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Angiogenesis, the sprouting of new blood vessels from existing vessels, is one of six known mechanisms employed by solid tumors to recruit blood vessels necessary for their initiation, growth, and metastatic spread. The vascular network within the tumor facilitates the transport of nutrients, oxygen, and immune cells and is regulated by pro- and anti-angiogenic factors. Nearly four decades ago, VEGF was identified as a critical factor promoting vascular permeability and angiogenesis, followed by identification of VEGF family ligands and their receptors (VEGFR). Since then, over a dozen drugs targeting the VEGF/VEGFR pathway have been approved for approximately 20 solid tumor types, usually in combination with other therapies. Initially designed to starve tumors, these agents transiently "normalize" tumor vessels in preclinical and clinical studies, and in the clinic, increased tumor blood perfusion or oxygenation in response to these agents is associated with improved outcomes. Nevertheless, the survival benefit has been modest in most tumor types, and there are currently no biomarkers in routine clinical use for identifying which patients are most likely to benefit from treatment. However, the ability of these agents to reprogram the immunosuppressive tumor microenvironment into an immunostimulatory milieu has rekindled interest and has led to the FDA approval of seven different combinations of VEGF/VEGFR pathway inhibitors with immune checkpoint blockers for many solid tumors in the past 3 years. In this review, we discuss our understanding of the mechanisms of response and resistance to blocking VEGF/VEGFR, and potential strategies to develop more effective therapeutic approaches., (©2022 American Association for Cancer Research.)

Immune checkpoint inhibitors are associated with immune-related adverse events (irAEs), including arthritis (arthritis-irAE). Management of arthritis-irAE is challenging because immunomodulatory therapy for arthritis should not impede antitumor immunity. Understanding of the mechanisms of arthritis-irAE is critical to overcome this challenge, but the pathophysiology remains unknown. Here, we comprehensively analyze peripheral blood and/or synovial fluid samples from 20 patients with arthritis-irAE, and unmask a prominent Th1-CD8 + T cell axis in both blood and inflamed joints. CX3CR1 hi CD8 + T cells in blood and CXCR3 hi CD8 + T cells in synovial fluid, the most clonally expanded T cells, significantly share TCR repertoires. The migration of blood CX3CR1 hi CD8 + T cells into joints is possibly mediated by CXCL9/10/11/16 expressed by myeloid cells. Furthermore, arthritis after combined CTLA-4 and PD-1 inhibitor therapy preferentially has enhanced Th17 and transient Th1/Th17 cell signatures. Our data provide insights into the mechanisms, predictive biomarkers, and therapeutic targets for arthritis-irAE., (© 2022. The Author(s).)

Background: Preclinical studies suggest that combining vandetanib (VAN), a multi-tyrosine kinase inhibitor of rearranged during transfection (RET) proto-oncogene, vascular endothelial growth factor receptor (VEGFR), and epidermal growth factor receptor (EGFR), with everolimus (EV), a mammalian target of rapamycin (mTOR) inhibitor, may improve antitumor activity. We determined the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), and dose-limiting toxicities (DLTs) of VAN + EV in patients with advanced solid cancers and the effect of combination therapy on cancer cell proliferation and intracellular pathways., Patients and Methods: Patients with refractory solid tumors were enrolled in a phase I dose-escalation trial testing VAN (100-300 mg orally daily) + EV (2.5-10 mg orally daily). Objective responses were evaluated using RECIST v1.1. RET mutant cancer cell lines were used in cell-based studies., Results: Among 80 patients enrolled, 72 (90%) patients were evaluable: 7 achieved partial response (PR) (10%) and 37 had stable disease (SD) (51%; duration range: 1-27 cycles). Clinical benefit (SD or PR ≥ 6 months) was observed in 26 evaluable patients [36%, 95% confidence intervals (CI) (25% to 49%)]. In 80 patients, median overall survival (OS) was 10.5 months [95% CI (8.5-16.1)] and median progression-free survival (PFS) 4.1 months [95% CI (3.4-7.3)]. Six patients (7.5%) experienced DLTs and 20 (25%) required dose modifications. VAN + EV was safe, with fatigue, rash, diarrhea, and mucositis being the most common toxicities. In cell-based studies, combination therapy was superior to monotherapy at inhibiting cancer cell proliferation and intracellular signaling., Conclusions: The MTDs and RP2Ds of VAN + EV are 300 mg and 10 mg, respectively. VAN + EV combination is safe and active in refractory solid tumors. Further investigation is warranted in RET pathway aberrant tumors., Competing Interests: Disclosure TC: speaker's fees from Society for Immunotherapy of Cancer and Bristol Myers Squibb; consulting/advisory role fees from MedImmune/AstraZeneca, EMD Serono, and Bristol Myers Squibb, research funding to MD Anderson Cancer Center from Boehringer Ingelheim, MedImmune/AstraZeneca, and Bristol Myers Squibb. SAP-P: research/grant funding (institutional) from AbbVie, Inc.; Aminex Therapeutics; Amphivena Therapeutics, Inc.; BioMarin Pharmaceutical, Inc.; Boehringer Ingelheim; Bristol Myers Squib; Cerulean Pharma Inc.; Chugai Pharmaceutical Co., Ltd.; Curis, Inc.; Five Prime Therapeutics; Genmab A/S; GlaxoSmithKline; Helix BioPharma Corp.; Incyte Corp.; Jacobio Pharmaceuticals Co., Ltd.; Medimmune, LLC; Medivation, Inc.; Merck Sharp and Dohme Corp.; NewLink Genetics Corporation/Blue Link Pharmaceuticals; Novartis Pharmaceuticals; Pieris Pharmaceuticals, Inc.; Pfizer; Principia Biopharma, Inc.; Puma Biotechnology, Inc.; Rapt Therapeutics, Inc.; Seattle Genetics; Syneos Health; Taiho Oncology; Tesaro, Inc.; TransThera Bio; and Xuanzhu Biopharma. DSH: research/grant funding from AbbVie, Adaptimmune, Aldi-Norte, Amgen, Astra-Zeneca, Bayer, BMS, Daiichi Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, LOXO, Merck, MedImmune, Mirati, miRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer, Seattle Genetics, Takeda, and Turning Point Therapeutics; funding for travel, accommodations, and expenses from Bayer, LOXO, miRNA, Genmab, AACR, ASCO, and SITC; consultant/advisor for Alpha Insights, Amgen, Axiom, Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H, Guidepoint, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Prime Oncology, Seattle Genetics, Takeda, Trieza Therapeutics, WebMD; ownership interests in Molecular Match (Advisor), OncoResponse (Founder), Presagia Inc. (Advisor). SF: clinical trial research support through the institution from NIH/NCI; AstraZeneca; Abbisko; Anaeropharma Science; Arrien Pharmaceuticals; BeiGene; BioAtla, LLC; Boehringer Ingelheim; Eli Lilly & Co.; Hookipa Biotech; Huya Bioscience International; IMV, Inc.; Innovent Biologics, Co., Ltd.; Lyvgen Biopharma, Co., Ltd.; MacroGenics; Medivir AB; Millennium Pharmaceuticals, Inc.; Nerviano Medical Sciences; Neupharma, Inc.; Novartis; OncoMed Pharmaceuticals; Parexel International, LLC; Sellas Life Sciences Group; Soricimed Biopharma, Inc.; Tolero Pharmaceuticals; NovoCure; Turnstone Biologics; Taiho Oncology; and NCCN. AN: Research funding from NCI, EMD Serono, MedImmune, Healios, Atterocor, Amplimmune, ARMO BioSciences, Eli Lilly, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, BMS, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, Top Alliance Biosciences, Kymab, PsiOxus, Arcus Biosciences, NeoImmuneTech, ImmuneOncia, Surface Oncology; on advisory board of CytomX Therapeutics, Novartis, and Genome & Company, OncoSec KEYNOTE-695, STCube Pharmaceuticals, Kymab; travel and accommodation expense from ARMO BioSciences. Spouse: Research funding from Immune Deficiency Foundation, Jeffery Modell Foundation and Chao Physician-Scientist, and Baxalta; advisory board from Takeda, CSL Behring, Horizon Pharma. FJ: grant/research funding (institutional) from Novartis, Genentech, Biomed Valley Discoveries, Plexxikon, Deciphera, PIQUR Therapeutics, Symphogen, Bayer, Fujifilm Corporation and Upsher-Smith Laboratories, Astex, Asana, Astellas, Agios, Proximagen, and Bristol Myers Squibb; advisory board member for Deciphera, IFM Therapeutics, Synlogic, Guardant Health, IDEAYA, PureTech Health, and Jazz pharmaceuticals; consultant fees from Trovagene, Immunomet, Primmune Therapeutics, Jazz Pharmaceuticals, and SOTIO; ownership interests in Trovagene. GSF: research funding from 3-V Biosciences, AbbVie, ADC Therapeutics, Aileron, American Society of Clinical Oncology, Amgen, ARMO, AstraZeneca, BeiGene, BioAtla, Biothera, Celldex, Celgene, CicloMed, Curegenix, Curis, Cyteir, Daiichi, Delmar, eFFECTOR, Eli Lilly, EMD Serono, Exelixis, Fujifilm, Genmab, GlaxoSmithKline, Hutchison MediPharma, Ignyta, Incyte, Jacobio, Jounce, Kolltan, LOXO, MedImmune, Millennium, Merck, miRNA Therapeutics, National Institutes of Health, Novartis, OncoMed, Oncothyreon, Precision Oncology, Regeneron, Rgenix, Ribon, Strategia, Syndax, Taiho, Takeda, Tarveda, Tesaro, Tocagen, Turning Point Therapeutics, U.T. MD Anderson Cancer Center, VEGENICS, and Xencor; advisor fees from Fujifilm and EMD Serono; royalties from Wolters Kluwer; funding for travel from Bristol Myers Squibb, EMD Serono, Fujifilm, Millennium, and Sarah Cannon Research Institute; speaker's bureau fees from Total Health Conferencing. APC: consultant fees from Deciphera Pharmaceuticals, Guidepoint Global, Genentech, Inc., Bayer Healthcare Pharmaceuticals, OncLive, Novartis Pharmaceuticals, and Ignyta, Inc.; speaker fees from Medscape. SIS: research support from Exelixis; consultant fees from Fortress Biotech and LOXO oncology; honoraria from Eisai. FM-B: Consulting fees from Aduro Biotech Inc., Alkermes, AstraZeneca, Debiopharm, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., Genentech Inc., IBM Watson, Jackson Laboratory, Kolon Life Science, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics Inc., Tyra Biosciences, Xencor, Zymeworks; advisory committee fees from Immunomedics, Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals, Zentalis; sponsored research from Aileron Therapeutics, Inc., AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Klus Pharma, Millennium Pharmaceuticals Inc., Novartis, Puma Biotechnology Inc., Taiho Pharmaceutical Co.; honoraria from Chugai Biopharmaceuticals, Mayo Clinic, Rutgers Cancer Institute of New Jersey; other (Travel Related) from Beth Israel Deaconess Medical Center. JVH: research support from AstraZeneca, GlaxoSmithKline, and Spectrum; consultant/advisory board member for AstraZeneca, Boehringer Ingelheim, Catalyst, Genentech, GlaxoSmithKline, Guardant Health, Foundation medicine, Hengrui Therapeutics, Eli Lilly, Novartis, Spectrum, EMD Serono, Sanofi, Takeda, Mirati Therapeutics, BMS, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, EMD Serono, Pneuma Respiratory, Kairos Venture Investments, Roche, Leads Biolabs; royalties and patents from Spectrum. VS and IMS: research funding/grant support from Novartis, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berg Health, Incyte, Fujifilm, PharmaMar, D3, Pfizer, MultiVir, Amgen, AbbVie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint medicines, LOXO oncology, MedImmune, ALTUM, Dragonfly therapeutics, Takeda, and Roche/ Genentech, National Comprehensive Cancer Network, NCI-CTEP, and UT MD Anderson Cancer Center; consultant/advisory board for Helsinn, LOXO Oncology/ Eli Lilly, R-Pharma US, INCYTE, QED pharma, MedImmune, Novartis; funding for travel from Novartis, PharmaMar, ASCO, ESMO, Helsinn, Incyte. All other authors have declared no conflicts of interest. Data sharing The data supporting the findings presented in this manuscript are available upon reasonable academic request to the study principal investigator (VS)., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Rapid advances in science challenge the timely adoption of evidence-based care in community settings. To bridge the gap between what is possible and what is practiced, we researched approaches to developing an artificial intelligence (AI) application that can provide real-time patient-specific decision support., Materials and Methods: The Oncology Expert Advisor (OEA) was designed to simulate peer-to-peer consultation with three core functions: patient history summarization, treatment options recommendation, and management advisory. Machine-learning algorithms were trained to construct a dynamic summary of patients cancer history and to suggest approved therapy or investigative trial options. All patient data used were retrospectively accrued. Ground truth was established for approximately 1,000 unique patients. The full Medline database of more than 23 million published abstracts was used as the literature corpus., Results: OEA's accuracies of searching disparate sources within electronic medical records to extract complex clinical concepts from unstructured text documents varied, with F1 scores of 90%-96% for non-time-dependent concepts (e.g., diagnosis) and F1 scores of 63%-65% for time-dependent concepts (e.g., therapy history timeline). Based on constructed patient profiles, OEA suggests approved therapy options linked to supporting evidence (99.9% recall; 88% precision), and screens for eligible clinical trials on ClinicalTrials.gov (97.9% recall; 96.9% precision)., Conclusion: Our results demonstrated technical feasibility of an AI-powered application to construct longitudinal patient profiles in context and to suggest evidence-based treatment and trial options. Our experience highlighted the necessity of collaboration across clinical and AI domains, and the requirement of clinical expertise throughout the process, from design to training to testing., Implications for Practice: Artificial intelligence (AI)-powered digital advisors such as the Oncology Expert Advisor have the potential to augment the capacity and update the knowledge base of practicing oncologists. By constructing dynamic patient profiles from disparate data sources and organizing and vetting vast literature for relevance to a specific patient, such AI applications could empower oncologists to consider all therapy options based on the latest scientific evidence for their patients, and help them spend less time on information "hunting and gathering" and more time with the patients. However, realization of this will require not only AI technology maturation but also active participation and leadership by clincial experts., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)

The c-Met/hepatocyte growth factor receptor and its family members are known to promote cancer cell migration and invasion. Signaling within and beyond this pathway contributes to the systemic spread of metastases through induction of the epithelial-mesenchymal transition, a process also implicated in mediating resistance to current anticancer therapies, including radiation. Induction of c-Met has also been observed after irradiation, suggesting that c-Met participates in radiation-induced disease progression through the epithelial-mesenchymal transition. Therefore, c-Met inhibition is an attractive target for potentially mitigating radiation resistance. This article summarizes key findings regarding crosstalk between radiotherapy and c-Met and discusses studies performed to date in which c-Met inhibition was used as a strategy to increase cellular radiosensitivity., (Copyright © 2013 American Cancer Society.)

Over the last decade, the concept of targeted biological therapy for the treatment of cancer has emerged. However, a better understanding of these targets and their role in tumor cells and in the surrounding stromal cells is required. Two interesting biological targets are the epidermal growth factor receptor (EGFR) and the vascular endothelia growth factor (VEGF) and its receptors. A number of agents that target these pathways have been described. Many of these are currently in clinical trials and a few have recently been approved by the regulatory authorities in USA and in the European Union. The molecular pathways involved in the proliferation of cancer cells and in tumor-related angiogenesis are very complex and the interference with only a single step of these pathways may often reveal an insufficient therapeutic approach. Moreover, cancer cells have an inherent ability to harness different growth factor signaling pathways for growth advantage and cell survival, a process that may even be facilitated by the use of selective targeted agents. Because of these escape mechanisms, monotherapy with selective targeted agents is unlikely to be a fully effective cancer treatment. For these reasons, targeting different pathways is an attractive and effective therapeutic strategy with a strong rationale for investigating this approach in the clinic. This review focuses on the preclinical rationale of combining targeted agents such as EGFR and VEGF inhibitors in the treatment of cancer and on the clinical trials that have emerged from these studies.