Targeting the Innate Immune Kinase IRAK1 in Radioresistant Cancer: Double-Edged Sword or One-Two Punch?

Antitumor immunity has emerged as a favorable byproduct of radiation therapy (RT), whereby tumor-associated antigens released from irradiated cells unleash innate and adaptive attacks on tumors located both within and outside the radiation field. RT-induced immune responses further provide actionable targets for overcoming tumor resistance to RT (R-RT); immunotherapy (IT) with checkpoint inhibitors or Toll-like receptor (TLR) agonists can markedly improve, if not synergize with, RT in preclinical models, and several of these drugs are currently investigated as radiosensitizers in patients. In an unbiased chemical-genetic screen in a zebrafish model of tumor R-RT, we unexpectedly found that Interleukin 1 Receptor-Associated Kinase 1 (IRAK1), a core effector of TLR-mediated innate immunity, also functions in live fish and human cancer models to counter RT-induced cell death mediated by the PIDDosome complex (PIDD-RAIDD-caspase-2). IRAK1 acting both as a driver of intrinsic tumor R-RT and as an effector of RT-induced antitumor immunity would, at first glance, pose obvious therapeutic conundrums. IRAK1 inhibitors would be expected to sensitize the irradiated tumor to RT but simultaneously thwart RT-induced antitumor immunity as initiated by stromal dendritic cells. Conversely, TLR agonist-based immunotherapy would be expected to intensify RT-induced antitumor immunity but at the expense of fueling IRAK1-mediated cell survival in the irradiated tumor. We discuss how IRAK1's differ...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research

Related Links:

Opinion statementStandard-of-care treatment for the majority of patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN) is either upfront surgery followed by adjuvant treatment as indicated by intraoperative or pathologic findings or concurrent chemoradiation reserving surgical salvage for non-responsive disease. An attempt at upfront complete resection should be pursued if feasible in patients with oral cavity or paranasal sinus primary tumors. Given multimodality treatment paradigms, patients with locoregionally advanced SCCHN should be managed in a multidisciplinary setting. Modern rad...
Source: Current Treatment Options in Oncology - Category: Cancer & Oncology Source Type: research
Memorial Sloan Kettering Cancer Center in New York City has opened its latest clinical trial for patients with pleural mesothelioma, studying the effectiveness of an immunotherapy and chemotherapy combination prior to aggressive surgery. The novel feasibility study will determine if the use of Opdivo (nivolumab) with Alimta (pemetrexed) and either cisplatin or carboplatin — without delaying scheduled surgery — can significantly extend patient survival time. The hope is to duplicate earlier effectiveness of that same combination with other cancers. “It has been tried with promising results,” Memorial...
Source: Asbestos and Mesothelioma News - Category: Environmental Health Authors: Source Type: news
CONCLUSIONS: Extramammary Paget disease is a rare vulvar tumor. Surgical excision is the main treatment option while other modalities are rarely employed. Overall survival rates are encouraging. PMID: 31780234 [PubMed - as supplied by publisher]
Source: Gynecologic Oncology - Category: Cancer & Oncology Authors: Tags: Gynecol Oncol Source Type: research
Objective: Anti-PD-1 antibodies can cause drug-induced pneumonitis. We aimed to identify the clinical and radiologic characteristics, the incidence, risk factors, and appropriate management of pneumonitis related to anti-PD-1 immunotherapy in patients with non-small cell lung cancer (NSCLC).Materials and Methods: Medical records and chest computed tomography scans of patients with NSCLC treated with anti-PD-1 antibodies between January 2016 and June 2018 at the Kanagawa Cancer Center were retrospectively analyzed. Clinical characteristics of patients treated with anti-PD-1 antibodies who developed pneumonitis were compared...
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: Lung cancer Source Type: research
We present a prospective study of hypofractionated, image-guided radiation therapy (HIGRT) to a single site of metastatic disease concurrently with atezolizumab in patients with metastatic NSCLC.
Source: International Journal of Radiation Oncology * Biology * Physics - Category: Radiology Authors: Source Type: research
The effectiveness of cancer treatment must be assessed early in the course of the therapy so that regimens can be tailored in an individualized manner. Whole-body metabolic burden, metabolic tumor volume and total lesion glycolysis are the newer quantitative PET metrics that reflect the overall disease burden and take into account the stage of the disease, the heterogeneous intra-tumoral metabolism and uptake of PET tracer. Immunotherapy response evaluation in solid tumors is challenging, and combined use of anatomical and molecular imaging could evolve as the optimal way for assessing treatment response to immunotherapy. ...
Source: PET Clinics - Category: Radiology Authors: Source Type: research
Conditions:   Metastatic Lung Non-Small Cell Carcinoma;   Recurrent Lung Non-Small Cell Carcinoma;   Stage IV Lung Cancer AJCC v8;   Stage IVA Lung Cancer AJCC v8;   Stage IVB Lung Cancer AJCC v8 Interventions:   Procedure: Positron Emission Tomography;   Procedure: Computed Tomography;   Drug: Chemotherapy;   Biological: Immunotherapy;   Radiation: Radiation Therapy Sponsors:   University of Washingto...
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
AbstractDiffusing alpha-emitters radiation therapy (DaRT) is the only known method for treating solid tumors with highly destructive alpha radiation. More importantly, as a monotherapy, DaRT has been shown to induce a systemic antitumor immune response following tumor ablation. Here, immunomodulatory strategies to boost the antitumor immune response induced by DaRT, and the response specificity, were investigated in the colon cancer CT26 mouse model. Local treatment prior to DaRT,  with the TLR3 agonist poly I:C, was sufficient to inhibit tumor growth relative to poly I:C or DaRT alone. DaRT used in combination with t...
Source: Cancer Immunology, Immunotherapy - Category: Cancer & Oncology Source Type: research
Conclusions: We describe here the first report of a potential abscopal effect in meningioma, summarize the limited literature on the topic of abscopal effects in cancer, and detail the existing hypothesis on how this phenomenon may occur and possibly relate to the development of future treatments for patients with metastatic disease.
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
More News: Cancer | Cancer & Oncology | Chemistry | Fish | Genetics | Immunotherapy | Radiation Therapy