DOCSLIB.ORG

The Angiopoietin-2 and TIE Pathway As a Therapeutic Target for Enhancing Antiangiogenic Therapy and Immunotherapy in Patients with Advanced Cancer

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Angiopoietin-2 and TIE Pathway As a Therapeutic Target for Enhancing Antiangiogenic Therapy and Immunotherapy in Patients with Advanced Cancer International Journal of Molecular Sciences Review The Angiopoietin-2 and TIE Pathway as a Therapeutic Target for Enhancing Antiangiogenic Therapy and Immunotherapy in Patients with Advanced Cancer Alessandra Leong and Minah Kim * Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA; afl[email protected] * Correspondence: [email protected] Received: 26 September 2020; Accepted: 13 November 2020; Published: 18 November 2020 Abstract: Despite significant advances made in cancer treatment, the development of therapeutic resistance to anticancer drugs represents a major clinical problem that limits treatment efficacy for cancer patients. Herein, we focus on the response and resistance to current antiangiogenic drugs and immunotherapies and describe potential strategies for improved treatment outcomes. Antiangiogenic treatments that mainly target vascular endothelial growth factor (VEGF) signaling have shown efficacy in many types of cancer. However, drug resistance, characterized by disease recurrence, has limited therapeutic success and thus increased our urgency to better understand the mechanism of resistance to inhibitors of VEGF signaling. Moreover, cancer immunotherapies including immune checkpoint inhibitors (ICIs), which stimulate antitumor immunity, have also demonstrated a remarkable clinical benefit in the treatment of many aggressive malignancies. Nevertheless, the emergence of resistance to immunotherapies associated with an immunosuppressive tumor microenvironment has restricted therapeutic response, necessitating the development of better therapeutic strategies to increase treatment efficacy in patients. Angiopoietin-2 (ANG2), which binds to the receptor tyrosine kinase TIE2 in endothelial cells, is a cooperative driver of angiogenesis and vascular destabilization along with VEGF. It has been suggested in multiple preclinical studies that ANG2-mediated vascular changes contribute to the development and persistence of resistance to anti-VEGF therapy. Further, emerging evidence suggests a fundamental link between vascular abnormalities and tumor immune evasion, supporting the rationale for combination strategies of immunotherapy with antiangiogenic drugs. In this review, we discuss the recent mechanistic and clinical advances in targeting angiopoietin signaling, focusing on ANG2 inhibition, to enhance therapeutic efficacy of antiangiogenic and ICI therapies. In short, we propose that a better mechanistic understanding of ANG2-mediated vascular changes will provide insight into the significance of ANG2 in treatment response and resistance to current antiangiogenic and ICI therapies. These advances will ultimately improve therapeutic modalities for cancer treatment. Keywords: ANG2; antiangiogenic therapy; immunotherapy; resistance; cancer treatment 1. Introduction The vascular network is comprised of blood vessels that act as a crucial delivery system of oxygen and other nutrients to tissues and organs. Healthy blood vessels are lined with endothelial cells that maintain vascular stability and facilitate proper blood flow. Angiogenesis, which is the formation of new blood vessels, plays a vital role in tissue development and maintenance under physiological conditions. However, vascular abnormalities characterized by neovascularization and destabilization are a feature of many diseases including cancer [1,2]. Unlike healthy vasculature, tumor blood vessels are irregularly Int. J. Mol. Sci. 2020, 21, 8689; doi:10.3390/ijms21228689 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 8689 2 of 20 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 21 destabilization are a feature of many diseases including cancer [1,2]. Unlike healthy vasculature, patternedtumor and blood morphologically vessels are irregularly tortuous. patterned Pericytes, and morphologically which surround tortuous. healthy Pericytes, blood which vessels and maintainsurround vascular healthy stability, blood are oftenvessels detached and maintain from thevascular endothelial stability, cells are ofoften tumor detached vasculature. from the Further, impairedendothelial endothelial cells junctions of tumor and vasculature. depleted basementFurther, impaired membranes endothelial make thesejunctions tumor and vessels depleted unstable. Functionally,basement this membranes impaired endothelial make these integritytumor vessels causes unstable. increased Functionally, vascular this leakage impaired that endothelial disrupts normal pressureintegrity across tumor causes vesselsincreased and vascular promotes leakage dysfunctional that disrupts flow.normal The pressure resulting across elevated tumor vessels interstitial and fluid promotes dysfunctional flow. The resulting elevated interstitial fluid pressure hinders drug transport pressureinto hinders the tumor drug microenvironment, transport into the impeding tumor microenvironment, therapeutic interventions. impeding Additionally, therapeutic flow stasis interventions. in Additionally,impaired flow tumor stasis vessels in impaired promotes tumorhypoxia, vessels which up promotesregulates hypoxia,angiogenic whichmolecules upregulates such as vascular angiogenic moleculesendothelial such as growth vascular factor-A endothelial (VEGF-A, growthreferred to factor-A as VEGF), (VEGF-A, further promoting referred tumor to as growth VEGF), [3]. further promotingTogether, tumor the growth structural [3]. and Together, functional the abnormalities structural andof tumor functional blood vessels abnormalities contribute of to tumortumor blood vessels contributeprogression toand tumor potentially progression facilitate and the potentially development facilitate and persistence the development of resistance and to persistence cancer of therapies. Therefore, the reversal of aberrant tumor vasculature, termed “vascular normalization”, resistance to cancer therapies. Therefore, the reversal of aberrant tumor vasculature, termed “vascular serves as a promising target for the treatment of cancer (Figure 1) [3,4]. normalization”, serves as a promising target for the treatment of cancer (Figure1)[3,4]. Figure 1. Vascular destabilization and normalization in the tumor microenvironment. Vascular endothelialFigure growth 1. Vascular factor-A destabilization (VEGF) and and angiopoietin-2 normalization (ANG2)in the tumor levels microenvironment. are upregulated Vascular in the tumor microenvironmentendothelial growth where factor-A vessels (VEGF) are functionally and angiopoiet andin-2 structurally (ANG2) levels altered. are upregulated Destabilized in the tumor tumorvessels are characterizedmicroenvironment by pericyte where vessels loss, impaired are functionally endothelial and structurally junctions, altered. increased Destabilized vascular tumor vessels leakage and poor vascularare characterized perfusion. by Vascular pericyte lo normalizationss, impaired endothelial by VEGF junction and/ors, increased ANG2 blockade vascular leakage stabilizes and tumor vessels andpoor inducesvascular perfusion. increased Vascular vascular normalization perfusion, by which VEGF consequentlyand/or ANG2 blockade improves stabilizes drug tumor delivery in vessels and induces increased vascular perfusion, which consequently improves drug delivery in cancer treatment. cancer treatment. Tumor vascularTumor vascular remodeling remodeling and and destabilization destabilization are regulated regulated by by a set a setof angiogenic of angiogenic signaling signaling pathways.pathways. Indeed, Indeed, intensive intensive preclinical preclinical and and clinical clinical studiesstudies targeting targeting VEGF/VEGF VEGF/VEGF receptor receptor (VEGFR) (VEGFR) signaling,signaling, a predominant a predominant angiogenic angiogenic pathway, pathway, havehave shown antiangiogenic antiangiogenic and andantitumor antitumor effects. effects. However,However, a high a incidence high incidence of resistance of resistance to to VEGF VEGF signaling-targeted signaling-targeted drugs, drugs, characterized characterized by disease by disease progressionprogression after initial after initial therapy therapy response, response, has has limited limited thethe therapeutic therapeutic success success of antiangiogenic of antiangiogenic drugs drugs in cancer treatment [5–7]. This emphasizes the need for improved treatment modalities such as in cancer treatment [5–7]. This emphasizes the need for improved treatment modalities such as combination treatments with other targeted drugs. Angiopoietin-2 (ANG2) is another predominant combinationangiogenic treatments factor withand cooperative other targeted driver drugs. of vascular Angiopoietin-2 destabilization. (ANG2) The ANG2/TIE is another pathway predominant angiogeniccontrols factor vascular and cooperative permeability driverin pathologic of vascular conditions destabilization. and thus acts as The a master ANG2 regulator/TIE pathway of vascular controls vascularstability. permeability Increasing in pathologic evidence also conditions suggests that and vascular thus acts destabili as a masterzation is regulator linked to tumor of vascular immune stability. Increasingevasion evidence and resistance also suggests to current that immunotherapy vascular destabilization [8,9]. Therefore, is linked targetin tog tumorthe ANG2/TIE immune pathway evasion and resistancein tocombination current immunotherapy with other cancer [8 therapeutics,9]. Therefore, represents targeting a promising the ANG2 clinical/TIE pathwaystrategy for in combinationcancer with other cancer therapeutics
Load more

Recommended publications
  • Polatuzumab Vedotin - R/R DLBCL RG7769 PD1-TIM3 Bimab - Solid Tumors NSCLC RG7446 Tecentriq – Her2-Pos
    Pipeline summary Marketed products additional indications Global Development late-stage trials pRED (Roche Pharma Research & Early Development) gRED (Genentech Research & Early Development) 1 Changes to the development pipeline FY 2018 update New to phase I New to phase II New to phase III New to registration 3 NMEs: 2 NMEs transitioned from Ph1 1 NME transitioned from Ph2: 2 NMEs + 1 AI transitioned from Ph2 RG6217 - HBV RG7906 - psychiatric disorders RG6042 HTT ASO - Huntington’s following filing in EU and US: RG6237 - neuromuscular disorders RG6058 tiragolumab + Tecentriq - 6 AIs: RG7596 polatuzumab vedotin - r/r DLBCL RG7769 PD1-TIM3 biMAb - solid tumors NSCLC RG7446 Tecentriq – Her2-pos. BC neoadj RG6268 entrectinib - NSCLC ROS1+ 1 AI: 1 NME starting Ph2 RG7446 Tecentriq – high risk NMIBC RG6268 entrectinib – NTRK1 pan-tumor RG7601 Venclexta + gilteritinib – r/r RG6180 iNeST (personalized cancer RG6152 Xofluza - influenza hosp. patients 3 AIs transitioned from Ph3 following AML vaccine) + pembrolizumab - malignant RG6152 Xofluza – influenza pediatric filing in EU and US: melanoma patients RG7446 Tecentriq + nab-paclitaxel 1L 1 NME following termination of Ph3 RG7601 Venclexta - r/r MM t(11:14) non sq NSCLC RG7412 crenezumab – familial RG7601 Venclexta + HMA/LDAC - 1L RG7446 Tecentriq + nab-paclitaxel Alzheimer’s disease healthy individuals AML* 1LTNBC RG7446 Tecentriq + chemo - 1L extensive 1 AI: stage SCLC RG7446 Tecentriq SC – NSCLC Removed from phase I Removed from phase II Removed from phase III Removed from registration 2 NMEs:
    [Show full text]
  • The Interplay Between Angiopoietin-Like Proteins and Adipose Tissue: Another Piece of the Relationship Between Adiposopathy and Cardiometabolic Diseases?
    International Journal of Molecular Sciences Review The Interplay between Angiopoietin-Like Proteins and Adipose Tissue: Another Piece of the Relationship between Adiposopathy and Cardiometabolic Diseases? Simone Bini *,† , Laura D’Erasmo *,†, Alessia Di Costanzo, Ilenia Minicocci , Valeria Pecce and Marcello Arca Department of Translational and Precision Medicine, Sapienza University of Rome, Viale del Policlinico 155, 00185 Rome, Italy; [email protected] (A.D.C.); [email protected] (I.M.); [email protected] (V.P.); [email protected] (M.A.) * Correspondence: [email protected] (S.B.); [email protected] (L.D.) † These authors contributed equally to this work. Abstract: Angiopoietin-like proteins, namely ANGPTL3-4-8, are known as regulators of lipid metabolism. However, recent evidence points towards their involvement in the regulation of adipose tissue function. Alteration of adipose tissue functions (also called adiposopathy) is considered the main inducer of metabolic syndrome (MS) and its related complications. In this review, we intended to analyze available evidence derived from experimental and human investigations highlighting the contribution of ANGPTLs in the regulation of adipocyte metabolism, as well as their potential role in common cardiometabolic alterations associated with adiposopathy. We finally propose a model of ANGPTLs-based adipose tissue dysfunction, possibly linking abnormalities in the angiopoietins to the induction of adiposopathy and its related disorders. Keywords: adipose tissue; adiposopathy; brown adipose tissue; ANGPTL3; ANGPTL4; ANGPTL8 Citation: Bini, S.; D’Erasmo, L.; Di Costanzo, A.; Minicocci, I.; Pecce, V.; Arca, M. The Interplay between 1. Introduction Angiopoietin-Like Proteins and Adipose tissue (AT) is an important metabolic organ and accounts for up to 25% of Adipose Tissue: Another Piece of the healthy individuals’ weight.
    [Show full text]
  • Scientific Annual Report 2019
    Scientific Annual Report 2019 Scientific Annual Report 2019 Contents 2 Introduction 14 Board members Director of Research 18 Group leaders 18 Neil Aaronson 37 Kees Jalink 56 Hein te Riele 19 Reuven Agami 38 Jos Jonkers 57 Lonneke van de Poll 20 Leila Akkari 39 Marleen Kok 58 Winette van der Graaf 21 Regina Beets-Tan 40 Pia Kvistborg and Olga Husson 22 Roderick Beijersbergen 41 Tineke Lenstra 60 Uulke van der Heide 23 Jos Beijnen 42 Sabine Linn 61 Michiel van der Heijden 24 André Bergman 43 René Medema 62 Wim van Harten 25 René Bernards 44 Gerrit Meijer and 63 Flora van Leeuwen and 26 Christian Blank Remond Fijneman Matti Rookus 27 Eveline Bleiker 46 Daniel Peeper 65 Fred van Leeuwen 28 Gerben Borst 47 Anastassis Perrakis 66 Maarten van Lohuizen 29 Thijn Brummelkamp 48 Benjamin Rowland 67 Jacco van Rheenen 30 Karin de Visser 49 Sanne Schagen 68 Bas van Steensel 31 Elzo de Wit 50 Alfred Schinkel 69 Olaf van Tellingen 32 William Faller 51 Marjanka Schmidt 70 Emile Voest 33 John Haanen 52 Ton Schumacher 71 Jelle Wesseling 34 Hugo Horlings 53 Titia Sixma 72 Lodewyk Wessels 35 Heinz Jacobs 54 Jan-Jakob Sonke 73 Lotje Zuur 36 Jacqueline Jacobs 55 Arnoud Sonnenberg 74 Wilbert Zwart 78 Division of 84 Division of 90 Division of Diagnostic Oncology Medical Oncology Surgical Oncology 96 Division of 102 Division of 110 Technology Radiation Oncology Pharmacology Transfer Office and Biometrics 112 Research Facilities 126 Education in 134 Clinical Oncology trials 164 Invited 166 Research 194 Personnel speakers projects index Netherlands Cancer Institute Plesmanlaan 121 1066 CX Amsterdam The Netherlands www.nki.nl Scientific Annual Report 2019 Introduction It is my pleasure to present the 2019 Scientific Annual Report of the Netherlands Cancer Institute.
    [Show full text]
  • Predictive QSAR Tools to Aid in Early Process Development of Monoclonal Antibodies
    Predictive QSAR tools to aid in early process development of monoclonal antibodies John Micael Andreas Karlberg Published work submitted to Newcastle University for the degree of Doctor of Philosophy in the School of Engineering November 2019 Abstract Monoclonal antibodies (mAbs) have become one of the fastest growing markets for diagnostic and therapeutic treatments over the last 30 years with a global sales revenue around $89 billion reported in 2017. A popular framework widely used in pharmaceutical industries for designing manufacturing processes for mAbs is Quality by Design (QbD) due to providing a structured and systematic approach in investigation and screening process parameters that might influence the product quality. However, due to the large number of product quality attributes (CQAs) and process parameters that exist in an mAb process platform, extensive investigation is needed to characterise their impact on the product quality which makes the process development costly and time consuming. There is thus an urgent need for methods and tools that can be used for early risk-based selection of critical product properties and process factors to reduce the number of potential factors that have to be investigated, thereby aiding in speeding up the process development and reduce costs. In this study, a framework for predictive model development based on Quantitative Structure- Activity Relationship (QSAR) modelling was developed to link structural features and properties of mAbs to Hydrophobic Interaction Chromatography (HIC) retention times and expressed mAb yield from HEK cells. Model development was based on a structured approach for incremental model refinement and evaluation that aided in increasing model performance until becoming acceptable in accordance to the OECD guidelines for QSAR models.
    [Show full text]
  • Classification Decisions Taken by the Harmonized System Committee from the 47Th to 60Th Sessions (2011
    CLASSIFICATION DECISIONS TAKEN BY THE HARMONIZED SYSTEM COMMITTEE FROM THE 47TH TO 60TH SESSIONS (2011 - 2018) WORLD CUSTOMS ORGANIZATION Rue du Marché 30 B-1210 Brussels Belgium November 2011 Copyright © 2011 World Customs Organization. All rights reserved. Requests and inquiries concerning translation, reproduction and adaptation rights should be addressed to [email protected]. D/2011/0448/25 The following list contains the classification decisions (other than those subject to a reservation) taken by the Harmonized System Committee ( 47th Session – March 2011) on specific products, together with their related Harmonized System code numbers and, in certain cases, the classification rationale. Advice Parties seeking to import or export merchandise covered by a decision are advised to verify the implementation of the decision by the importing or exporting country, as the case may be. HS codes Classification No Product description Classification considered rationale 1. Preparation, in the form of a powder, consisting of 92 % sugar, 6 % 2106.90 GRIs 1 and 6 black currant powder, anticaking agent, citric acid and black currant flavouring, put up for retail sale in 32-gram sachets, intended to be consumed as a beverage after mixing with hot water. 2. Vanutide cridificar (INN List 100). 3002.20 3. Certain INN products. Chapters 28, 29 (See “INN List 101” at the end of this publication.) and 30 4. Certain INN products. Chapters 13, 29 (See “INN List 102” at the end of this publication.) and 30 5. Certain INN products. Chapters 28, 29, (See “INN List 103” at the end of this publication.) 30, 35 and 39 6. Re-classification of INN products.
    [Show full text]
  • Tanibirumab (CUI C3490677) Add to Cart
    5/17/2018 NCI Metathesaurus Contains Exact Match Begins With Name Code Property Relationship Source ALL Advanced Search NCIm Version: 201706 Version 2.8 (using LexEVS 6.5) Home | NCIt Hierarchy | Sources | Help Suggest changes to this concept Tanibirumab (CUI C3490677) Add to Cart Table of Contents Terms & Properties Synonym Details Relationships By Source Terms & Properties Concept Unique Identifier (CUI): C3490677 NCI Thesaurus Code: C102877 (see NCI Thesaurus info) Semantic Type: Immunologic Factor Semantic Type: Amino Acid, Peptide, or Protein Semantic Type: Pharmacologic Substance NCIt Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor tyrosine kinase expressed by endothelial cells, while VEGF is overexpressed in many tumors and is correlated to tumor progression. PDQ Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor
    [Show full text]
  • Roche Template
    Changes to the development pipeline Q3 2020 update New to phase I New to phase II New to phase III New to registration 7 NMEs: 2 NMEs: 4 NMEs: 1 NME: RG6091 UBE3A LNA - Angelman syndrome RG7992 FGFR1 x KLB - NASH RG6107 crovalimab - PNH RG6396 Gavreto (pralsetinib) - RET fusion- RG6286 NME - colorectal cancer CHU Oncolytic Type 5 adenovirus - esophageal RG6413+RG6412 REGN-COV2 - SARS-CoV-2 positive NSCLC RG6315 NME - systemic sclerosis cancer prophylaxis RG6330 KRAS G12C - KRAS-mutant solid tumors RG6171 SERD(3) ER+/HER2 - metastatic breast 2 AIs: RG6418 NLRP3 inhibitor - inflammation 5 AIs: cancer RG3648 Xolair - asthma home use 4D-MT 4D-R125 - X-linked retinitis pigmentosa RG6171 SERD(3) - neoadjuvant HR+ breast 7 AIs: RG6396 Gavreto (pralsetinitb) - RET-mutant CHU CD137 agonist switch antibody - solid tumors cancer RG6058 tiragolumab+Tecentriq - stage III medullary thyroid cancer (MTC) RG6413+RG6412 REGN-COV2 - COVID-19+ unresectable 1L NSCLC 2 AIs: adult – ambulatory RG6058 tiragolumab+Tecentriq - locally adv RG7440 ipatasertib+Tecentriq - prostate cancer RG6413+RG6412 REGN-COV2 - COVID-19+ esophageal cancer previously treated with androgen receptor-targeted adult – hospitalized RG6321 PDS with ranibizumab - diabetic therapy retinopathy RG7446 Tecentriq+Venclexta - maintenance 1L RG7159 Gazyva - lupus nephritis ES-SCLC RG7601 Venclexta - 1L MDS RG7446 Tecentriq+cabozantinib - adv RCC RG7446 Tecentriq+cabozantinib - 2L NSCLC Removed from phase I Removed from phase II Removed from phase III Approvals 2 NMEs: 2 AIs: 3 AIs: 3 NMEs approved
    [Show full text]
  • Erbitux® (Cetuximab)
    Erbitux® (cetuximab) (Intravenous) -E- Document Number: MODA-0494 Last Review Date: 06/01/2021 Date of Origin: 09/03/2019 Dates Reviewed: 09/2019, 01/2020, 04/2020, 07/2020, 10/2020, 01/2021, 04/2021, 06/2021 I. Length of Authorization 1 Coverage will be provided for six months and may be renewed unless otherwise specified. • SCCHN in combination with radiation therapy: Coverage will be provided for the duration of radiation therapy (6-7 weeks). II. Dosing Limits A. Quantity Limit (max daily dose) [NDC Unit]: Weekly Every two weeks Erbitux 100 mg/50 mL solution for injection 1 vial every 7 days 1 vial every 14 days 3 vials every 7 days Erbitux 200 mg/100 mL solution for injection 6 vials every 14 days (5 vials for first dose only) B. Max Units (per dose and over time) [HCPCS Unit]: Weekly Every two weeks − Load: 100 billable units x 1 dose 120 billable units every 14 days − Maintenance Dose: 60 billable units every 7 days III. Initial Approval Criteria 1 Coverage is provided in the following conditions: • Patient is at least 18 years of age; AND Colorectal Cancer (CRC) † ‡ 1,2,12,13,17,19,2e,5e-8e,10e-12e,15e • Patient is both KRAS and NRAS mutation negative (wild-type) as determined by FDA- approved or CLIA-compliant test*; AND • Will not be used as part of an adjuvant treatment regimen; AND • Patient has not been previously treated with cetuximab or panitumumab; AND • Will not be used in combination with an anti-VEGF agent (e.g., bevacizumab, ramucirumab); AND Moda Health Plan, Inc.
    [Show full text]
  • Primary and Acquired Resistance to Immunotherapy in Lung Cancer: Unveiling the Mechanisms Underlying of Immune Checkpoint Blockade Therapy
    cancers Review Primary and Acquired Resistance to Immunotherapy in Lung Cancer: Unveiling the Mechanisms Underlying of Immune Checkpoint Blockade Therapy Laura Boyero 1 , Amparo Sánchez-Gastaldo 2, Miriam Alonso 2, 1 1,2,3, , 1,2, , José Francisco Noguera-Uclés , Sonia Molina-Pinelo * y and Reyes Bernabé-Caro * y 1 Institute of Biomedicine of Seville (IBiS) (HUVR, CSIC, Universidad de Sevilla), 41013 Seville, Spain; [email protected] (L.B.); [email protected] (J.F.N.-U.) 2 Medical Oncology Department, Hospital Universitario Virgen del Rocio, 41013 Seville, Spain; [email protected] (A.S.-G.); [email protected] (M.A.) 3 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain * Correspondence: [email protected] (S.M.-P.); [email protected] (R.B.-C.) These authors contributed equally to this work. y Received: 16 November 2020; Accepted: 9 December 2020; Published: 11 December 2020 Simple Summary: Immuno-oncology has redefined the treatment of lung cancer, with the ultimate goal being the reactivation of the anti-tumor immune response. This has led to the development of several therapeutic strategies focused in this direction. However, a high percentage of lung cancer patients do not respond to these therapies or their responses are transient. Here, we summarized the impact of immunotherapy on lung cancer patients in the latest clinical trials conducted on this disease. As well as the mechanisms of primary and acquired resistance to immunotherapy in this disease. Abstract: After several decades without maintained responses or long-term survival of patients with lung cancer, novel therapies have emerged as a hopeful milestone in this research field.
    [Show full text]
  • HY 2021 Results
    Roche HY 2021 results Basel, 22 July 2021 This presentation contains certain forward-looking statements. These forward-looking statements may be identified by words such as ‘believes’, ‘expects’, ‘anticipates’, ‘projects’, ‘intends’, ‘should’, ‘seeks’, ‘estimates’, ‘future’ or similar expressions or by discussion of, among other things, strategy, goals, plans or intentions. Various factors may cause actual results to differ materially in the future from those reflected in forward-looking statements contained in this presentation, among others: 1 pricing and product initiatives of competitors; 2 legislative and regulatory developments and economic conditions; 3 delay or inability in obtaining regulatory approvals or bringing products to market; 4 fluctuations in currency exchange rates and general financial market conditions; 5 uncertainties in the discovery, development or marketing of new products or new uses of existing products, including without limitation negative results of clinical trials or research projects, unexpected side-effects of pipeline or marketed products; 6 increased government pricing pressures; 7 interruptions in production; 8 loss of or inability to obtain adequate protection for intellectual property rights; 9 litigation; 10 loss of key executives or other employees; and 11 adverse publicity and news coverage. Any statements regarding earnings per share growth is not a profit forecast and should not be interpreted to mean that Roche’s earnings or earnings per share for this year or any subsequent period will necessarily match or exceed the historical published earnings or earnings per share of Roche. For marketed products discussed in this presentation, please see full prescribing information on our website www.roche.com All mentioned trademarks are legally protected.
    [Show full text]
  • Cyramza® (Ramucirumab)
    Cyramza® (ramucirumab) (Intravenous) -E- Document Number: MODA-0405 Last Review Date: 07/01/2021 Date of Origin: 09/03/2019 Dates Reviewed: 09/2019, 10/2019, 01/2020, 04/2020, 07/2020, 10/2020, 01/2021, 04/2021, 07/2021 I. Length of Authorization Coverage will be provided for 6 months and may be renewed. II. Dosing Limits A. Quantity Limit (max daily dose) [NDC Unit]: • Cyramza 100 mg/10 mL: 4 vials per 14 days • Cyramza 500 mg/50 mL: 2 vials per 14 days B. Max Units (per dose and over time) [HCPCS Unit]: Gastric, Gastroesophageal, HCC, and Colorectal Cancer: • 180 billable units every 14 days NSCLC: • 240 billable units every 14 days III. Initial Approval Criteria 1 Coverage is provided in the following conditions: • Patient is at least 18 years of age; AND Universal Criteria 1 • Patient does not have uncontrolled severe hypertension; AND • Patient must not have had a surgical procedure within the preceding 28 days or have a surgical wound that has not fully healed; AND Gastric, Esophageal, and Gastro-esophageal Junction Adenocarcinoma † Ф 1-3,5-7,14,17,2e,5e • Used as subsequent therapy after fluoropyrimidine- or platinum-containing chemotherapy; AND • Used as a single agent OR in combination with paclitaxel; AND o Used for one of the following: Moda Health Plan, Inc. Medical Necessity Criteria Page 1/27 Proprietary & Confidential © 2021 Magellan Health, Inc. – Patient has unresectable locally advanced, recurrent, or metastatic disease; OR – Used as palliative therapy for locoregional disease in patients who are not surgical candidates
    [Show full text]
  • Human Epidermal Growth Factor Receptor 2 Regulates Angiopoietin-2 Expression in Breast Cancer Via AKT and Mitogen-Activated Protein Kinase Pathways Guilian Niu and W
    Research Article Human Epidermal Growth Factor Receptor 2 Regulates Angiopoietin-2 Expression in Breast Cancer via AKT and Mitogen-Activated Protein Kinase Pathways Guilian Niu and W. Bradford Carter Don and Erika Wallace Comprehensive Breast Program, H. Lee Moffitt Cancer Center and Research Institute, Department of Interdisciplinary Oncology, University of South Florida College of Medicine, Tampa, Florida Abstract signaling pathways. None of the ligands bind HER2, but HER2 is Abnormal activation of human epidermal growth factor the preferred dimerization partner for all of the ErbB receptors. receptor 2 (HER2; ErbB-2) in breast tumors results in The role of HER2 as an important predictor of patient outcome increased metastasis and angiogenesis, as well as reduced and response to various therapies in breast cancer has been clearly survival.Here, we show that angiopoietin-2 (Ang-2) expression established (2, 5–7). Patients with HER2-overexpressing breast correlates with HER2 activity in human breast cancer cell tumors have an increased incidence of metastasis and a poorer lines.Inhibiting HER2 activity with anti-HER2 monoclonal survival rate when compared with patients whose tumors express antibody trastuzumab (Herceptin) or HER2 short interfering HER2 at normal levels. The angiopoietins (Ang) are novel endothelial growth factors, RNA in tumor cells down-regulates Ang-2 expression.Consis- tent with the important roles of AKT and mitogen-activated found to be ligands for the endothelium-specific tyrosine receptor protein kinase in the HER2 signaling pathway, AKT and ERK Tie-2 (8, 9). Ang-1 plays a role in maintaining and stabilizing mitogen-activated protein kinase (MAPK) kinase activity is mature vessels by promoting the interaction between endothelial necessary for Ang-2 up-regulation by HER2.Moreover, over- cells and the surrounding support cells (10–12).
    [Show full text]