1.0) population, "reasonable" knowledge of HBV was lower in Korean (OR = 0.3, 95% CI: 0.1-0.5), Filipino (OR = 0.3, 95% CI: 0.2-0.6), South Asian (OR = 0.3, 95% CI: 0.2-0.4), and Southeast Asian (OR = 0.3, 95% CI: 0.1-0.6) populations. 54.8% (555/1013) felt that HBV education was inadequate and 80.1% (811/1013) preferred HBV education in their native languages. Conclusion. Compared to the Chinese population, other Asian communities in BC have lower HBV awareness and knowledge. Public education should target older and less educated and Korean, Filipino, South Asian, and Southeast Asian populations in their native languages via media and Internet.
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http://dx.doi.org/10.1155/2016/4278724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4904637PMC
March 2017

Correlative Analysis of Genetic Alterations and Everolimus Benefit in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From BOLERO-2.

J Clin Oncol 2016 Feb 26;34(5):419-26. Epub 2015 Oct 26.

Gabriel N. Hortobagyi, University of Texas MD Anderson Cancer Center, Houston, TX; David Chen, Tetiana Taran, and David Lebwohl, Novartis Pharmaceuticals, East Hanover, NJ; Martine Piccart and Fabienne Lebrun, Université Libre de Bruxelles, Brussels; Ines Deleu, Oncology Centre, AZ Nikolaas, Sint-Nikolaas, Belgium; Hope S. Rugo, University of California, San Francisco; Ian Anderson, Redwood Regional Oncology Center, Santa Rosa, CA; Howard A. Burris III, Sarah Cannon Research Institute, Nashville, TN; Kathleen I. Pritchard, Sunnybrook Odette Cancer Centre and the University of Toronto, Toronto, Ontario, Canada; Mario Campone, Centre de Recherche en Cancerologie, Nantes-Saint-Herblain; Thomas Bachelot, Centre Léon Bérard, Lyon, France; Shinzaburo Noguchi, Osaka University Medical School; Norikazu Masuda, Osaka National Hospital, Osaka, Japan; Alejandra T. Perez, Memorial Cancer Institute, Hollywood, FL; Mikhail Shtivelband, Ironwood Cancer & Research Centers, Chandler, AZ; Shaker Dakhil, Cancer Center of Kansas, Wichita, KS; Douglas M. Robinson, Wei He, Abhishek Garg, E. Robert McDonald III, Hans Bitter, and Alan Huang, Novartis Institutes for BioMedical Research, Cambridge, MA; and José Baselga, Memorial Sloan-Kettering Cancer Center, New York, NY.

Purpose: To explore the genetic landscape of tumors from patients enrolled on the BOLERO-2 trial to identify potential correlations between genetic alterations and efficacy of everolimus treatment. The BOLERO-2 trial has previously demonstrated that the addition of everolimus to exemestane prolonged progression-free survival by more than twofold in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer previously treated with nonsteroidal aromatase inhibitors.

Patients And Methods: Next-generation sequencing was used to analyze genetic status of cancer-related genes in 302 archival tumor specimens from patients representative of the BOLERO-2 study population. Correlations between the most common somatic alterations and degree of chromosomal instability, and treatment effect of everolimus were investigated.

Results: Progression-free survival benefit with everolimus was maintained regardless of alteration status of PIK3CA, FGFR1, and CCND1 or the pathways of which they are components. However, quantitative differences in everolimus benefit were observed between patient subgroups defined by the exon-specific mutations in PIK3CA (exon 20 v 9) or by different degrees of chromosomal instability in the tumor tissues.

Conclusion: The data from this exploratory analysis suggest that the efficacy of everolimus was largely independent of the most commonly altered genes or pathways in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. The potential impact of chromosomal instabilities and low-frequency genetic alterations on everolimus efficacy warrants further investigation.
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http://dx.doi.org/10.1200/JCO.2014.60.1971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070556PMC
February 2016

Quantitative theory for the longitudinal relaxation time of blood water.

Magn Reson Med 2016 07 18;76(1):270-81. Epub 2015 Aug 18.

Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Purpose: To propose and evaluate a model for the blood water T1 that takes into account the effects of hematocrit fraction, oxygenation fraction, erythrocyte hemoglobin concentration, methemoglobin fraction, and plasma albumin concentration.

Methods: Whole blood and lysed blood T1 data were acquired at magnetic fields of 3 Tesla (T), 7T, 9.4T, and 11.7T using inversion-recovery measurements and a home-built blood circulation system for maintaining physiological conditions. A quantitative model was derived based on multivariable fitting of this data.

Results: Fitting of the model to the data allowed determination of the different parameters describing the blood water T1 such as those for the diamagnetic and paramagnetic effects of albumin and hemoglobin, and the contribution of methemoglobin. The model correctly predicts blood T1 at multiple fields, as verified by comparison with existing literature.

Conclusion: The model provides physical and physiological parameters describing the effects of hematocrit fraction, oxygenation, hemoglobin concentration, methemoglobin fraction, and albumin concentration on blood water T1 . It can be used to predict blood T1 at multiple fields. Magn Reson Med 76:270-281, 2016. © 2015 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/mrm.25875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758918PMC
July 2016

Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors.

Cancer Discov 2015 Aug 13;5(8):850-9. Epub 2015 May 13.

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.

Unlabelled: Focal amplification and activating point mutation of the MET gene are well-characterized oncogenic drivers that confer susceptibility to targeted MET inhibitors. Recurrent somatic splice site alterations at MET exon 14 (METex14) that result in exon skipping and MET activation have been characterized, but their full diversity and prevalence across tumor types are unknown. Here, we report analysis of tumor genomic profiles from 38,028 patients to identify 221 cases with METex14 mutations (0.6%), including 126 distinct sequence variants. METex14 mutations are detected most frequently in lung adenocarcinoma (3%), but also frequently in other lung neoplasms (2.3%), brain glioma (0.4%), and tumors of unknown primary origin (0.4%). Further in vitro studies demonstrate sensitivity to MET inhibitors in cells harboring METex14 alterations. We also report three new patient cases with METex14 alterations in lung or histiocytic sarcoma tumors that showed durable response to two different MET-targeted therapies. The diversity of METex14 mutations indicates that diagnostic testing via comprehensive genomic profiling is necessary for detection in a clinical setting.

Significance: Here we report the identification of diverse exon 14 splice site alterations in MET that result in constitutive activity of this receptor and oncogenic transformation in vitro. Patients whose tumors harbored these alterations derived meaningful clinical benefit from MET inhibitors. Collectively, these data support the role of METex14 alterations as drivers of tumorigenesis, and identify a unique subset of patients likely to derive benefit from MET inhibitors.
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http://dx.doi.org/10.1158/2159-8290.CD-15-0285DOI Listing
August 2015

AXL mediates resistance to PI3Kα inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas.

Cancer Cell 2015 Apr;27(4):533-46

Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA. Electronic address:

Phosphoinositide-3-kinase (PI3K)-α inhibitors have shown clinical activity in squamous cell carcinomas (SCCs) of head and neck (H&N) bearing PIK3CA mutations or amplification. Studying models of therapeutic resistance, we have observed that SCC cells that become refractory to PI3Kα inhibition maintain PI3K-independent activation of the mammalian target of rapamycin (mTOR). This persistent mTOR activation is mediated by the tyrosine kinase receptor AXL. AXL is overexpressed in resistant tumors from both laboratory models and patients treated with the PI3Kα inhibitor BYL719. AXL dimerizes with and phosphorylates epidermal growth factor receptor (EGFR), resulting in activation of phospholipase Cγ (PLCγ)-protein kinase C (PKC), which, in turn, activates mTOR. Combined treatment with PI3Kα and either EGFR, AXL, or PKC inhibitors reverts this resistance.
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http://dx.doi.org/10.1016/j.ccell.2015.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4398915PMC
April 2015

Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus.

Mol Cancer Ther 2015 May 27;14(5):1224-35. Epub 2015 Feb 27.

Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and hyperactivation of mTOR signaling plays a pivotal role in HCC tumorigenesis. Tuberous sclerosis complex (TSC), a heterodimer of TSC1 and TSC2, functions as a negative regulator of mTOR signaling. In the current study, we discovered that TSC2 loss-of-function is common in HCC. TSC2 loss was found in 4 of 8 HCC cell lines and 8 of 28 (28.6%) patient-derived HCC xenografts. TSC2 mutations and deletions are likely to be the underlying cause of TSC2 loss in HCC cell lines, xenografts, and primary tumors for most cases. We further demonstrated that TSC2-null HCC cell lines and xenografts had elevated mTOR signaling and, more importantly, were significantly more sensitive to RAD001/everolimus, an mTORC1 inhibitor. These preclinical findings led to the analysis of TSC2 status in HCC samples collected in the EVOLVE-1 clinical trial of everolimus using an optimized immunohistochemistry assay and identified 15 of 139 (10.8%) samples with low to undetectable levels of TSC2. Although the sample size is too small for formal statistical analysis, TSC2-null/low tumor patients who received everolimus tended to have longer overall survival than those who received placebo. Finally, we performed an epidemiology survey of more than 239 Asian HCC tumors and found the frequency of TSC2 loss to be approximately 20% in Asian HBV(+) HCC. Taken together, our data strongly argue that TSC2 loss is a predictive biomarker for the response to everolimus in HCC patients.
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http://dx.doi.org/10.1158/1535-7163.MCT-14-0768DOI Listing
May 2015

FGFR-Mediated Reactivation of MAPK Signaling Attenuates Antitumor Effects of Imatinib in Gastrointestinal Stromal Tumors.

Cancer Discov 2015 Apr 11;5(4):438-51. Epub 2015 Feb 11.

Oncology Translational Research, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.

Unlabelled: Activating mutations in either KIT or PDGFRA are present in approximately 90% of gastrointestinal stromal tumors (GIST). Although treatment with the KIT and PDGFR inhibitor imatinib can control advanced disease in about 80% of GIST patients, the beneficial effect is not durable. Here, we report that ligands from the FGF family reduced the effectiveness of imatinib in GIST cells, and FGF2 and FGFR1 are highly expressed in all primary GIST samples examined. The combination of KIT and FGFR inhibition showed increased growth inhibition in imatinib-sensitive GIST cell lines and improved efficacy in patient-derived GIST xenografts. In addition, inhibition of MAPK signaling by imatinib was not sustained in GIST cells. An ERK rebound occurred through activation of FGF signaling, and was repressed by FGFR1 inhibition. Downregulation of Sprouty proteins played a role in the imatinib-induced feedback activation of FGF signaling in GIST cells.

Significance: We here show that FGFR-mediated reactivation of the MAPK pathway attenuates the antiproliferation effects of imatinib in GISTs. The imatinib-induced ERK rebound can be repressed by the FGFR inhibitor BGJ398, and combined KIT and FGFR inhibition leads to increased efficacy in vitro and in patient-derived xenografts.
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http://dx.doi.org/10.1158/2159-8290.CD-14-0763DOI Listing
April 2015

Measurement of PIP3 levels reveals an unexpected role for p110β in early adaptive responses to p110α-specific inhibitors in luminal breast cancer.

Cancer Cell 2015 Jan 24;27(1):97-108. Epub 2014 Dec 24.

Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Electronic address:

BYL719, which selectively inhibits the alpha isoform of the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (p110a), is currently in clinical trials for the treatment of solid tumors, especially luminal breast cancers with PIK3CA mutations and/or HER2 amplification. This study reveals that, even among these sensitive cancers, the initial efficacy of p110α inhibition is mitigated by rapid re-accumulation of the PI3K product PIP3 produced by the p110β isoform. Importantly, the reactivation of PI3K mediated by p110β does not invariably restore AKT phosphorylation, demonstrating the limitations of using phospho-AKT as a surrogate to measure PI3K activation. Consistently, we show that the addition of the p110β inhibitor to BYL719 prevents the PIP3 rebound and induces greater antitumor efficacy in HER2-amplified and PIK3CA mutant cancers.
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http://dx.doi.org/10.1016/j.ccell.2014.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4745884PMC
January 2015

Fatal pulmonary embolization after negative serial ultrasounds.

J Emerg Med 2015 Feb 13;48(2):158-60. Epub 2014 Nov 13.

Elmhurst Hospital Center, Mount Sinai School of Medicine, New York, New York.

Background: Isolated distal deep vein thrombosis (DVT) is not traditionally viewed as a potentially life-threatening condition. There are conflicting recommendations regarding its evaluation and treatment, and wide variability in clinical practice. The presentation of this case highlights the fatal potential of this condition.

Case Report: This is the report of a previously healthy young woman who presented to the emergency department with calf pain concerning for a DVT. She received two radiologist-performed duplex ultrasound examinations of the affected extremity, both of which were negative, but suffered a sudden cardiac arrest several hours after the second study. Autopsy attributed the death to DVT and pulmonary embolism. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case highlights the risk for fatal pulmonary embolization, even after normal serial ultrasound examinations to exclude DVT.
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http://dx.doi.org/10.1016/j.jemermed.2014.10.006DOI Listing
February 2015
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