Tumor Evolution, Heterogeneity, and Therapy for Our Patients With Advanced Cancer: How Far Have We Come?

2017 ◽  
pp. e8-e15 ◽  
Author(s):  
Wafik S. El-Deiry ◽  
Barry Taylor ◽  
Joel W. Neal
Keyword(s):  
Immune Cell ◽  
Clinical Care ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Patient Treatment ◽  
Immune Checkpoints ◽  
Tumor Evolution ◽  
Molecular Heterogeneity ◽  
Precision Oncology ◽  
Liquid Biopsies

The clinical and molecular heterogeneity of various cancer types is well documented. In the era of precision oncology whereby molecular profiling of tumors is incorporated into clinical care, both intra- and intertumoral molecular and genetic heterogeneity have been described. Together, they impact patient treatment and outcomes. Host genetics and the tumor microenvironment impact on tumor evolution and heterogeneity through variations in immune cell infiltration, stromal variations, and selection pressures from hypoxia or nutrient stress, among others. Tumor progression and exposure to therapeutic agents lead to further molecular evolution and heterogeneity that is clinically relevant. Moreover, tumors that evolve after diagnosis and as a function of therapy generally become more aggressive and refractory to available therapeutics, including targeted agents and immunotherapy. The evolving clinical and molecular heterogeneity of patient tumors can be explored with various clinical and research-based specimens and testing such as pre- and post-treatment biopsies; serial liquid biopsies; single cell analysis; PDX and organoid models; anatomic, functional, and molecular imaging; and rapid postmortem studies. Other factors that influence tumor heterogeneity include immune checkpoints, cancer stem cells, therapy-acquired resistance mechanisms that may occur through secondary mutations, and adaptive responses. Modern technologic advances for tumor characterization provide opportunities to understand tumor evolution and its impact on clinical outcomes to improve therapeutic regimens. Characterization of novel targets and development of effective therapeutics are needed to target heterogeneity and the evolution of resistance mechanisms.

scholarly journals The future of immune checkpoint combinations with tumor-targeted small molecule drugs

2021 ◽  
Author(s):  
Jaclyn Sceneay ◽  
Charles Sinclair
Keyword(s):  
Signaling Pathways ◽  
Immune Checkpoint ◽  
Cell Function ◽  
Immune Cell ◽  
Immune Escape ◽  
Acquired Resistance ◽  
Immune Checkpoint Blockade ◽  
Tumor Evolution ◽  
Full Potential ◽  
Precision Oncology

Immune-checkpoint blockade (ICB) has transformed the landscape of cancer treatment. However, there is much to understand around refractory or acquired resistance in patients in order to utilize ICB therapy to its full potential. In this perspective article, we discuss the opportunities and challenges that are emerging as our understanding of immuno-oncology resistance matures. Firstly, there has been remarkable progress made to understand the exquisite overlap between oncogenic and immune signaling pathways. Several cancer-signaling pathways are constitutively active in oncogenic settings and also play physiological roles in immune cell function. A growing number of precision oncology tumor-targeted drugs show remarkable immunogenic properties that might be harnessed with rational combination strategies. Secondly, we now understand that the immune system confers a strong selective pressure on tumors. Whilst this pressure can lead to novel tumor evolution and immune escape, there is a growing recognition of tumor-intrinsic dependencies that arise in immune pressured environments. Such dependencies provide a roadmap for novel tumor-intrinsic drug targets to alleviate ICB resistance. We anticipate that rational combinations with existing oncology drugs and a next wave of tumor-intrinsic drugs that specifically target immunological resistance will represent the next frontier of therapeutic opportunity.

scholarly journals Liquid Biopsies in Sarcoma Clinical Practice: Where Do We Stand?

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1315
Author(s):  
Pia van der Laan ◽  
Winan J. van Houdt ◽  
Daan van den Broek ◽  
Neeltje Steeghs ◽  
Winette T. A. van der Graaf
Keyword(s):  
Clinical Practice ◽  
Liquid Biopsy ◽  
Current Knowledge ◽  
Clinical Care ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Tumor Evolution ◽  
Liquid Biopsies ◽  
Golden Standard ◽  
First Results

Sarcomas are rare tumors of bone and soft tissue with a mesenchymal origin. This uncommon type of cancer is marked by a high heterogeneity, consisting of over 70 subtypes. Because of this broad spectrum, their treatment requires a subtype-specific therapeutic approach. Tissue biopsy is currently the golden standard for sarcoma diagnosis, but it has its limitations. Over the recent years, methods to detect, characterize, and monitor cancer through liquid biopsy have evolved rapidly. The analysis of circulating biomarkers in peripheral blood, such as circulating tumor cells (CTC) or circulating tumor DNA (ctDNA), could provide real-time information on tumor genetics, disease state, and resistance mechanisms. Furthermore, it traces tumor evolution and can assess tumor heterogeneity. Although the first results in sarcomas are encouraging, there are technical challenges that need to be addressed for implementation in clinical practice. Here, we summarize current knowledge about liquid biopsies in sarcomas and elaborate on different strategies to integrate liquid biopsy into sarcoma clinical care.

scholarly journals Molecular findings reveal possible resistance mechanisms in a patient with ALK-rearranged lung cancer: a case report and literature review

ESMO Open ◽  
2019 ◽  
Vol 4 (5) ◽  
pp. e000561 ◽  
Author(s):  
Anastasia Kougioumtzi ◽  
Panagiotis Ntellas ◽  
Eirini Papadopoulou ◽  
George Nasioulas ◽  
Eleftherios Kampletsas ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Disease Progression ◽  
Kinase Inhibitors ◽  
Wide Spectrum ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Molecular Testing ◽  
Liquid Biopsies ◽  
Disease Biology ◽  
Remarkable Progress

Background: Non-small-cell lung cancer (NSCLC) is recognised as a particularly heterogeneous disease, encompassing a wide spectrum of distinct molecular subtypes. With increased understanding of disease biology and mechanisms of progression, treatment of NSCLC has made remarkable progress in the past two decades. Molecular testing is considered the hallmark for the diagnosis and treatment of NSCLC, with liquid biopsies being more and more often applied in the clinical setting during the recent years. Rearrangement of the ALK gene which results in the generation of fusion oncogenes is a common molecular event in NSCLCs. Among ALK fusion transcripts, EML4-ALK fusion is frequently observed and can be targeted with ALK tyrosine kinase inhibitors (TKI). However, acquired resistance and disease progression in many cases are inevitable.Method: Here, we present the case of a patient with NSCLC treated with TKIs, in which molecular profiling of the tumour was performed with different methods of tissue and plasma testing at each disease progression. A review of the literature was further conducted to offer insights into the resistance mechanisms of ALK-rearranged NSCLC.Conclusions: Based on the results, the EML4-ALK fusion initially detected in tumour tissue was preserved throughout the course of the disease. Two additional ALK mutations were later detected in the tissue and plasma and are likely to have caused resistance to the administered TKIs. Continued research into the mechanisms of acquired resistance is required in order to increase the benefit of the patients treated with targeted ALK TKIs.

Non-invasive detection of acquired resistance to FGFR inhibition in patients with cholangiocarcinoma harboring FGFR2 alterations.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4096-4096 ◽  
Author(s):  
Anna M. Varghese ◽  
Juber Ahamad A Patel ◽  
Yelena Yuriy Janjigian ◽  
Fanli Meng ◽  
S Duygu Selcuklu ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Acquired Resistance ◽  
High Sensitivity ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Tumor Evolution ◽  
Background Error ◽  
Tumor Biopsy ◽  
Invasive Approach ◽  
Non Invasive

4096 Background: FGFR2 alterations are present in 14% of cholangiocarcinomas (CCA) and are promising targets of investigational FGFR-directed therapies. Cell-free DNA profiling has emerged as a non-invasive approach to monitor disease and longitudinally characterize tumor evolution. We describe the use of circulating tumor DNA (ctDNA) among patients (pts) with FGFR2-altered CCA receiving FGFR-targeted therapy in the identification of acquired FGFR2 mutations (mut) at resistance. Methods: Serial blood samples were collected from 8 pts with FGFR-altered CCA for ctDNA isolation and next generation sequencing. Plasma ctDNA collected at baseline and resistance to FGFR-targeted therapy were sequenced using a custom ultra-deep coverage cfDNA panel, MSK-ACCESS, incorporating dual index primers and unique molecular barcodes to enable background error suppression and high-sensitivity mut detection. The assay was enhanced to include all protein-coding exons and relevant introns of FGFR2. In 5/8 pts, genomic profiling of an initial tumor biopsy was performed. Results: 8 pts with FGFR2-altered CCA (7 gene fusions, 1 amplification) were treated with FGFR-targeted therapies. 7/8 pts exhibited stable disease or partial response. 19 total acquired mut in FGFR2 were detected at resistance in 5/8 pts (between 1-9 unique mut identified in each sample). All mut were located in the kinase domain. Conclusions: Acquired mut in FGFR2 are seen in pts who have developed resistance to targeted therapy. CtDNA can be used to identify these mut at the time of acquired resistance. The multitude of FGFR2 mut observed within individual pts suggest heterogeneity and evolutionary convergence of resistance mechanisms. Our results illustrate the utility of ctDNA as a less invasive way to monitor for signs of resistance and to identify other potential targetable alterations. [Table: see text]

scholarly journals Plasma Circulating Tumor DNA Levels for the Monitoring of Melanoma Patients: Landscape of Available Technologies and Clinical Applications

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Benoit Busser ◽  
Julien Lupo ◽  
Lucie Sancey ◽  
Stéphane Mouret ◽  
Patrice Faure ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Digital Pcr ◽  
Circulating Tumor Dna ◽  
Clinical Applications ◽  
Molecular Heterogeneity ◽  
Liquid Biopsies ◽  
Melanoma Patients ◽  
Ctdna Analysis ◽  
Next Generation Sequencing Ngs ◽  
Tumor Dna

Melanoma is a cutaneous cancer with an increasing worldwide prevalence and high mortality due to unresectable or metastatic stages. Mutations inBRAF,NRAS, orKITare present in more than 60% of melanoma cases, but a useful blood-based biomarker for the clinical monitoring of melanoma patients is still lacking. Thus, the analysis of circulating tumor cells (CTCs) and/or cell-free circulating tumor DNA (ctDNA) analysis from blood (liquid biopsies) appears to be a promising noninvasive, repeatable, and systemic sampling tool for detecting and monitoring melanoma. Here, we review the molecular biology-based strategies used for ctDNA quantification in melanoma patients, as well as their main clinical applications. Droplet digital PCR (ddPCR) and next generation sequencing (NGS) technologies appear to be two versatile and complementary strategies to study rare variant mutations for the detection and monitoring of melanoma progression. Among the different clinical uses of ctDNA, we highlight the assessment of molecular heterogeneity and the identification of genetic determinants for targeted therapy as well as the analysis of acquired resistance. Importantly, ctDNA quantification might also be a novel biomarker with a prognostic value for melanoma patients.

scholarly journals Acquired Resistance to Immune Checkpoint Blockades: The Underlying Mechanisms and Potential Strategies

2021 ◽  
Vol 12 ◽  
Author(s):  
Binghan Zhou ◽  
Yuan Gao ◽  
Peng Zhang ◽  
Qian Chu
Keyword(s):  
Immune Checkpoint ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Immune Checkpoint Blockade ◽  
Treatment Modalities ◽  
Immune Checkpoints ◽  
Number Of Patients ◽  
Clinical Responses ◽  
Underlying Mechanisms ◽  
Definition Of

The immune checkpoint blockade therapy has completely transformed cancer treatment modalities because of its unprecedented and durable clinical responses in various cancers. With the increasing use of immune checkpoint blockades in clinical practice, a large number of patients develop acquired resistance. However, the knowledge about acquired resistance to immune checkpoint blockades is limited and poorly summarized. In this review, we clarify the principal elements of acquired resistance to immune checkpoint blockades. The definition of acquired resistance is heterogeneous among groups or societies, but the expert consensus of The Society for Immunotherapy of Cancer can be referred. Oligo-progression is the main pattern of acquired resistance. Acquired resistance can be derived from the selection of resistant cancer cell clones that exist in the tumor mass before therapeutic intervention or gradual acquisition in the sensitive cancer cells. Specifically, tumor intrinsic mechanisms include neoantigen depletion, defects in antigen presentation machinery, aberrations of interferon signaling, tumor-induced exclusion/immunosuppression, and tumor cell plasticity. Tumor extrinsic mechanisms include upregulation of other immune checkpoints. Presently, a set of treatment modalities is applied to patients with similar clinical characteristics or resistance mechanisms for overcoming acquired resistance, and hence, further research is required.

scholarly journals Combined Radiochemotherapy: Metalloproteinases Revisited

2021 ◽  
Vol 11 ◽  
Author(s):  
Verena Waller ◽  
Martin Pruschy
Keyword(s):  
Posttranslational Modifications ◽  
Intercellular Communication ◽  
Immune Cell ◽  
Therapeutic Potential ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Treatment Modalities ◽  
Matrix Remodeling ◽  
Intercellular Signaling ◽  
Combined Radiochemotherapy

Besides cytotoxic DNA damage irradiation of tumor cells triggers multiple intra- and intercellular signaling processes, that are part of a multilayered, treatment-induced stress response at the unicellular and tumor pathophysiological level. These processes are intertwined with intrinsic and acquired resistance mechanisms to the toxic effects of ionizing radiation and thereby co-determine the tumor response to radiotherapy. Proteolysis of structural elements and bioactive signaling moieties represents a major class of posttranslational modifications regulating intra- and intercellular communication. Plasma membrane-located and secreted metalloproteinases comprise a family of metal-, usually zinc-, dependent endopeptidases and sheddases with a broad variety of substrates including components of the extracellular matrix, cyto- and chemokines, growth and pro-angiogenic factors. Thereby, metalloproteinases play an important role in matrix remodeling and auto- and paracrine intercellular communication regulating tumor growth, angiogenesis, immune cell infiltration, tumor cell dissemination, and subsequently the response to cancer treatment. While metalloproteinases have long been identified as promising target structures for anti-cancer agents, previous pharmaceutical approaches mostly failed due to unwanted side effects related to the structural similarities among the multiple family members. Nevertheless, targeting of metalloproteinases still represents an interesting rationale alone and in combination with other treatment modalities. Here, we will give an overview on the role of metalloproteinases in the irradiated tumor microenvironment and discuss the therapeutic potential of using more specific metalloproteinase inhibitors in combination with radiotherapy.

scholarly journals Proof-of-concept pilot study on comprehensive spatiotemporal intra-patient heterogeneity for colorectal cancer with liver metastasis

2021 ◽  
Author(s):  
Ioannis Dimitrios Kyrochristos ◽  
Georgios K. Glantzounis ◽  
Anna Goussia ◽  
Alexia Eliades ◽  
Achilleas Achilleos ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
De Novo ◽  
Tumor Resection ◽  
Tumor Evolution ◽  
Precision Oncology ◽  
Proof Of Concept ◽  
De Novo Mutations ◽  
Liquid Biopsies ◽  
Patient Heterogeneity

Purpose: The mechanisms underlying high drug resistance and relapse rates after multi-modal treatment in patients with colorectal cancer (CRC) and liver metastasis (LM) remain poorly understood. We evaluate the potential translational implications of intra-patient heterogeneity (IPH) comprising primary and matched metastatic intratumor heterogeneity (ITH) coupled with circulating tumor DNA (ctDNA) variability. Patients and methods: According to our IPH-based protocol, 18 eligible patients with CRC-LM, who underwent complete tumor resection after neo-adjuvant treatment, with a total of 122 multi-regional tumor and perioperative liquid biopsies were analyzed via next-generation sequencing (NGS) of a custom 77-gene panel. The primary endpoints were the extent of IPH and the frequency of actionable mutations. Results: The proportion of patients with ITH were 53% and 56% in primary CRC and LM respectively, while 35% of patients harbored de novo mutations in LM indicating spatiotemporal tumor evolution and the necessity of multiregional analysis. Among the 56% of patients with alterations in liquid biopsies, de novo mutations in cfDNA were identified in 25% of patients, which were undetectable in both CRC and LM. All 17 patients with driver alterations harbored actionable mutations, with an average of 3.2 oncogenic events per patient, for molecularly targeted drugs either approved or under evaluation in ongoing clinical trials or in pre-clinical studies. Conclusions: Our proof-of-concept prospective study provides initial evidence and warrants the conduction of precision oncology trials to test the potential clinical utility of IPH-driven matched therapy.

scholarly journals Beyond PD-1: The Next Frontier for Immunotherapy in Melanoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Anjali Rohatgi ◽  
John M. Kirkwood
Keyword(s):  
Immune Cell ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Current State ◽  
Inflammatory State ◽  
Checkpoint Receptors ◽  
Molecular Patterns ◽  
First And Second Generation

The advent of first and second-generation immune checkpoint blockade (ICI) has resulted in improved survival of patients with metastatic melanoma over the past decade. However, the majority of patients ultimately progress despite these treatments, which has served as an impetus to consider a range of subsequent therapies. Many of the next generation of immunotherapeutic agents focus on modifying the immune system to overcome resistance to checkpoint blockade. ICI resistance can be understood as primary, or acquired—where the latter is the most common scenario. While there are several postulated mechanisms by which resistance, particularly acquired resistance, occurs, the predominant escape mechanisms include T cell exhaustion, upregulation of alternative inhibitory checkpoint receptors, and alteration of the tumor microenvironment (TME) into a more suppressive, anti-inflammatory state. Therapeutic agents in development are designed to work by combating one or more of these resistance mechanisms. These strategies face the added challenge of minimizing immune-related toxicities, while improving antitumor efficacy. This review focuses upon the following categories of novel therapeutics: 1) alternative inhibitory receptor pathways; 2) damage- or pathogen-associated molecular patterns (DAMPs/PAMPs); and 3) immune cell signaling mediators. We present the current state of these therapies, including preclinical and clinical data available for these targets under development.

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