With the advent of precision oncology, there is an urgent need to develop improved methods for rapidly detecting responses to targeted therapies. Here, we have developed an ultrasensitive measure of ...cell-free tumor load using targeted and whole-genome sequencing approaches to assess responses to tyrosine kinase inhibitors in patients with advanced lung cancer. Analyses of 28 patients treated with anti-EGFR or HER2 therapies revealed a bimodal distribution of cell-free circulating tumor DNA (ctDNA) after therapy initiation, with molecular responders having nearly complete elimination of ctDNA (>98%). Molecular nonresponders displayed limited changes in ctDNA levels posttreatment and experienced significantly shorter progression-free survival (median 1.6 vs. 13.7 months,
< 0.0001; HR = 66.6; 95% confidence interval, 13.0-341.7), which was detected on average 4 weeks earlier than CT imaging. ctDNA analyses of patients with radiographic stable or nonmeasurable disease improved prediction of clinical outcome compared with CT imaging. These analyses provide a rapid approach for evaluating therapeutic response to targeted therapies and have important implications for the management of patients with cancer and the development of new therapeutics.
Cell-free tumor load provides a novel approach for evaluating longitudinal changes in ctDNA during systemic treatment with tyrosine kinase inhibitors and serves an unmet clinical need for real-time, noninvasive detection of tumor response to targeted therapies before radiographic assessment.
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Circulating Biomarkers in Glioblastoma Mathios, Dimitrios; Phallen, Jillian
The cancer journal (Sudbury, Mass.),
9/2021, Letnik:
27, Številka:
5
Journal Article
Recenzirano
Abstract
Liquid biopsy approaches for detection of circulating biomarkers of cancer have been utilized in oncology in many clinical settings from early detection to disease monitoring. Recent ...approaches have focused on circulating tumor cells, circulating tumor DNA, and circulating RNAs in a variety of biofluids. However, very little progress has been made in implementing such approaches for detection of brain tumors, despite the tremendous clinical need for earlier and less invasive diagnosis, as well as more accurate assessment of disease status. In this review, we highlight the recent methodological improvements in the field of liquid biopsy technologies specifically for glioblastoma. Although many retrospective and few prospective studies have been conducted to assess the utility of circulating biomarkers for detection of brain tumors, none have yet moved forward to clinical implementation.
Glioblastoma multiforme (GBM) modulates the immune system to engance its malignant potential. Signal transducer and activator of transcription 3 (STAT3) activation is a regulatory node in modulating ...the immune microenvironment in several human tumors, including GBM. To investigate whether STAT3 inhibition might enhance anti-tumor responses, we inhibited STAT3 signaling using small interfering RNA against STAT3. We tested the human GBM cell lines U87, U251, and HS683, which are known to constitutively express high levels of phospho-STAT3. STAT3 inhibition resulted in enhanced expression of several pro-inflammatory cytokines and chemokines and supernatants from STAT3-silenced human GBM cell lines increased lipopolysaccharide-induced dendritic cell activation in vitro. We obtained comparable results when STAT3 activity was suppressed with specific small molecule inhibitors. Our results support the hypothesis that activated STAT3 contributes to the immunosuppressive microenvironment in GBM and support previous studies implicating STAT3 as a potential target for immunotherapy.
Abstract
There have been significant strides toward understanding the molecular landscape of brain cancer. These advances have been focused on analyses of the tumor microenvironment and have recently ...expanded to include liquid biopsies to identify molecular biomarkers noninvasively. Moving from tissue to liquid-based analyses of molecular biomarkers has been challenging and currently, there are no approved noninvasive tests that are clinically useful. However, the emerging field of molecular liquid biopsy assay development in the neuro-oncology space has great potential to revolutionize the detection and monitoring of patients with brain cancer.
Immunotherapy is a potential new therapeutic option in patients with high-grade gliomas (HGGs). Phase I/II trials have assessed the efficacy of increasing immune activity using vaccines made from ...lymphokine-activated killer cells, cytotoxic T cells, autologous tumor cells, or dendritic cells. Studies to decrease tumor immunoresistance have focused on cytokine modulation of known immunosuppressive factors in the tumor microenvironment. Several early studies have reported a survival benefit using different forms of immunotherapy. This article discusses past clinical trials using immunotherapy in HGGs, their efficacy, limits, and biologic and clinical design challenges that must be overcome to advance immunotherapy for patients with HGGs.
Pituitary adenomas with local invasion and high secretory activity remain a therapeutic challenge. The HIV protease inhibitor nelfinavir is a radiosensitizer in multiple tumor models. We tested ...nelfinavir as a radiosensitizer in pituitary adenoma cells in vitro and in vivo. We examined the effect of nelfinavir with radiation on in vitro cell viability, clonogenic survival, apoptosis, prolactin secretion, cell cycle distribution, and the PI3K-AKT-mTOR pathway. We evaluated tumor growth delay and confirmed nelfinavir's effect on the PI3K-AKT-mTOR pathway in a hind-flank model. Nelfinavir sensitized pituitary adenoma cells to ionizing radiation as shown by viability assays and clonogenic assay with an enhancement ratio of 1.2 (p
Cell-free DNA in the blood provides a non-invasive diagnostic avenue for patients with cancer
. However, characteristics of the origins and molecular features of cell-free DNA are poorly understood. ...Here we developed an approach to evaluate fragmentation patterns of cell-free DNA across the genome, and found that profiles of healthy individuals reflected nucleosomal patterns of white blood cells, whereas patients with cancer had altered fragmentation profiles. We used this method to analyse the fragmentation profiles of 236 patients with breast, colorectal, lung, ovarian, pancreatic, gastric or bile duct cancer and 245 healthy individuals. A machine learning model that incorporated genome-wide fragmentation features had sensitivities of detection ranging from 57% to more than 99% among the seven cancer types at 98% specificity, with an overall area under the curve value of 0.94. Fragmentation profiles could be used to identify the tissue of origin of the cancers to a limited number of sites in 75% of cases. Combining our approach with mutation-based cell-free DNA analyses detected 91% of patients with cancer. The results of these analyses highlight important properties of cell-free DNA and provide a proof-of-principle approach for the screening, early detection and monitoring of human cancer.
Abstract
Non-invasive approaches for cell-free DNA (cfDNA) assessment provide an opportunity for cancer detection and intervention. Here, we use a machine learning model for detecting tumor-derived ...cfDNA through genome-wide analyses of cfDNA fragmentation in a prospective study of 365 individuals at risk for lung cancer. We validate the cancer detection model using an independent cohort of 385 non-cancer individuals and 46 lung cancer patients. Combining fragmentation features, clinical risk factors, and CEA levels, followed by CT imaging, detected 94% of patients with cancer across stages and subtypes, including 91% of stage I/II and 96% of stage III/IV, at 80% specificity. Genome-wide fragmentation profiles across ~13,000 ASCL1 transcription factor binding sites distinguished individuals with small cell lung cancer from those with non-small cell lung cancer with high accuracy (AUC = 0.98). A higher fragmentation score represented an independent prognostic indicator of survival. This approach provides a facile avenue for non-invasive detection of lung cancer.
e18752
Background: Despite the wide adoption of noninvasive liquid biopsy approaches for cancer genotyping, little is known about the longitudinal performance of these assays for monitoring ...therapeutic responses in patients with advanced disease. Here, we report results of a pooled analysis that collects existing evidence regarding the failure rates of circulating tumor DNA (ctDNA) assays designed for therapeutic monitoring in patients with advanced or metastatic lung cancer. Methods: We searched PubMed for original studies published between February 2012 and January 2022, following these inclusion criteria: (1) Adults older than 18 years old with advanced or metastatic lung cancer treated with chemotherapy, targeted therapy, or immunotherapy; (2) Tumor-informed or plasma-only circulating tumor DNA assays based on droplet digital PCR (ddPCR) or targeted deep sequencing technologies for the detection of tumor-specific allele fractions; (3) Measurement of circulating tumor DNA levels at sequential timepoints. We defined failures as a lack of detectable mutant allele fraction (MAF) in patients with metastatic lung cancer in samples collected before treatment initiation. Two reviewers independently screened studies, extracted data, assessed the risk of bias, and evaluated the quality of evidence. Divergences were resolved by a third independent reviewer reaching a consensus. Study quality assessment covered: (1) representativeness of patient population, (2) risk of funding bias, (3) description of ctDNA analysis and outcomes, and (4) statistical quality and interpretation. Results: From 142 studies retrieved by an automated PubMed query, we extracted data from 42 studies which fulfilled the eligibility criteria - 11 registered trials, 31 prospective/retrospective cohorts. MAF levels in the circulation were measured using PCR-based assays (23/42, 55%); the remainder used NGS-based approaches (19/42, 45%). The median number of targeted genes was 1 (range 1-6) vs 73 (range 36-214), respectively. The median number of samples analyzed per study was 79 (range 3-334). On average, 31% of samples collected before treatment did not have a detectable MAF in any of the target genes analyzed, despite the high disease burden typically experienced in patients with metastatic lung cancer. Only 57% of PCR-based and 78% NGS-based studies succeeded in providing molecular response assessment metrics. We identified 10/42 studies with critical quality assessment concerns and 18 studies had funding provided by a company with investments in the commercial cfDNA assay. Conclusions: Available liquid biopsy assays that report tumor-specific mutations have a high rate of failure for measuring disease burden and response outcomes during therapy. Approaches that could be reliably used for monitoring patients with advanced cancers undergoing treatment are needed to improve patient care.
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