Tumor organoids have been proposed as a model system for precision medicine. The ability of tumor organoids to retain characteristics of the original tumor makes them unique for cancer research on an ...individual patient level. Hence, the idea to use tumor organoids for clinical decision making and optimize patient outcome is tempting. In vitro responses of tumor organoids to a wide array of drugs have been positively correlated to patient responses. However, substantial challenges remain and prospective studies with large cohorts are highly needed before implementation in clinical cancer care can be considered. Because of their personalized characteristics and the immediate link with patient data, tumor organoids also have great potential in preclinical research. Here, we provide a critical overview of both clinical and preclinical advances using tumor organoids.
Tumor organoids have been proposed as a model system for precision medicine. The ability of tumor organoids to retain characteristics of the original tumor makes them unique for cancer research on an individual patient level. Hence, the idea to use tumor organoids for clinical decision making and optimize patient outcome is tempting. In vitro responses of tumor organoids to a wide array of drugs have been positively correlated to patient responses. However, substantial challenges remain and prospective studies with large cohorts are highly needed before implementation in clinical cancer care can be considered. Because of their personalized characteristics and the immediate link with patient data, tumor organoids also have great potential in preclinical research. Here, we provide a critical overview of both clinical and preclinical advances using tumor organoids.
Tumor organoids are 3D cultures of cancer cells that can be derived on an individual patient basis with a high success rate. This creates opportunities to build large biobanks with relevant patient ...material that can be used to perform drug screens and facilitate drug development. The high take rate will also allow side-by-side comparison to evaluate the translational potential of this model system to the patient. These tumors-in-a-dish can be established for a variety of tumor types including colorectal, pancreas, stomach, prostate, and breast cancers. In this review, we highlight what is currently known about tumor organoid culture, the advantages and challenges of the model system, compare it with other pre-clinical cancer models, and evaluate its value for drug development.
Weeber and Ooft et al. reviewed the current literature on tumor organoid cultures and highlight what is presently known, the advantages and challenges of the system, and the relevance of this pre-clinical cancer model in the context of drug development.
Infiltration of human cancers by T cells is generally interpreted as a sign of immune recognition, and there is a growing effort to reactivate dysfunctional T cells at such tumor sites
. However, ...these efforts only have value if the intratumoral T cell receptor (TCR) repertoire of such cells is intrinsically tumor reactive, and this has not been established in an unbiased manner for most human cancers. To address this issue, we analyzed the intrinsic tumor reactivity of the intratumoral TCR repertoire of CD8
T cells in ovarian and colorectal cancer-two tumor types for which T cell infiltrates form a positive prognostic marker
. Data obtained demonstrate that a capacity to recognize autologous tumor is limited to approximately 10% of intratumoral CD8
T cells. Furthermore, in two of four patient samples tested, no tumor-reactive TCRs were identified, despite infiltration of their tumors by T cells. These data indicate that the intrinsic capacity of intratumoral T cells to recognize adjacent tumor tissue can be rare and variable, and suggest that clinical efforts to reactivate intratumoral T cells will benefit from approaches that simultaneously increase the quality of the intratumoral TCR repertoire.
Clinical implementation of tumor organoids for personalized medicine requires that pure tumor organoids can be reliably established. Here, we present our experience with organoid cultures from >70 ...non-small cell lung cancer (NSCLC) samples. We systematically evaluate several methods to identify tumor purity of organoids established from intrapulmonary tumors. Eighty percent of organoids from intrapulmonary lesions have a normal copy number profile, suggesting overgrowth by normal airway organoids (AOs). This is further supported by the failure to detect mutations found in the original tumor in organoids. Histomorphology alone is insufficient to determine tumor purity, but when combined with p63 immunostaining, tumor and normal AOs can be distinguished. Taking into account overgrowth by normal AOs, the establishment rate of pure NSCLC organoids is 17%. Therefore, current methods are insufficient to establish pure NSCLC organoids from intrapulmonary lesions. We discourage their use unless steps are taken to prevent overgrowth by normal AOs.
Display omitted
•Frequent overgrowth of lung cancer organoids by normal airway organoids•Copy number profiling and IHC can be used to distinguish tumor and normal organoids•Low establishment rate of pure lung cancer organoids limits their clinical utility
Using a combination of genetic analyses and immunohistochemistry, Dijkstra et al. find that the majority of organoids derived from intrapulmonary lung cancers are overgrown by normal airway organoids. This limits the overall establishment rate of pure lung cancer organoids to 17%, restricting their utility for personalized medicine.
Large numbers of inhibitors for polo-like kinases and aurora kinases are currently being evaluated as anticancer drugs. Interest in these drugs is fuelled by the idea that these kinases have unique ...functions in mitosis. Within the polo-like kinase family, the emphasis for targeted therapies has been on polo-like kinase 1 (PLK1), and in the aurora kinase family drugs have been developed to specifically target aurora kinase A (AURKA; also known as STK6) and/or aurora kinase B (AURKB; also known as STK12). Information on the selectivity of these compounds in vivo is limited, but it is likely that off-target effects within the same kinase families will affect efficacy and toxicity profiles. In addition, it is becoming clear that interplay between polo-like kinases and aurora kinases is much more extensive than initially anticipated, and that both kinase families are important factors in the response to classical chemotherapeutics that damage the genome or the mitotic spindle. In this Review we discuss the implications of these novel insights on the clinical applicability of polo-like kinase and aurora kinase inhibitors.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Tumor organoids are 3D cultures of cancer cells. They can be derived from the tumor of each individual patient, thereby providing an attractive ex vivo assay to tailor treatment. Using ...patient-derived tumor organoids for this purpose requires that organoids derived from biopsies maintain the genetic diversity of the in vivo tumor. In this study tumor biopsies were obtained from 14 patients with metastatic colorectal cancer (i) to test the feasibility of organoid culture from metastatic biopsy specimens and (ii) to compare the genetic diversity of patient-derived tumor organoids and the original tumor biopsy. Genetic analysis was performed using SOLiD sequencing for 1,977 cancer-relevant genes. Copy number profiles were generated from sequencing data using CopywriteR. Here we demonstrate that organoid cultures can be established from tumor biopsies of patients with metastatic colorectal cancer with a success rate of 71%. Genetic analysis showed that organoids reflect the metastasis from which they were derived. Ninety percent of somatic mutations were shared between organoids and biopsies from the same patient, and the DNA copy number profiles of organoids and the corresponding original tumor show a correlation of 0.89. Most importantly, none of the mutations that were found exclusively in either the tumor or organoid culture are in driver genes or genes amenable for drug targeting. These findings support further exploration of patient-derived organoids as an ex vivo platform to personalize anticancer treatment.
The current COVID-19 pandemic challenges oncologists to profoundly re-organize oncological care in order to dramatically reduce hospital visits and admissions and therapy-induced immune-related ...complications without compromising cancer outcomes. Since COVID-19 is a novel disease, guidance by scientific evidence is often unavailable, and impactful decisions are inevitably made on the basis of expert opinions. Here we report how the seven comprehensive cancer centers of Cancer Core Europe have organized their healthcare systems at an unprecedented scale and pace to make their operations 'pandemic proof'. We identify and discuss many commonalities, but also important local differences, and pinpoint critical research priorities to enable evidence-based remodeling of cancer care during the COVID-19 pandemic. Also, we discuss how the current situation offers a unique window of opportunity for assessing the effects of de-escalating anticancer regimens, which may fast-forward the development of more-refined and less-toxic treatments. By sharing our joint experiences, we offer a roadmap for proceeding and aim to mobilize the global research community to generate the data that are critically needed to offer the best possible care to patients.
Fixed Dosing of Monoclonal Antibodies in Oncology Hendrikx, Jeroen J.M.A.; Haanen, John B.A.G.; Voest, Emile E. ...
The oncologist (Dayton, Ohio),
October 2017, Letnik:
22, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Most monoclonal antibodies in oncology are administered in body–size‐based dosing schedules. This is believed to correct for variability in both drug distribution and elimination between patients. ...However, monoclonal antibodies typically distribute to the blood plasma and extracellular fluids only, which increase less than proportionally with the increase in body weight. Elimination takes place via proteolytic catabolism, a nonspecific immunoglobulin G elimination pathway, and intracellular degradation after binding to the target. The latter is the primary route of elimination and is related to target expression levels rather than body size. Taken together, the minor effects of body size on distribution and elimination of monoclonal antibodies and their usually wide therapeutic window do not support body–size‐based dosing. We evaluated effects of body weight on volume of distribution and clearance of monoclonal antibodies in oncology and show that a fixed dose for most of these drugs is justified based on pharmacokinetics. A survey of the savings after fixed dosing of monoclonal antibodies at our hospital showed that fixed dosing can reduce costs of health care, especially when pooling of preparations is not possible (which is often the case in smaller hospitals). In conclusion, based on pharmacokinetic parameters of monoclonal antibodies, there is a rationale for fixed dosing of these drugs in oncology. Therefore, we believe that fixed dosing is justified and can improve efficiency of the compounding. Moreover, drug spillage can be reduced and medication errors may become less likely.
Implications for Practice
The currently available knowledge of elimination of monoclonal antibodies combined with the publicly available data from clinical trials and extensive population pharmacokinetic (PopPK) modeling justifies fixed dosing. Interpatient variation in exposure is comparable after body weight and fixed dosing and most monoclonal antibodies show relatively flat dose‐response relationships. For monoclonal antibodies, this results in wide therapeutic windows and no reduced clinical efficacy after fixed dosing. Therefore, we believe that fixed dosing at a well‐selected dose can increase medication safety and help in reduction of costs of health care without the loss of efficacy or safety margins.
In the field of oncology, most drugs are administered in a body–size‐based dosing schedule instead of a fixed dose for all patients. This article presents the advantages of fixed dosing of monoclonal antibodies, arguing in favor of fixed dosing schemes for all currently approved antibodies in oncology.
Metastatic castration-resistant prostate cancer (mCRPC) has a highly complex genomic landscape. With the recent development of novel treatments, accurate stratification strategies are needed. Here we ...present the whole-genome sequencing (WGS) analysis of fresh-frozen metastatic biopsies from 197 mCRPC patients. Using unsupervised clustering based on genomic features, we define eight distinct genomic clusters. We observe potentially clinically relevant genotypes, including microsatellite instability (MSI), homologous recombination deficiency (HRD) enriched with genomic deletions and BRCA2 aberrations, a tandem duplication genotype associated with CDK12
and a chromothripsis-enriched subgroup. Our data suggests that stratification on WGS characteristics may improve identification of MSI, CDK12
and HRD patients. From WGS and ChIP-seq data, we show the potential relevance of recurrent alterations in non-coding regions identified with WGS and highlight the central role of AR signaling in tumor progression. These data underline the potential value of using WGS to accurately stratify mCRPC patients into clinically actionable subgroups.
PDF
